Focus Article · mitters, peptides, endocannabinoids, cytokines, and hormones, an ensemble of interdependent nervous, endocrine, and immune processes operates in concert to cope with

F

PE

C*†

‡

Dtaw

SHAUS1©d

The Journal of Pain, Vol 9, No 2 (February), 2008: pp 122-145Available online at www.sciencedirect.com

1

ocus Article

ain and Stress in a Systems Perspective: Reciprocal Neural,ndocrine, and Immune Interactions

. Richard Chapman,* Robert P. Tuckett,† and Chan Woo Song‡

Pain Research Center, Department of Anesthesiology, University of Utah, Salt Lake City, Utah.Department of Physiology, University of Utah, Salt Lake City, Utah.Department of Anesthesiology, Jung Dong Hospital, Seoul, Korea.

Abstract: This paper advances a psychophysiological systems view of pain in which physical injury,or wounding, generates a complex stress response that extends beyond the nervous system andcontributes to the experience of pain. Through a common chemical language comprising neurotrans-mitters, peptides, endocannabinoids, cytokines, and hormones, an ensemble of interdependentnervous, endocrine, and immune processes operates in concert to cope with the injury. Theseprocesses act as a single agent and comprise a supersystem. Acute pain in its multiple dimensions, andthe related symptoms that commonly occur with it, are products of the supersystem. Chronic pain candevelop as a result of unusual stress. Social stressors can compound the stress resulting from a woundor act alone to dysregulate the supersystem. When the supersystem suffers dysregulation, health,function, and sense of well-being suffer. Some chronic pain conditions are the product of supersystemdysregulation. Individuals vary and are vulnerable to dysregulation and dysfunction in particularorgan systems due to the unique interactions of genetic, epigenetic and environmental factors, aswell as the past experiences that characterize each person.Perspective: Acute tissue injury activates an ensemble of interdependent nervous, endocrine, andimmune processes that operate in concert and comprise a supersystem. Some chronic pain conditionsresult from supersystem dysregulation. Individuals vary and are vulnerable to dysregulation due to theunique interactions of genetic, epigenetic, and environmental factors and past experiences that char-acterize each person. This perspective can potentially assist clinicians in assessing and managingchronic pain patients.

© 2008 by the American Pain Society
Key words: Pain, stress, allostasis, complex adaptive system, hypothalamo-pituitary-adrenocortical axis.
npnrp

lenaimte

espite parallel advances in neurophysiological andbiopsychosocial models of pain, an integrated ex-planation for chronic pain still eludes us. Conven-

ional understanding holds that acute pain is an unpleas-nt sensory and affective experience normally associatedith injury. It arises from activation of the peripheral

upported by a grant to the first author from the National Institutes ofealth, R01 CA074249.ddress reprint requests to C. Richard Chapman, Pain Research Center,niversity of Utah, Department of Anesthesiology, 615 Arapeen Drive,uite 200, Salt Lake City, UT 84108. E-mail: [email protected]/$34.002008 by the American Pain Society

coi:10.1016/j.jpain.2007.09.006

22

ervous system and emerges from complex higher levelrocessing. Chronic pain, in contrast, relates poorly orot at all to a focus of injury and incurs a constellation ofelated miseries such as fatigue, sleep disturbance, im-aired physical and mental function, and depression.This paper calls attention to an inconvenient and over-

ooked fact: Any injurious event provokes autonomic,ndocrine, and immune processes as well as sensory sig-aling. These processes interact and collectively comprisedefensive biological response to injury. Because the

nteractions of sensory, autonomic, endocrine, and im-une responses to tissue injury are complex and adap-

ive, a systems approach can advance understanding andngage difficult questions such as how pain becomes
hronic.
[email protected]

baetpaattrtlctmv

F

S

pmpncttmt

iteetcsncpaesaiicfo

W

rWttm

oevrbbptdtpflpabptcbn

aTmctoPpdhtmcrvss

aatvmssywma

D

wrsifl

123FOCUS ARTICLE/Chapman et al

The organization of this paper is as follows. We beginy fitting a complex adaptive systems framework tocute tissue injury, or wounding, and review nervous,ndocrine and immune responses to wounding withinhis framework. To set the stage for a systems model ofain, we review evidence for the cross-communicationnd feedback interdependence of nervous, endocrine,nd immune systems. On the basis of this, we postulatehat the nervous-endocrine-immune ensemble consti-utes a single overarching system, or supersystem, thatesponds as a whole to tissue trauma and contributes tohe multidimensional subjective experience of pain. Thiseads to the hypothesis that supersystem dysregulationontributes significantly to chronic pain and related mul-isymptom disorders. Finally, we discuss factors thatake the individual patient uniquely susceptible to de-

eloping a particular pattern of chronic pain.

undamental Concepts

ystems PerspectiveA human being is an open, living, adaptive system thatursues the dual objectives of adaptation to the environ-ent and survival. The term system denotes a set of com-onents constituting a whole within which each compo-ent interacts with or is related to at least 1 otheromponent, and all components serve a common objec-ive. Every system contains nested subsystems that func-ion as component parts. Nervous, endocrine, and im-une systems are among the subsystems that comprise

he body. These subsystems function interdependently.All adaptive systems have 3 essential features. The first

s irritability: The system is dynamic and responds to per-urbations such as tissue injury by moving away fromquilibrium to meet the challenge and returning towardquilibrium afterward. Second, connections and interac-ions exist among the components of a system; this is itsonnectivity. Through connectivity, patterns form andelf-regulating feedback occurs. Consequently, the con-ectivity of a system is more important than the systemomponents themselves. Third, adaptive systems havelasticity. They change selectively in response to alter-tions in the environment, and change is often nonlin-ar. System theorists describe nonlinear transitions astate or phase shifts. For example, the development ofllodynia around a focus of injury is a central state shiftn sensory processing. A key aspect of system nonlinear-ty is that small perturbations can produce large systemhanges while large perturbations often do not. Othereatures of adaptive systems include emergence, self-rganization, and self-regulation.

oundsPain fosters survival after wounding. A wound is dis-

uption of normal anatomic structure and function.114

ounds result from pathologic processes that begin ex-ernally or internally, originating in accidental or inten-ional trauma or disease. They are normally acute, but
ay become chronic. m
Acute wounds are those that repair themselves in anrderly and timely fashion. Injury disrupts local tissuenvironment, triggers inflammation, constricts bloodessels, promotes coagulation, and stimulates immuneesponse. Sympathetic responses at the wound restrictlood flow. Immediate vasoconstriction temporarilylanches the wound and reduces hemorrhage, fosterslatelet aggregation, and keeps healing factors withinhe wound. Subsequently, a period of vasodilation pro-uces the erythema, edema, and heat observed afterissue injury. C fibers interact with wounds, by secretingroinflammatory peptides and signaling injury. Proin-ammatory cytokines, neutrophils, macrophages, com-lement, and acute phase proteins generate a systemiccute phase reaction34,202 that protects against micro-ial invasion, and they sensitize the wounded area torotect and promote healing. Acute wound healing en-ails a series of interrelated cellular and molecular pro-esses that first re-establish the immune barrier violatedy traumatic injury and then repair or regenerate lostormal tissue architecture.Chronic wounds are those that fail to repair themselves in

n orderly and timely fashion and remain indefinitely.114

he healing process is incomplete and disorganized. Fa-iliar examples include chronic diabetic and pressure ul-

ers. Local wound environments depend on myriad sys-emic factors, particularly those that influence tissuexygenation such as peripheral venous hypertension.sychophysiologically, emotional arousal increases sym-athetic activity systemically through autonomic and en-ocrine mechanisms, and this may disrupt normal woundealing processes by compromising blood flow. Like cu-aneous wounds, musculoskeletal and visceral woundsay fail to heal after injury, persisting as a focus of

hronically disorganized, locally inflamed processes thatespond maladaptively to systemic changes at the ner-ous, endocrine and immune levels. Some chronic paintates reflect chronic wounds, but the key concept is per-istence of chronic disorganization.In many chronic cases, the local tissue environment

ppears to repair itself but sensory processes remainbnormal, creating chronic pain. One hypothesis forhis type of chronic pain is failure of the central ner-ous system processes to “reset” sensitizing adjust-ents implemented during injury when peripheral tis-

ue complete wound healing. This underscores aecond key point: The impact of a wound extends be-ond its local tissue environment to its interactionsith higher-order systems. Incomplete wound healingay involve altered relationships between local tissue

nd higher order systems.

efense ResponseThis term has multiple meanings in the literature, all ofhich underscore its adaptive function. Here, defense

esponse refers to sensory detection and multisubsystem,elf-organizing arousal to tissue injury or threat of tissuenjury. Related physiological changes facilitate fight,ight, or freezing. Although the defense response can
ean the psychophysiological response to wounding,

tarrigmiTiphps

H

H

ahcnttmdum

ttaruh

A

edshtpdotew

loeesscAr

erstibs

iacawlpscr

TI

T

ftfmsp“ntfztcmlht

pctscpmattiiot

124 Pain and Stress in a Systems Perspective

he term incorporates the anticipation of wounding andppraisal of threat. The nervous system plays a strongole in defense by detecting threat in the external envi-onment, cognition (anticipation, appraisal), signaling ofncurred tissue injury, and through motor responseseared to escape or fighting. The endocrine systemounts a major physiological arousal response that max-

mizes the chances for survival, ie, the stress response.he immune system detects microbial invasion and tox-ns16 and initiates complex inflammatory responses thatrotects against microbial threat and promote woundealing. Thus, the term defense response designates pur-oseful, coordinated activity in 3 interdependent sub-ystems.

omeostasis, Allostasis, and Stress

omeostasisAlthough the term homeostasis commonly connotes

djustment to achieve balance, McEwen127 asserts thatomeostasis strictly applies to a limited set of systemsoncerned with maintaining the essentials of the inter-al milieu. The maintenance of homeostasis is the con-rol of internal processes truly necessary for life such ashermoregulation, blood gases, acid base, fluid levels,etabolite levels, and blood pressure. McEwen’s strictistinction means that homeostasis does not contrib-te to adaptation; rather, adaptation protects ho-eostasis.Failure to sustain homeostasis is fatal. Generic threats

o homeostasis include environmental extremes, ex-reme physical exertion, depletion of essential resources,bnormal feedback processes, aging, and disease. Envi-onmental perturbations can threaten homeostatic reg-lation at any time. The stress response exists to sustainomeostasis.

llostasis and StressThree interdependent systems contribute to the pres-

rvation of homeostasis when injury occurs: Neural, en-ocrine, and immune.71 Adaptive response involves sub-tantial autonomic activity and the connectivity ofumoral messenger substances that also serve as media-ors and determinants of neural regulatory processes,articularly hormones, neurotransmitters, peptides, en-ocannabinoids, and cytokines. The term for the physi-logical protective, coordinated, adaptive reaction inhe service of homeostasis is allostasis.111,127 Allostasisnsures that the processes sustaining homeostasis stayithin normal range.Stress is the resource-intensive process of mounting al-

ostatic responses to challenges that occur in the externalr internal environment. A stressor is any event thatlicits a stress response. It may be a physical or socialvent, an invading micro-organism, or a signal of tis-ue trauma. Selye179 first described this response as ayndrome produced by “diverse nocuous agents.” Heharacterized the stress response as having 3 stages:larm reaction, resistance, and if the stressor does not

elent, exhaustion. The normal stress responses of ev- i

ryday life consist of the alarm reaction, resistance andecovery. The primary features of stressors are inten-ity, duration and frequency. The impact of a stressor ishe magnitude of the response it elicits. This impactnvolves cognitive mediation because it is a function ofoth the predictability and the controllability of thetressor.Allostasis is the essence of the stress response because

t mobilizes internal resources to meet the challenge thatstressor represents. Stressors may be multimodal and

omplex or unimodal and simple. When a stressor, suchs tissue trauma, persists for a long period of time, orhen repeated stressors occur in rapid succession, al-

ostasis may burn resources faster than the body can re-lenish them. The cost to the body, or burden, of allo-tatic adjustment, whether in response to extreme acutehallenges or to lesser challenges over an extended pe-iod of time, is allostatic load.

hree Systems Responding to Tissuenjury

he Nervous SystemProgress in pain research and theory moves steadily

rom simple to more complex concepts. Early thinking inhe previous century favored a sensory modality with theollowing cardinal processes: Transduction, transmission,odulation, projection, and realization. This position

till dominates thinking outside of the interdisciplinaryain community. As Zhang and Huang228 (p 930) put it,Pain is generally considered a purely neural phenome-on.” One may argue in defense of this approach thathe best way to engage a puzzle in the life sciences is toorm the simplest acceptable representation of that puz-le and solve it. Unfortunately, pain stubbornly resistshis Procrustean fit; clinical problems of acute andhronic pain do not easily conform to the purely neuralodel. The persistence of chronic pain as a major prob-

em in medicine indicates that the purely neural modelas largely failed to guide clinicians toward curative in-erventions.We emphasize that tissue trauma initiates multiplerocesses that exert an extensive non-neural physiologi-al impact. Such processes affect overall health, func-ional capability, and sense of well-being. Pain is the con-cious end product of this multifaceted impact. Althoughomplex patterns of brain activation are a part of therocess from which pain emerges,4 pain reflects muchore than activation of thalamus, somatosensory cortex,

nd various limbic structures. Two often overlooked fea-ures of pain are (1) The subjective awareness of tissuerauma is inherently multimodal and typically includesntegrated visual, kinesthetic, and enteric sensory modal-ties as well as noxious signaling; and (2) Tissue traumaccurs against background of overall bodily awarenesshat encompasses interdependent neural, endocrine and
mmune states.

FP

T

ttvnabCttl(tptai

ntaicTpdnphttsIp

D

wrmtstcaircit

pnnS

hhiSdtVgcft

tlaowAtnNwatar

octnsp

H

oggcpa

ttlltaahtLibbmda


rom Periphery to Brain: Bidirectionalrocesses

ransductionThe sensory organ for the detection of tissue trauma is

he nociceptor, a primary afferent lacking specializederminal structures that innervates skin, muscle, bloodessels, viscera, connective tissue, and bone. The termociceptor encompasses both the unmyelinated C fibernd the thinly myelinated, faster conducting A� fi-er.30,221 Most nociceptors are C fibers, although not allfibers are nociceptors. The nociceptive C fiber is more

han a feature detector that responds preferentially toissue injury; it participates actively in the wound by re-easing substance P (SP), calcitonin gene-related peptideCGRP), neurokinin A (NKA), and other peptides and ni-ric oxide (NO), all of which contribute to the dynamicrocess of inflammation. In this way, nociceptor activa-ion initiates neurogenic inflammatory processes thatmplify responses to subsequent stimuli, whether nox-ous or innocuous.

At the periphery, the nervous system cooperates dy-amically with the immune system to create inflamma-ion and associated chemotaxis62 in the acute phase re-ction.78 Macrophages, lymphocytes, and mast cells

nteract with SP, CGRP, and NKA released from C fibers toreate a chemical “soup” of proalgesic mediators.101

hese substances induce vasodilation, extravasation oflasma proteins, and the release of further chemical me-iators including K�, H�, bradykinin, histamine, seroto-in, NO, nerve growth factor (NGF), cytokines, and therostaglandins.169 Collectively, they sensitize normallyigh threshold nociceptors and awaken silent nocicep-ors so that they respond to normally innocuous stimula-ion. Sympathetic nerve terminals contribute to this sen-itization by releasing norepinephrine and prostanoids.ncreased NGF expression occurs in the presence of theroinflammatory cytokines IL-1� and TNF-�.153

orsal HornThe dorsal horn is a complex, multisynaptic structureith multiple functions.196 It produces spinal reflexes,

elays nociceptive messages to higher structures, andodulates to either inhibit or facilitate nociceptive

ransmission, depending on information from highertructures or from the periphery. The integration of mul-imodality sensory input begins at the dorsal horn, whichontains multireceptive neurons. These neurons receivend integrate information from multiple sensory modal-ties and interface with both external and internal envi-onments.115 This is the first step in the nervous system’sonstruction of a somesthetic image of the body. Furtherntegration occurs in the medullary brain, particularlyhe solitary nucleus,88 and cortex.37

The spinal cord demonstrates plasticity by shifting bi-hasically between states of nociceptive inhibition andociceptive facilitation.171 Sandkuhler177 classified spi-al nociceptive inhibitory mechanisms into 3 types: (1)
upraspinal descending inhibition, (2) propriospinal, c
eterosegmental inhibition, and (3) segmental spinal in-ibition. The short-range adaptive value of nociceptive

nhibition is clear; pain must not impair flight or fight.ustained inflammation may bring about time-depen-ent changes in dorsal horn function, favoring nocicep-ive facilitation where previously there was inhibition.52

anegas and Schaible208 identified the periaqueductalray and rostal ventromedial medulla as an efferenthannel for nociceptive control and proposed that a shiftrom inhibitory to facilitatory influence might contributeo chronic pain.208

Dorsal horn facilitation results from wound inflamma-ion or from intense or prolonged nociceptive input. Itowers pain threshold, amplifies nociceptive responses,nd expands the receptive fields of nociceptive higherrder neurons to incorporate noninjured areas near theound and normally non-nociceptive sensory signals.94

major mechanism is activation of N-methyl-D-aspar-ate (NMDA) receptors via glutamate, the main centralervous system (CNS) excitatory neurotransmitter.52,135

ormally, acute dorsal horn facilitation subsides withound healing. Changes at the spinal cord level bringbout changes in higher systems. For example, sensitiza-ion at the dorsal horn results in long-term potentiationt hippocampal and cortical levels, and this enhancesesponses to noxious input.94

The CNS can shift from normal functioning to statesf either facilitation or inhibition. Sensory thresholdshange in response to prolonged noxious stimulation inwo ways. First, hitherto non-noxious stimuli generateoxious signaling (eg, mechanical allodynia) and second,timuli that previously would have produced minimalain become intensely painful (hyperalgesia).

igher StructuresPain, as aversive somatic awareness, involves integrationf information from multiple sensory modalities that be-ins at the dorsal horn115 and continues in the basalanglia,144 solitary nucleus,88 superior colliculus,190 andortex,116 which contains multimodal neurons.66 Thisrocess is selective and bidirectional in that cortex medi-tes multisensorial integration in deeper structures.95

Unimodal studies of nociceptive transmission, projec-ion and processing sketch a complex picture. Signals ofissue trauma reach higher CNS levels via the spinotha-amic, spinohypothalamic, spinoreticular including theocus caeruleus (LC) and the solitary nucleus, spinopon-oamygdaloid pathways, the periaqueductal gray (PAG),nd the cerebellum.29,157 The thalamus projects to limbicreas including the insula and anterior cingulate. Craig37

olds that anterior insula integrates emotional and mo-ivational processes. Noradrenergic pathways from theC project to these and further limbic structures. Accord-ngly, functional brain imaging studies of the humanrain during the experience of pain reveal extensive lim-ic, prefrontal and somatosensory cortical activation. Aeta-analysis of the literature described brain activity

uring pain as a network involving thalamus, primarynd secondary somatosensory cortices, insula, anterior
ingulate, and prefrontal cortices.4 Thus, the brain en-

gs

cantpnbsiitca

pwetpr

H

issbdsnhtncrcfocca

ttactgpsslTwacO

mtflad

T

T

ssttrarTia

D

lhiapnpetnsr(o�

tCmtdCTtFa

C

taTatsp


ages in massive, distributed, parallel processing in re-ponse to noxious signaling.The mechanisms of multimodal integration pose a fas-

inating challenge. For example, Hollis and colleagues88

ddressed how catecholaminergic neurons in the solitaryucleus integrate visceral and somatic sensory informa-ion when inflammation is present peripherally. Intensehysiological arousal, pre-existing fatigue, dysphoria, orausea, and a systemic inflammatory response inducedy proinflammatory cytokines2,61 could all contributeensory information to the brain’s processing load dur-ng the construction of pain. Apart from Craig,37 fewnvestigators have addressed the integration of informa-ion from multiple sensory modalities and central pro-esses related to emotion and cognition in the formationnd emergence of pain.Descending modulation of noxious signaling operatesrincipally at the dorsal horn. Through descending path-ays, higher structures can facilitate or inhibit the painxperience. Frontal-amygdalar circuits may modulatehe affective intensity of injury.119 Frontal-PAG circuitslay a role in pain modulation. Tracey and Mantyh201

eview top down influences in nociceptive modulation.

igher Processes and DefenseMany functional brain imaging pain studies to date

mplicitly assume that pain results from a unimodal sen-ory process. The dynamic interaction of multiple brainubsystems generates a dynamic, coherent model of theody and the social self in the world. Research on theefense response sheds light on the integration of aver-ive conditions in general, including, but not limited to,oxious input. The main neural substrates are the medialypothalamus, amygdala and dorsal PAG.24 These struc-ures respond reliably but not exclusively to noxious sig-aling, interact with one another, and actively integrateognitive, sensory and emotional processes. Some painesearch has begun to address the issue of integration inognitive processes.37 Tracey and colleagues200 usedunctional brain imaging to study subjects attending tor distracting themselves from, painful stimuli cued witholored lights. Distraction and pain reduction occurred inonjunction with PAG activation, linking cortical controlnd the PAG.Frontal-amygdalar circuits are a well-studied aspect of

he defense response.119 Cognitive variables such as in-erpretation, attention, and anticipation can influencemygdalar response through the frontal-amygdalar cir-uit. The amygdala, in turn, can influence the hypo-halamo-pituitary-adrenocortical axis,86,130 a major or-an of the stress response. Frontal influences also affectatterns of activity at the LC.6 Endogenous cognitivetimuli generated during anticipation or memory recon-truction can activate complex neural circuits that mobi-ize the stress response in the absence of tissue trauma.he central nucleus of amygdala projects to the PAG,hich coordinates defensive behaviors.140 In general,mygdala is the mechanism of conditioned fear.149,175 Itommunicates with hypothalamus via neural circuitry.227

ther issues requiring scientific inquiry include how i

emory shapes expectancy, presumably involving fron-al-amygdalar pathways, how these processes in turn in-uence physiological functioning through the centralutonomic network10,11,197 and how other sensory mo-alities integrate with noxious signaling.

he Endocrine System

he Endocrine Stress ResponseThe stress literature tends to group all reactions to a

tressor such as wounding under the single heading oftress response. However, DeKloet and Derijk45 charac-erize the stress response as having 2 modes of opera-ion, or states. The first state is immediate arousal inesponse to the stressor to enable adaptive behaviorsnd the second state is a slower process that promotesecovery, behavioral adaptation and return to normalcy.hey describe these phases as the fast and slow respond-ng modes. We designate the first state as defensiverousal and the second as recovery.

efensive ArousalThe major mechanisms of the stress response at the

evel of the brain are the LC noradrenergic system, theypothalamo-pituitary-adrenocortical (HPA) axis based

n the hypothalamic periventricular nucleus (PVN),204

nd the sympathoadrenomedullary (SAM) axis.148 Theeripheral effectors of these mechanisms are the auto-omic nervous system, the SAM circulating hormones,rincipally the catecholamines epinephrine (E) and nor-pinephrine (NE), together with the sympathetic co-ransmitter neuropeptide Y (NPY),230 all of which origi-ate in the chromaffin cells of the adrenal medulla. Thetress response also involves hypothalamically-inducedelease of peptides derived from pro-opiomelanocortinPOMC) at the anterior pituitary. The POMC-related familyf anterior pituitary hormones includes ACTH, �-lipotropin,-melanocyte–stimulating hormone, and �-endorphin.Corticotropin-releasing hormone (CRH), produced at

he hypothalamic PVN, initiates the stress response.RH initiates and coordinates the stress response atany levels,60 including the LC.163 It is the key excita-

ory central neurotransmitter and regulator in the en-ocrine response to injury. Two receptors respond toRH and CRH-related peptides, CRH-1, and CRH-2.hese distribute widely in limbic brain.118 CRH-145 ishe key mechanism of the defensive arousal response.ig 1 illustrates the HPA axis response to a stressor suchs tissue injury.

entral Noradrenergic MechanismsNoxious signaling inevitably and reliably increases ac-

ivity in the LC noradrenergic neurons, and LC excitationppears to be a consistent response to nociception.192,194

he LC heightens vigilance, attention, and fear as wells facilitating general defensive reactions mediatedhrough the sympathetic nervous system. Basically, anytimulus that threatens the biological, psychological, orsychosocial integrity of the individual increases the fir-

ng rate of the LC, and this in turn increases the release

aecmnsrt

A

tbipscatfihbtTo

R

aoactfisat

scnttcosrtt

sti(trcmtpc

T

TI

deadaodpt

wodteapl

FrlcfaavpcvsntPdt


nd turnover of NE in the brain areas having noradren-rgic innervation. The LC exerts a powerful influence onognitive processes such as attention and task perfor-ance.6,12 In addition to directly receiving noxious sig-als during spinoreticular transmission, the LC also re-ponds to CRH.163 LC neurons increase firing rates inesponse to CRH, and this increases NE levels throughouthe CNS.93

drenomedullary MechanismsThe adrenal medulla, an endocrine organ, is a func-

ional expression of the sympathetic nervous system thatroadcasts excitatory messages by secreting substances

nto the blood stream. Acetylcholine (Ach) released fromreganglionic sympathetic nerves during the stress re-ponse triggers secretion of E, NE, and NPY into systemicirculation. E and NE exert their effects by binding todrenergic receptors on the surface of target cells, andhey induce a general systemic arousal that mobilizesght-or-flight behaviors. These catecholamines increaseeart rate and breathing, tighten muscles, constrictlood vessels in parts of the body, and initiate vasodila-ion in other parts such as muscle, brain, lung, and heart.hey increase blood supply to organs involved in fighting

igure 1. The hypothalamo-pituitary-adrenocortical axis stressesponse. Nociceptive signaling acts directly on the hypotha-amic PVN but also on the PAG, the LC, the cortico-amygdalarircuit, and also triggers release of proinflammatory cytokinesrom various immune cells and the adrenal medulla. All of thesectivate the PVN, which normally responds to diurnal rhythmnd associated circulating cortisol levels. Stressor-induced acti-ation of the PVN releases CRH from the median eminence intoortal circulation. This stimulates the anterior pituitary andauses the release of ACTH into systemic circulation. ACTH pro-okes cortisol release at the adrenal cortex. Cortisol has wide-pread effects on a wide array of target organs. Because this is aegative feedback system, cortisol provides feedback to bothhe PVN and the anterior pituitary, thus controlling axis activity.VN, Periventricular nucleus of hypothalamus; PAG, periaque-uctal gray; ACTH, adrenocorticotropic hormone, or cortico-ropin; CRH, corticotropin-releasing hormone.

r fleeing but decrease flow in other areas. fl

ecoveryThe recovery phase commences before the defensive

rousal, or alarm, phase, ends to protect against arousalvershoot. The defensive state is catabolic and, if thellostatic response is too strong or goes on too long, itan deplete neurotransmitters and/or dysregulate sys-em functions. The purposes of the recovery response arerst to regulate the intensity of the alarm reaction andecond, when it is safe to stop defense, to terminatellostasis, minimize the costs of allostatic load, and bringhe body back to normalcy.CRH synthesis and release occur in response to a stres-

or such as tissue injury and also in response to levels ofirculating cortisol (CORT) and the diurnal rhythm. Theeurons of the median eminence secrete CRH intohe hypophyseal portal circulation, and this carries it tohe anterior pituitary where it binds to CRH receptors onorticotropes. This generates POMC synthesis and releasef ACTH136 into systemic circulation. Circulating ACTHtimulates production of CORT at adrenal cortex withelease into systemic circulation. Circulating CORT, inurn, provides a negative feedback signal to the PVN andhe anterior pituitary (Fig 1).The mechanism for recovery is CRH-2 receptor expres-

ion. This receptor responds to the CRH family of pep-ides44 including the urocortins. The anterior pituitarynitiates production of adrenocortical glucocorticoidsGCs), including CORT, that bind to glucocorticoid recep-ors (GRs). The primary agent and classic marker for stressecovery in human is CORT. It normally functions in con-ert with the catecholamines and CRH. GR activation pro-otes energy storage and termination of inflammation

o prepare for future emergency. Although the recoveryrocess is inherently protective, prolonged CORT canause substantial damage.44,45,60

he Immune System

he Immune Defense Response andnflammationJust as the nervous system is the primary agent foretecting and defending against threat arising in thexternal environment, the immune system is the primarygent of defense for the internal environment. Kohl110

escribed it as “a network of complex danger sensorsnd transmitters.” This interactive network of lymphoidrgans, cells, humoral factors, and cytokines works inter-ependently with the nervous and endocrine systems torotect homeostasis. Parkin and Cohen150 provide a de-ailed overview of the immune system.The immune system detects an injury event in at least 3ays: (1) Through blood-borne immune messengersriginating at the wound; (2) through nociceptor-in-uced sympathetic activation and subsequent stimula-ion of immune tissues, and (3) through SAM and HPAndocrine signaling. Immune messaging begins with thecute phase reaction at the wound.78 Local macro-hages, neutrophils, and granulocytes produce and re-

ease into intracellular space and circulation the proin-
ammatory cytokines IL-1, IL-6, IL-8, and TNF-�. This

ahtit

ttcppoifo

pmfhc

anbcaptRIsmniaspt

C

ihpccsfCctcmk(lgmk

ee

2tmseaItiigci

T

rkacsgts

opadamami

scttntIsaTms

I

lhYsc


lerts and activates other immune tissues and cells thatave a complex systemic impact. The acute phase reac-ion to injury is the immune counterpart to nociceptionn the nervous system, as it encompasses transduction,ransmission, and effector responses.The immune and nervous systems interact coopera-

ively at the wound. Tissue injury releases the immunos-imulatory neuropeptides SP and NKA. These activate T-ells and cause them to increase production of theroinflammatory cytokine IFN-�.113 In addition, anotherroinflammatory cytokine, IL1-� stimulates the releasef SP from primary afferent neurons.91 The neurogenic

nflammatory response helps initiate the immune de-ense response and at the same time is in part a productf that response.62

Immune-nervous system interaction is feedback-de-endent. Sympathetic outflow after injury can directlyodulate many aspects of immune activity and provide

eedback. This can occur because all lymphoid organsave sympathetic nervous system innervation58 and be-ause many immune cells express adrenoceptors.105,210

Inflammation assists the immune system in defensegainst the microbial invasion that normally accompa-ies any breach of the skin. If microorganisms reach thelood stream, sepsis occurs. The inflammatory processreates a barrier against the invading microorganisms,ctivates various cells including macrophages and lym-hocytes that find and destroy invaders, and sensitizeshe wound, thereby minimizing the risk of further injury.edness, pain, heat, and swelling are its cardinal signs.

nflammation reduces function and increases pain byensitizing nociceptors. Tracey202 described the “inflam-atory reflex” as an Ach-mediated process by which theervous system recognizes the presence of, and exerts

nfluence on, peripheral inflammation. Through vagalnd glossopharyngeal bidirectional nerves, the nervousystem modulates circulating cytokine levels. The keyoint is that certain nervous structures sense the activi-ies of the immune system.

ytokines and InflammationAlthough a wide variety of cell types produce cytokines

n response to an immune stimulus, classic descriptionolds that their principal origin is leukocytes. They exertowerful effects on many tissues and one another, butytokines are also major signaling compounds that re-ruit many cell types in response to injury. They bindpecifically to cell surface receptors to achieve their ef-ects, and exogenous antagonists can block their effects.ytokines act on: (1) The cells that secrete them, auto-rine mode; (2) nearby cells, paracrine mode, and (3) dis-ant cells, endocrine mode. Chemokines are chemotacticytokines that attract specific types of immune cells,ainly leukocytes, to an area of injury. Broadly, cyto-

ines group into 4 families based on their receptor types:a) Hematopoietins, including IL-1 to IL-7 and the granu-ocyte macrophage colony stimulating factor (GM-CSF)roup; (b) interferons, including INF-�. and INF-�; (c) tu-or necrosis factors, including TNF-�; and (d) chemo-

ines, including IL-8. For a basic review, see Elenkov s

t al61 and Gosain and Garnelli.72 Cytokines can act syn-rgistically or antagonistically in many dimensions.Soon after formation, helper T-cells differentiate intotypes in response to existing cytokines and then secrete

heir own cytokines with 1 of 2 profiles: Th1, proinflam-atory; and Th2, anti-inflammatory. Most cytokines clas-

ify readily as either Th1 or Th2 according to the influ-nce they exert. For example, IL-4 stimulates Th2 activitynd suppresses Th1 activity, so it is anti-inflammatory.L-12, on the other hand, promotes proinflammatory ac-ivity and is therefore Th1. Pro-inflammatory cytokinesnclude IL1-�, IL-2, IL-6, IL-8, IL-12, IFN-�, and TNF-�. Anti-nflammatory cytokines include IL-4, IL-10, insulin-likerowth factor 1 (IGF-10), and IL-13. Some investigatorsharacterize an individual’s immune response profile us-ng a Th1/Th2 ratio.

he Sickness ResponseFever and sickness with pain is an immune systemic

esponse.61,191,216,217,225 This sickness response is cyto-ine-mediated and depends on the CNS. Macrophagesnd other cells release proinflammatory cytokines in-luding IL1-�, IL-6, IL-8, IL-12, IFN-�, and TNF-� in re-ponse to injury. These substances act on the vagus andlossopharyngeal nerves, hypothalamus and elsewhereo trigger a cascade of unpleasant, activity-limitingymptoms.174,226

The sickness response, a system-wide change in modef operation triggered by cytokines, is a vivid and dys-horic subjective experience characterized by fever, mal-ise, fatigue, difficulty concentrating, excessive sleep,ecreased appetite and libido, stimulation of the HPAxis, and hyperalgesia. The sickness-related hyperalgesiaay reflect the contributions of spinal cord microglia

nd astrocytes.226 Functionally, this state is adaptive; itinimizes risk by limiting normal behavior and social

nteractions and forcing recuperation.Depression may be another complex immune re-

ponse. Mounting evidence supports the hypothesis thatytokines are causal mechanisms of depression, evenhough specifics are still at issue.164 Proinflammatory cy-okines instigate the behavioral, neuroendocrine, andeurochemical features of depressive disorders.3 Theherapeutic use of proinflammatory cytokines INF-� andL-2 for cancer treatment produces depression32; morepecifically, hyperactivity and dysregulation in the HPAxis, which are common features of severe depression.he sickness response and depression overlap in thatany of the behavioral and sensory manifestations of

ickness are also manifestations of a depressive disorder.

mmune ComplexityImmune organs such as bone marrow, thymus, spleen,

ymph nodes, and various cells are widely distributed,ighly varied, and they lack a focus of central control.et, they function with extraordinary coordination as aingle adaptive system.32,83,150 The immune system has alear sensory function, in that it detects what the nervous
ystem cannot: Microbial invasion, toxins, tumors, and

ccmepi

C

tifpisd

NC

A

htsctprrtlterptttca

G

wromIvati

vwtcf

atrclgtpp

bgonfdmhhtnd

P

iptttiattapagdpc

tipotpans

CaSalai


ell injury.18 It evaluates, (eg, self vs not-self), makes de-isions (eg, cell trafficking), takes action (eg, the inflam-atory response, cell trafficking), and it learns from past

xperience (adaptive immunity and conditioning). Theseroperties approximate sentience, cognition, and behav-

or as we know them in the nervous system.

onnectivityThe literature makes a strong case for the communica-

ion and interdependence of nervous, endocrine, andmmune systems, but nearly all of the studies and reviewsocus on 2 systems rather than all 3. To generate a com-rehensive perspective, we follow the pairwise threads of

nquiry to marshal evidence for our contention that the 3ystems operate and respond to stressors interdepen-ently.

ervous System–Immune Systemonnectivity

utonomic MechanismsBecause all lymphoid organs, including bone marrow,ave autonomic innervation,58,133,191,210 events that ac-ivate the central autonomic network affect the immuneystem. When sympathetic nervous system arousal oc-urs, sympathetic axon terminals innervating lymphoidissues release E, NE, and NPY. Lymphocytes, macro-hages, and other immune cells bearing functional ad-enoceptors respond to the released substances.134 Theelease of SAM catecholamines into the systemic circula-ion exerts a similar effect. Through activation of circu-ating leukocytes and other immune cells and immuneissues at various locations throughout the body,133 cat-cholamine secretion modulates all aspects of immuneesponses, such as initiative, proliferative, and effectorhases, and it can alter lymphocyte proliferation, cellrafficking, antibody secretion, and cytokine produc-ion.59 In addition, NPY’s receptors, Y1 and Y2, existhroughout the immune system. NPY stimulates lympho-yte proliferation,212 enhances leukocyte function,193

nd modulates macrophage activity.42

lial CellsMicroglia, oligodendrocytes, and astrocytes resideithin the CNS and contribute to inflammation and pe-

ipheral injury-induced pain,217,225 including the spreadf pain.82 Microglia are immune cells closely related toacrophages that express the same surface markers.64

njury and other events that threaten homeostasis acti-ate microglia. These immune cells contribute to hyper-lgesia and allodynia by releasing proinflammatory cy-okines and chemokines, and they are probably involvedn several neuropathic pain conditions.125

The astrocyte, a nonmigratory subtype of glial cell, di-ersely supports CNS function. Through its direct contactith blood capillary networks, it provides vasomodula-

ion of localized blood flow, metabolic support (eg, glu-ose delivery), and control of the blood brain barrier
unction on micro and macro levels. Subpopulations of o
strocytes surround neurons and their synaptic connec-ions, thereby influencing pre-synaptic neurotransmitterelease through modulation of synaptic cleft calciumoncentration and membrane polarization. In control-ing local environments, they functionally organize re-ional synaptic connections. In addition, they providehe important function of neurotransmitter uptake, thusrotecting against glutamate neurotoxicity, which is im-licated in several central pathological states.Microglia and astrocytes play key roles in positive feed-ack circuits (described below) involving cytokines andlutamate.224 Activators and inhibitors can exacerbater block the influences of microglia and astrocytes onociception. Fractalkine, naturally expressed on the sur-ace of neurons, can activate microglia to produce allo-ynia and hyperalgesia.137 Conversely, minocycline ad-inistered preemptively at the time of injury reverses

yperalgesia and allodynia.117 The relationship of acuteyperalgesia and allodynia to microglial activation, andhe unfolding vision of microglial activation as mecha-isms in chronic neuropathic pain exemplify of the inter-ependence of nervous and immune systems.

eptidesMultiple peptides link the activities of the nervous and

mmune systems.152,195,207 CRH is a prominent sharedeptide produced at hypothalamic PVN and also at ex-rahypothalamic sites. CRH functions as a neurotransmit-er as well as a hormone. CRH and its family of neuropep-ides, including the urocortins, contribute to peripheralnflammatory responses.74 C fibers release it the woundlong with SP, and mast cells appear to be the primaryargets.33 In caudal dorsal raphe nucleus, CRH induceshe release of serotonin from neurons.80 At centralmygdala, CRH has an anxiogenic function131 and is im-ortant for memory consolidation,172 but these effectsre independent of its action at the HPA axis.143 Psycho-enic stressors can trigger the release of CRH at amyg-ala.130 Thus, CRH is clearly pleiotropic, exerting bothro- and anti-inflammatory effects, depending on its lo-ation and role.Other prominent neuropeptides are SP, CGRP, soma-

ostatin (SOM), vasoactive intestinal peptide (VIP), andts close relative, pituitary adenylate cyclase activatingeptide (PACAP). T-lymphocytes express receptors for allf these peptides, which play a role in immune regula-ion as well as pain. C-fibers innervating the various lym-hoid organs release some of these peptides.113,195 SPnd CGRP, released from peripheral C-nociceptor termi-als, participate in neurogenic inflammation.213 CGRPuppresses IL-2 production.215

In addition to proinflammatory peptides, peripheral-fibers release SOM, which enters systemic circulationnd exerts anti-inflammatory and analgesic effects.154

OM inhibits hormone release in the anterior pituitarynd inhibits T-cell proliferation. It also downregulatesymphocyte proliferation, immunoglobulin production,nd the release of proinflammatory cytokines. A SOM-SPmmunoregulatory circuit may exist,195 perhaps as part
f a deeply nested, feedback control system.

staaPmat

mntchitaBaatwa

martoWflt

ohctasi

aptanaTnocck

tlhtc

ac

C

soointLotflsini

N

ptrdIapr

E

pottsmpap

E

ddcacniEfTrr


VIP and PACAP are structurally related members of theecretin-glucagon-VIP family that perform multiple ac-ions within the nervous and immune systems.48,67 Theyct on the same receptors and share many biologicalctivities. VPAC1 and VPAC2 receptors bind both VIP andACAP with equal affinity but VPAC1 binds PACAP with auch higher affinity than VIP. VIP and PACAP exert an

nti-inflammatory influence in the periphery.48,67 Cen-rally, they inhibit chemokines in activated microglia.46

VIP and PACAP regulate both innate and adaptive im-unity.67,68 Most lymphoid organs contain VIPergic

erve fibers located close to immune cells.112 T-cells, par-icularly Th2 cells, produce VIP. VIP and PACAP limit theytotoxicity of CD4� and CD8� T-cells, probably by in-ibiting chemokine receptors.75 These peptides directly

nhibit macrophage proinflammatory cytokine produc-ion as well as production of proinflammatory cytokinesnd chemokines from microglia and dendritic cells.roadly, they promote Th2 anti-inflammatory responsesnd reduce proinflammatory Th1 type responses. Pozond Delgado156 contend that VIP qualifies for classifica-ion as a Th2, or anti-inflammatory cytokine. It groupsith IL-10 as an inflammatory cytokine because it medi-tes and regulates both neural and immune functions.PACAP modulates many macrophage functions such asigration, adherence, phagocytosis, as well as synthesis

nd release of IL-6 in resting macrophages.47 It inhibits IL-6elease in stimulated macrophages but enhances its secre-ion in unstimulated macrophages. PACAP exerts an effectn neutrophil inflammation even though VIP does not.106

hen injected intradermally, PACAP is strongly anti-in-ammatory, presumably modulating cytokine produc-ion.108

Other peptides serving as messenger substances includerphanin FQ/nociceptin,132 an endogenous ligand of theuman opioid receptor-like, ORL1, (hereafter termed noci-eptin receptor [Noci-R]). Noci-R is also present and func-ional in human leukocytes and neutrophils.5,65 Nociceptinnd its receptor recruit leukocytes to inflammatory sites inupport of host defense and the generation of appropriatemmune responses.181

Tachykinins are neuropeptides synthesized in neuronsnd released from nerve terminals. SP and NKA are theroducts of nociceptive afferents characterized by sensi-ivity to capsaicin. They are released during axon reflexnd by exposure to conditions such as low pH, bradyki-in, capsaicin, prostaglandins, and leukotrienes. Therere 3 types of tachykinin receptors: NK1, NK2, and NK3.hese receptors interact preferentially with SP, NKA, andeurokinin B (NKB), respectively.123,128 SP exists through-ut the CNS, in both neuronal and glial cells. In the CNS, SPan initiate and augment the immune responses of glialells after trauma or infection.126 IL-1� upregulates tachy-inin in the peripheral nervous system.99

Tachykinins also exist in the immune system,113,165 wherehey stimulate monocytes and macrophages,96 degranu-ate mast cells, and cause adherence and chemotaxis ofuman neutrophils and eosinophils. They also modulatehe chemotaxis, proliferation, and activation of lympho-
ytes. SP stimulates the release of cytokines such as Il-1, IL-6, p
nd TNF-� from peripheral blood monocytes and in boneells.73 SP receptors also exist in blood vessels.165

ytokines as MessengersCytokines help coordinate the nervous and immune

ystems. Proinflammatory cytokines act at multiple levelsf the neuraxis.54 They bind to sensory afferent terminalsf the vagus and glossopharyngeal nerves and thereby

nfluence the solitary nucleus and other mesencephalicoradrenergic sites.55,124,206 IL-1 triggers cerebral NE me-abolism and secretion53 and influences activity in theC.22 Proinflammatory cytokines act at the PVN and atther levels of the HPA axis to release adrenal glucocor-icoids184,206 and IL-1� stimulates CRH neurons.100 Proin-ammatory cytokines promote further cytokine synthe-is within the CNS at microglia. They appear to playmportant but as yet unspecified roles in positive andegative feedback loops that influence processes jointly

nvolving endocrine and immune responses to stressors.

eural Detection of CytokinesThe sensory vagus and glossopharyngeal nerves havearaganglia that detect immune products and are sensi-ive to immune system signaling.174,217 They detect pe-ipheral proinflammatory cytokine release. Conversely,irect electrical stimulation of the vagus nerve induces

L-1� release in hypothalamus and hippocampus.89 Thebility of other, noninvasive stressors to increase IL-1� de-ends on NE.20 IL-1� activates the HPA axis, increases NEelease at hypothalamus,223 and stimulates LC activity.22

ndogenous OpioidsThe immune system is a source of endogenous opioideptides, and tissue trauma enhances production of opi-id peptides within immune cells located in inflamedissue. CRH and IL-1� are releasing factors for opioid pep-ides.178 Leukocytes secrete endogenous opioids in re-ponse to releasing factors such as CRH, NE, and proinflam-atory cytokines.168,169 Endogenous opioids suppresseripheral C terminal excitability and inflammatory medi-tor release, thus contributing anti-inflammatory effects ineripheral nociceptor activation.

ndocannabinoidsEndocannabinoids constitute a lipid signaling systemerived from arachidonic acid.38 Nervous, blood, and en-othelial cells release endocannabinoids.160 The endo-annabinoid endogenous ligands anandamide (AEA)nd 2-arachidonoylglycerol (2AG) bind to the G protein-oupled receptors CB1 and CB2.107 Broadly, the endocan-abinoids exert immune-suppressing effects. Anandam-

de inhibits the migration of CD8� T-lymphocytes.98

xtended exposure to marijuana compromises immuneunction and may result in disturbance of the normalh1/Th2 cytokine ratio.31 Monocytes, helper T-cells, mac-ophages, and brain microglia all express cannabinoideceptors.214

CB1 cannabinoid receptors and ligands occur princi-
ally in brain, immune, and other peripheral tissues,

wmhpa(VPTtansctrnphmttrmciTTtl

NC

sstatesnn

A

aaccrttFoamct

ad

aicmgvmwtTCwCtMttnCdt

agairbirra

rctcleli

P

aaseslc

vt5c


hereas CB2 receptors and ligands occur primarily in im-une cells.107 As a general rule, cannabinoids appear toave anxiolytic, neuroprotective, and anti-inflammatoryroperties.36,151 However, in addition to binding to CB1nd CB2, AEA binds to the vanilloid receptor TRPV1transient receptor potential cation channel, subfamily, member 1; formerly termed vanilloid receptor 1, VR1).eripheral nociceptor terminals express and encodeRPV1 in response to multimodal stimuli related to tissuerauma. TRPV1 receptors exist on C nociceptive terminalsnd also reside on the central endings of primary sensoryeurons in the dorsal aspect of the spinal cord and brain-tem.255 Through its dual agonist effects on TRPV1 andannabinoid membrane receptors, AEA plays an impor-ant role in chemical nociception and in modulating pe-ipheral hyperalgesic mechanisms.84,120,186,199 Cannabi-oid effects depend on concentration and also on theresence of inflammatory mediators.186 On the oneand, low AEA concentrations induce CB1 receptor-ediated inhibition of electrically-induced neuropep-

ide release from dorsal root ganglion neurons.176 Onhe other hand, high AEA concentrations evoke TRPV1eceptor-mediated neuropeptide release at central ter-inals of capsaicin-sensitive sensory neurons,199 which

ould potentially oppose peripheral CB-mediated inhib-tory action. Cannabinoids may act solely through theRPV1 receptor151 or through simultaneous binding ofRPV1 and cannabinoid receptors. They exert modula-ory effects, extending from organ systems to cellularevels.

ervous System–Endocrine SystemonnectivityThe nervous and endocrine systems cooperate in the

tress response. Neural structures initiate hormonal re-ponses and provide the mechanisms of feedback-con-rolled regulation. Moreover, CRH, E, NE, �-endorphin,nd other substances assume the role of neurotransmit-er in the nervous system and the role of hormone in thendocrine system. As hormonal messengers, these sub-tances affect nervous structures at multiple levels of theeuraxis. Consequently, the literature often refers to theeuroendocrine stress response.

cute Stress Response MechanismsWounding triggers a neuroendocrine reaction with 3

spects: (1) Sympathomedulary release of NE, E, and NPYs hormones148; (2) CRH activation of the HPA axis in-luding the production of mineralocorticoids and glu-ocorticoids44,161; and (3) activation of LC and the norad-energic limbic brain,204 the sympathetic components ofhe central autonomic network. From the pain perspec-ive, the stress response has several key properties.86

irst, noxious signaling is among its triggers. Second, theverall reaction to the stressor includes both anticipatorynd reactive responses. Third, these responses occur inultiple, hierarchically organized, or nested, neurocir-

uitries. Furthermore, the stress response is not limited to
he HPA axis but invariably involves multiple limbic brain s
reas including the amygdala87 and the mesocorticolimbicopaminergic system.204

When a stressor occurs, the hypothalamic PVN receivesnd integrates neural input from diverse sources thatnclude sensory input, the limbic brain and the frontalortex. Serotonin (5-HT), Ach, and NE are among theost important neurotransmitters involved in neuro-

enic stimulation of CRH production15,44 and arginine-asopressin (AVP) production. Periventricular NE is theost salient neurotransmitter in HPA axis activationhen the stressor is noxious.147 AVP production is simul-

aneous and AVP interacts synergistically with CRH.204

hrough the median eminence of the hypothalamus,RH and AVP enter hypophyseal portal circulation,hich extends to the anterior pituitary gland. There,RH induces POMC, a precursor polypeptide that cleaveso form ACTH, �-melanocyte stimulating hormone (�-SH) and �-endorphin.138 ACTH enters systemic circula-

ion and activates CORT secretion at adrenal cortex. Cen-ral detection of circulating CORT completes theegative feedback loop (Fig 1) and constrains ACTH andORT production.136 These processes normally follow aiurnal rhythm as pulsations. In response to a stressor,he frequency of rhythmic secretory episodes increases.There are reciprocal connections between central CRH

nd LC noradrenergic neurons.93,147,204 The noradrener-ic LC system is not only involved in alarm reactions, butlso plays a key role in maintaining waking/vigilance andn many higher order cognitive processes.6,12 LC norad-energic projections extend widely throughout the lim-ic brain and can excite the amygdala, which is involved

n negative emotion and defense responses. In the pe-iphery, postganglionic sympathetic neurons are norad-energic, although CRH, NPY, and SOM colocalize in nor-drenergic vasoconstrictive neurons.The SAM endocrine response to a stressor involves the

elease of E, NE, and NPY from the adrenomedullaryhromaffin cells into systemic circulation. The ratio of Eo NE in plasma is 4:1 in humans, and the major source ofirculating NE is not adrenomedullary secretion but re-ease from sympathetic efferent endings. Circulating cat-cholamines increase blood pressure and heart rate, di-ate pupils, and increase skin conductance, therebynitiating arousal for the fight-or-flight response.

eptides and SerotoninPeptides link the endocrine and nervous systems. VIP

nd PACAP help regulate the HPA axis.146 The hypothal-mus contains both peptides. The pituitary gland synthe-izes VIP but not PACAP, although the adrenal glandxpresses both. Both peptides increase pituitary ACTHecretion. VIP from the pituitary elicits hypothalamic re-ease of CRH, and PACAP by directly stimulating pituitaryorticotropes and by activating CRH gene expression.77

The indoleamine neurotransmitter 5-HT also links ner-ous and endocrine stress response systems. The hypo-halamic PVN has dense serotonergic innervation, and-HT–containing axons innervate hypothalamic CRH-ontaining cells.81 5-HT stimulates secretion and synthe-
is of CRH.92 Conversely, CRH has multiple and complex

e5A(eaPatacIdIw

IC

M

biuittnaa

icedektaposcjs

C

aiAcis

tPaA

m�cesce

emoosnrCbckp

tesrfltsrCnikCa

E

ctCspAtcCr

C

taietdt


ffects on serotonergic neurons, as do glucocorticoids.-HT reuptake inhibition in rats significantly increasedCTH secretion 5-fold, CRH messenger ribonucleic acid

mRNA) expression in the PVN by 64% and POMC mRNAxpression in the anterior pituitary lobe by 17%.97 5-HTppears to increase synthesis of CRH in the PVN andOMC in the anterior pituitary lobe. High 5-HT has neg-tive immunoregulatory effects.121 5-HT inhibits produc-ion of INF-�, a proinflammatory cytokine, even thoughugmented CRH during stress generally tends to increaseertain other proinflammatory cytokines such as IL-1,L-2, and IL-6. CRH increases 5-HT activity in the caudalorsal raphe nucleus.80 Dunn summarized the impact of

L-1 administration on the HPA axis.53 Among the effectsas an increase in 5-HT metabolism.

mmune System–Endocrine Systemonnectivity

echanismsThe immune system distributes widely throughout theody, involves a variety of organs and cells and has both

nnate and acquired features.150 The endocrine systemses systemic circulation to evoke system-wide messag-

ng and feedback. Therefore, the immune–endocrine in-erface has many facets. Reciprocal interactions involvehe hypothalamus, pituitary gland, adrenal cortex, adre-al medulla, as well as multiple immune cells, which havedrenoceptors and receptors for various peptides. Theylso release peptides and cytokines.During stress, the immune and endocrine systems also

nteract at the periphery. For example, stress-activatedirculating E and NE bind to the �2 adrenoceptorsxpressed on mononuclear phagocytic cells33,59 andendritic antigen-presenting cells.122 In general, cat-cholamines including dopamine tend to shift the cyto-ine balance in the Th2, or anti-inflammatory, direc-ion.59 Similarly, glucocorticoids produced by HPA axisctivation suppress proinflammatory, or Th1, cytokineroduction. These hormones appear to protect againstvershoot in the proinflammatory response to a stressoruch as tissue damage. Together, the stress-induced, cir-ulating catecholamines and glucocorticoids are the ma-or integrative and regulatory influences on immune re-ponses.210

orticotropin-Releasing HormoneCentrally, CRH plays a major role in linking immune

nd endocrine function.100 CRH originating at the PVNnitiates the stress response at the HPA axis throughCTH secretion, leading to CORT release from adrenalortex and catecholamine release from adrenal medulla,n addition to activating central noradrenergic structuresuch as the LC.93,147,204

Central CRH activates the anterior pituitary, a part ofhe endocrine system, and causes expression of theOMC prohormone, which undergoes extensive cleav-ge to yield a range of biologically active peptides.
mong them are ACTH, the melanocyte-stimulating hor- a
ones �-, �-, and �-MSH, �-endorphin, as well as �- and-lipoprotein. �-MSH antagonizes the proinflammatoryytokine IL-1.17 In addition, POMC-expressing neuronsxist in hypothalamus, elsewhere in the CNS and in thekin.158 Circulating corticosteroids and proinflammatoryytokines appear to control circadian rhythms of POMCxpression.180

As a hormone and neuropeptide acting in the periph-ry, CRH is behaviorally anxiogenic and exerts proinflam-atory effects on immune cells by enhancing the release

f proinflammatory cytokines from macrophages andther immune cells.1 CRH presence in inflammatory tis-ues may be the product of immune cells, peripheralerves, or both.33 As with SP and CGRP, peripheral nerveselease this neuropeptide in response to tissue damage.RH is chemically similar to urocortin, also a peptide, andoth are over-expressed in inflammation. CRH and uro-ortin stimulate production of proinflammatory cyto-ines by immune cells. The mast cell is a major target oferipheral CRH release.On the other hand, CRH contributes to anti-inflamma-

ory processes by inducing POMC synthesis at the periph-ral and central interfaces of the endocrine and immuneystems. In the periphery, tissue injury increases opioideceptor expression in dorsal root ganglion neurons. In-ammatory processes induce releasing factors, amonghem CRH, cytokines and NE, that cause leukocytes toecrete endogenous opioids that bind to receptors on pe-ipheral nerve terminals and reduce their excitability.168,169

RH also fosters opioid receptor expression on sensoryeuron terminals in the wound. Opioid receptor-express-

ng leukocytes and macrophages responding to chemo-ines migrate to the inflammatory environment. Thus,RH participates in the control of local inflammation bycting as a releasing factor for endogenous opioids.

ndocannabinoidsAlthough classic descriptions of endocannabinoids fo-

us on interactions of nervous and immune systems,hese substances also play a role in endocrine function.annabinoid administration affects multiple hormoneystems including gonadal steroids, growth hormone,rolactin, thyroid hormone, and HPA axis activation.27

EA intracerebral ventricular administration activateshe HPA axis, increasing serum levels of ACTH and corti-osterone in a dose-related manner,219 probably via theB1 receptor and further hypothalamic PVN cannabinoideceptor binding.220

ytokinesFinally, the immune system exerts a powerful effect on

he endocrine stress system through cytokines, which actt the hypothalamus and pituitary. Cytokine receptors,ncluding the proinflammatory cytokines IL-1 and IL-6,xist at all levels of the HPA axis.184 Microglia are likelyhe primary central source of IL-1.20 In addition, IL-6 pro-uced at a peripheral site of injury/inflammation reacheshe hypothalamus through systemic circulation.55,170 IL-1
ctivates the LC and thereby the noradrenergic limbic

bs

ackGve

T

vmdptuastsaopcn

athsfac

CL

as“horasets

vfstdcmnttart

F

actsaiofepoiov

ftl

Fsmunsdfttcsi


rain.22,53 Increased 5-HT metabolism accompanies IL-1timulation of the HPA axis.53

Negative feedback processes limit cytokine HPA axisctivation. The HPA axis produces adrenal glucocorti-oid, which suppresses the effects of immune cell cyto-ines at the anterior pituitary and adrenal medulla.13

lucocorticoids also inhibit Th1 cytokine production in aariety of systems while increasing the production of sev-ral Th2 cytokines.60

he Single System Vision: SupersystemOur literature review indicates that wounding acti-

ates processes in nervous, endocrine, and immune do-ains, that these processes operate in an interdepen-ent and integrated manner rather than as distributedhysiological processes, and that their highly orches-rated agency in defending against threat uses self-reg-lation and self-direction. In light of this, we put forwardsupersystem model: The neural-endocrine-immune en-

emble is an agent that operates as an overarching sys-em, within which each individual system functions as aubsystem. A corollary is that the supersystem nests withlarger system that we characterize as the whole person,r individual. Fig 2 characterizes the supersystem, em-hasizing connectivity. It depicts a dynamic process ofonstant message interchange within the autonomicervous system and through systemic circulation.

igure 2. Connectivity. Nervous, endocrine, and immune sub-ystems communicate dynamically using the language of com-on chemical substances, as indicated in the center of the fig-

re. The major language elements are peptides, hormones,eurotransmitters, endocannabinoids, and cytokines. Theseubstances are pleiotropic in that they exert different effectsepending on context (eg, phase and location). Circulation, dif-usion, and migration are some of the processes of informationransmission. Systemic circulation and autonomic nervous sys-em activity are other vehicles of information transmission. Be-ause the nervous, endocrine, and immune systems have con-tant reciprocal communication, they tend to react to a stressor

bn a highly orchestrated manner, as a single unit.

Our model proposes that the supersystem governs thedaptive response to wounding and the generation ofhe related phenomenal pain state. It rests on 3 falsifiableypotheses, namely that the supersystem: (1) Demon-trates connectivity; (2) uses cross-subsystem informationeedback loops for self-regulation; and (3) demonstratesgency when perturbed by injury. Below, we clarify theoncepts behind these hypotheses.

onnectivity: A Common ChemicalanguageOur review reveals what Blalock19 and others had

lready detected, albeit with a more limited focus: Aystem of shared ligands and receptors comprises achemical language” that makes possible a complex, co-erent response to a stressor at all levels of human physiol-gy.16,195 The major elements of this language are neu-otransmitters, peptides, endocannabinoids, cytokinesnd hormones. Some versatile proteins, such as CRH, playeveral of these roles across systems and at multiple lev-ls. This language makes possible self-organizing, adap-ive responses. One can test the role of any given sub-tance in connectivity.Whether a “language” substance exerts an excitatory

ersus inhibitory, or pro- versus anti-inflammatory, ef-ect is not always straightforward because it depends onystem context: Many are pleiotropic. The impact ofhese messenger substances does not reduce merely toiscrete actions they exert in a specific physiological lo-us. At the systems level, they deliver information thatakes continuous coordination possible, participate in

egative or positive feedback loops that move a systemowards or away from equilibrium, and make possiblehe processes that comprise allostasis during stress. Theyllow the system to negotiate its environment, adapt ineal time, mount emergency responses, and recover fromhose responses.

eedback LoopsFeedback means that information about the output ofsystem passes back to the input and thereby dynami-

ally controls the level of the output. System self-regula-ion and self-organization depend on feedback, as doeself-direction. Feedback-dependent regulatory processesnd stress responses cross the nervous, endocrine, andmmune system boundaries and thereby contribute toverall system regulation. For example, cross-subsystemeedback loops play key roles in the interdependence ofndocrine and immune systems.13,170 Glucocorticoidroducts of the HPA axis modulate the basal operationsf cytokine-producing immune cells. Cytokines, in turn,

nfluence the activity of the HPA axis. Thus, the productsf 1 subsystem provide messenger substances that pro-ide feedback for another subsystem.Feedback loops can be negative or positive. Negative

eedback permits stability while positive feedback allowshe organism to mount emergency responses. The regu-atory processes of homeostasis and allostasis are feed-
ack dependent. Negative feedback insures system sta-

bwcgcpf

rdsorhppttcp

rtfntntth

wdficosettabpsa

A

aoioeieaasa

tpsaa

irmsimas

wivvopancl

DR

slssycrfsth

F

smpMmcm“sdg

D


ility and maintains homeostasis. Feedback is positivehen a variable changes and the system responds by

hanging that variable even more in the same direction,enerating escalation and rapid acceleration.63 This pro-ess abandons stability for instability. From an adaptationoint of view, positive feedback loop capability is essentialor meeting acute threat with defensive arousal.Positive feedback loop activation plays a prominent

ole in pain. It allows systems to convert graded inputs toecisive all-or-none outputs25 that are essential bi-stabletate shifts. Abrupt, nonliner shifts to facilitative modesf noxious signaling within the nervous system typicallyesult from positive feedback loop activation, inducingyperalgesia and allodynia. It characterizes the interde-endence of peripheral and dorsal horn sensitizationrocesses and, as we noted above, dorsal horn sensitiza-ion generates hippocampal and cortical potentiationhat enhances responses to injury.94 Positive feedbackan also occur with inhibitory circuits, resulting in hy-oalgesia or analgesia.Each mode of operation has adaptive value as a short-

ange response in certain types of injurious events. Sus-ained periods of positive feedback have the potentialor destructive consequences. For example, excessiveoxious input to the dorsal horn can increase glutamateo excitotoxic levels and thereby destroy inhibitory inter-eurons. Such damage becomes evident as the forma-ion of dark neurons.85 This suggests that the persevera-ion of inflammatory noxious signaling can cause dorsalorn pathology.Negative and positive feedback processes can go awryithin the nervous, endocrine and immune systems andysregulate normal processes. Negative feedback mayail when an endogenous messenger substance provid-ng the feedback disappears, occurs in excess, or becomesonfounded by exogenous products such as medicationsr substances of abuse that resemble them in chemicaltructure. In some cases, negative feedback fails when anxtraneous influence alters the set point. For example,he presence of opioid medications in a male pain pa-ient dysregulates the hypothalamo-pituitary-gonadalxis and results in hypogonadism.21,40,41 Positive feed-ack processes can also malfunction. Positive feedbackrobably contributes to migraine headache, allodynia,evere idiopathic abdominal pain, noncardiac chest painnd a variety of multisymptom disorders.

gencyAn agent is an individual, self-organizing system oper-

ting purposefully within its environment in the servicef adaptation. The concept of agent equates with the

ndividual when the focus of study is on the interactionf an organism with its environment, especially its socialnvironment. Agent-based complex systems directlydentify the individual in the world as an agent.76 How-ver, agency exists within nested subsystems whenevern element exhibits some degree of autonomy. For ex-mple, dendritic cells serve as “professional antigen-pre-enting agents.” They appear in peripheral organs such
s skin where they encounter and capture antigens. They v
hen migrate to the T-cell areas of lymphoid tissues andresent the processed antigens in order to elicit antigen-pecific T-cell responses. Whatever the level of inquiry,gents are semi-autonomous units that evolve over timend help to maximize adaptation.We postulate that the supersystem is an agent for meet-

ng the challenge of wounding, engaging the threat itepresents at both the external and internal environ-ents, and resolving the wound by healing. The super-

ystem, as an agent, maximizes adaptation by represent-ng the wound in consciousness as pain. The dynamic,

ultidimensional, unpleasant pain experience with itsffective and sickness dimensions is the product of theupersystem, not just the nervous system.Put practically, the agency hypothesis states thatounding induces correlated nervous, endocrine and

mmune changes. These correlations define relationalariables, or outcomes if interventions exist. Relationalariables determine on the one hand wound healing andn the other hand the various subjective aspects of theain experience such as pain intensity, unpleasantness,ffect, quality, interference with normal function, sick-ess, and rate of change. Multivariate statistical methodsan evaluate the agency hypothesis by modeling corre-ations.

ysfunction During Stress: Acuteesponses Become Chronic DisordersWe have emphasized that the individual patient is a

ystem, but every system exists within a larger, encapsu-ating system that influences it. The psychosocial systemurrounding the individual patient a potential source oftressors that demand allostatic response above and be-ond that elicited by injury. Fig 3 illustrates the biopsy-hosocial interactions of the individual with his/her envi-onment and the various contributions of psychosocialactors to allostatic load. In the presence of psychosocialtressors, wound-induced acute stress responses can failo resolve properly, leading to chronic disorders. This canappen in 3 ways.

ailed Arousal-to-Recovery TransitionPain clinicians sometimes see pain patients who report

urviving a horrific accident or event that left them trau-atized. A single trauma of sufficient magnitude can

roduce a stress response that does not resolve properly.cEwen described other allostatic load scenarios thatight lead to system malfunction: (1) Unremitting or

hronic stressors; (2) inability to adjust to a stressor ofodest duration and demand; and (3) not hearing the

all clear” in which the stress response persists after thetressor has disappeared.128 These concepts, collectively,escribe an arousal or fast response phase that fails toive way to a recovery or slow response phase.

ysfunctional RecoveryThe recovery process in the HPA axis invokes the in-

erted “U” principle: CORT insufficiency and CORT excess

aacstsorc

trkcta

oore

dvwT

D

tCitisttf

SC

D

attwvasnsddtdpttamT

B

rrcrsacDprtrtP

Fchnsttpdtesascsas


re both damaging.44 Too little CORT means prolongednabolism. Moreover, positive feedback arousal pro-esses can go unchecked and conversion to the recoverytate may not occur. Conversely, too much CORT overime has negative catabolic consequences. Hypercorti-olism is a marker of severe depression. In both cases, lossf normal diurnal variation in CORT pulsing indicates dys-egulation. Thus, a dysfunctional endocrine recovery pro-ess is a mechanism for long-term endocrine dysregulation.The boundaries of endocrine dysregulation extend to

he immune subsystem. GCs profoundly affect cytokineesponses. Evidence indicates that GCs inhibit Th1 cyto-ine production while at the same time promoting Th2ytokines production.60 This is another form of protec-ion against overshoot of positive-feedback–drivenrousal responses.59

Many writers102 characterize the immune system asperating in either Th1 dominant (proinflammatory)r Th2 dominant (anti-inflammatory). These modesoughly parallel the stress response arousal and recov-

igure 3. Stressors and the chronic pain patient. A typicalhronic pain patient has medical problems related to 1 or moreistoric events. These problems limit vocational options andormal social interactions, with resulting financial problems,ocial isolation, and family distress. These processes comprisehe explicit stressor constellation. Past history and memories ofhe patient, together with negative thinking, comprise the im-licit stressor constellation. Catastrophic thinking is the ten-ency to frame every problem with a worst-case scenario. Pa-ients tend to engage in it because of anxiety about theirxplicit problems. The negative thinking becomes its own stres-or. Moreover, it makes relationships with people offering socialnd medical support difficult. Often, social problems and aense of being a victim generate anger, which complicates vo-ational and family relationships and exacerbates the explicittressor constellation. Measures of social conflict processes char-cterize patient social interactions as the interactions of a sub-ystem within the larger system that surrounds it.

ry phases. This is more than a parallel concept. Evi- r

ence indicates that proinflammatory cytokines acti-ate the HPA axis13 and thereby elicit MR and GC responseshereas VIP, PACAP and certain other peptides supporth2 processes.47,68

ysfunctional Subsystem InterfaceThe interface between systems can become dysfunc-

ional, impairing intersystem coordination. For example,alcagni and Elenkov,33 in reviewing both endocrine and

mmune system response patterns during stress, raisedhe possibility of dysregulation in the neuroendocrine–mmune interface. Weber identified the same potentialource of disease.218 By extension, one could explore po-ential dysfunction in the nervous-immune interface orhe nervous-endocrine interface as causal mechanismsor chronic pain states.

upersystem Dysregulation inhronic Pain

ysregulationDysregulation is prolonged dysfunction in the ability ofsystem to recover its normal relationship to other sys-

ems and its normal level of operation after perturba-ion. This concept applies to any level of system focus,hether it is the HPA axis or the adjustment of an indi-

idual to a social environment. An extensive literatureddresses the relationships of trauma and prolongedtress with dysregulation of the HPA axis, the centraloradrenergic system, and the SAM axis.44,145 The super-ystem model proposes that pain becomes a chronic andisabling condition as a result of regulatory problemseveloping over time within the supersystem; dysfunc-ion arising in 1 subsystem is likely to lead to lead toysfunction in the others because they operate interde-endently within the supersystem. Prolonged dysregula-ion can cause irreversible organ pathology, and this inurn can generate noxious signaling, as in rheumatoidrthritis and other auto-immune disorders. Dysregulationay manifest in at least 4 ways in chronic pain patients.

hese manifestations are not mutually exclusive.

iorhythm DisturbanceFirst, in a temporal frame of reference, dysregulation

efers to deviation from or loss of normal biologicalhythms. Humans eat, sleep, and work according to cir-adian rhythms, and social activity patterns reflect thesehythms. Rhythm is a fundamental feature of homeosta-is, as temperature regulation demonstrates. Subsystemslso operate according to rhythms. Hormones pulse atertain times, and the resting heart beats in rhythm.ysregulation of temporal processes may play a role ineripheral neuropathy.182 The concept of cross-systemhythm is still poorly defined, but some substances par-icipating in connectivity appear to coordinate biologicalhythms at multiple systems levels. The hormone mela-onin is 1 example.9 Among its many effects is control ofOMC gene expression.162 The relationship of temporal
hythm dysregulation to chronic pain is largely unex-

pbst

F

fpstsfasaaiclta

ftrdeoBbdw

stmgaern

D

aafdcttLsa

I

i

nMnpd

aamccdpvohsspad

I

frtpsaiaadhsatari

A

vItsnnhtdhh

ti


lored, apart from the documentation of sleep distur-ances. Inquiry into multirhythm dysregulation at multipleystem levels in chronic pain patients could prove informa-ive.

eedback DysfunctionMessenger substances play multiple roles, including

eedback messaging. Subsystems like the HPA axis de-end on negative feedback to terminate recovery fromtress processes. Subsystems also limit lower level posi-ive feedback loops that make possible emergency re-ponses, thus protecting against overshoot. Positiveeedback processes are not self-limiting by definitionnd without such control they continue until either atate shift occurs or the system self-destructs. Allodynia isfamiliar example of positive feedback in chronic pain,

s is panic attack in emotional regulation. Within themmune system, positive and negative feedback play aentral role in T-cell discrimination of self from non-selfigands.142,189 This process, too, is subject to dysregula-ion with negative health consequences manifesting asuto-immune disorders.The literature identifies many examples of disturbed

eedback-dependent regulatory processes in stressed pa-ients. For example, patients may develop HPA axis dys-egulation,51,86 autonomic dysregulation,109 peptideysregulation,187 Th1/Th2 cytokine dysregulation,61,209

ndogenous opioid dysregulation,167 and dysregulationf the relationship between pain and blood pressure.28

asically, a subsystem regulated by negative feedbackreaks down in 1 way or another, for example, throughepletion of a key neurotransmitter or peptide. In otherords, the allostatic load causes dysregulation.Feedback mechanisms may also falter under the oppo-

ite condition of resource excess. The medical introduc-ion of substances that resemble biological messengersay interfere with normal allostasis and produce iatro-enic disorder. Opioid medications provide a strong ex-mple, as they resemble �-endorphin and other endog-nous opioids. The hypothalamo-pituitary-gonadal axisesponds to such products as though they were endoge-ous signals and the result is often hypogonadism.41

isturbed Intersubsystem CoordinationWe have offered evidence that N, E, and I subsystems

re interdependent and coordinate their responding tostressor such as tissue injury. The connectivity essential

or cross-subsystem coordination may falter or breakown. Examples include the reciprocal relationship ofytokines with HPA axis regulation,33,53,170,209 the rela-ionship of cytokine regulation to autonomic regula-ion39 and the relationship of cytokine regulation to theC response.22 We propose that dysregulation in oneubsystem will tend to disrupt another, leading eventu-lly to supersystem dysfunction.

ncomplete RecoveryDysregulation could occur if a system alters its set point

n response to a stressor and then fails to readjust to the e

ormal level after the stress has passed. This correspondscEwen’s metaphor of failure to hear the all clear sig-

al.128 This explanatory model nicely describes the hy-ervigilance and hyper-reactivity of post-traumatic stressisorder (PTSD).8

Set points are often straightforward to define. For ex-mple, Vogeser and colleagues211 studied major surgerys a stressor and chose the cortisol:cortisone ratio as aarker of HPA axis activity and as a stress-sensitive indi-

ator of the overall set-point shift in the breakdown ofortisone to produce CORT, namely 11b-hydroxysteroidehydrogenase activity. Surgery caused a shift in this setoint that later returned to presurgical levels. Cardiacariability, MR/GR ratio and Th1/Th2 ratio representther potential system set point indicators that may ex-ibit pathological shifts in chronic pain. The auditorytartle response, which indicates excessive autonomic re-ponse activation to startling stimuli, may be a marker ofast trauma.183 Traumatic life events can permanentlylter the set point of an individual’s feedback-depen-ent HPA axis.26,43

ndices of DysregulationPsychological concepts of trait and state are useful

or describing how dysregulation manifests. A trait is aelatively enduring predisposition to respond in cer-ain ways when perturbed. It gauges the adaptive ca-ability of an individual challenged by a stressor. Atate is a transitory condition of the system, typicallyfter perturbation. During chronic pain, dysregulation

s likely to alter traits and this alteration may manifests abnormal state responses to perturbation. For ex-mple, a person with normal trait anxiety may un-ergo a traumatic event and afterwards becomeighly anxious in response to small problems andhows abnormal startle responses. This is high statenxiety. By analogy, the trait-state distinction applieso neural, endocrine, and immune subsystems. Below,re some examples of ways to quantify subsystem dys-egulation. One can either quantify traits directly ornfer them from challenge-induced changes in states.

utonomic DysregulationCardiac variability, sometimes called vagal tone, pro-

ides a trait measure for the autonomic nervous system.t indexes behavioral, cognitive, and emotional func-ion.7 Basically, cardiac variability reflects the balance ofympathetic and parasympathetic influence in auto-omic function as evident in cardiac activity. The vaguserve is bidirectional. Vagal afferent fibers from theeart project to the solitary nucleus. Efferent fibers fromhe brainstem terminate on the sinoatrial node, the car-iac pacemaker. Sympathetic activation accelerateseart rate and parasympathetic activation decelerateseart rate.Estimation of cardiac variability derives from respira-

ory sinus arrhythmia; that is, changes in heart rate dur-ng the respiratory cycle. During exhalation, vagal effer-
nt activity modulates this rate and causes deceleration.

Iswatvsmrf

S

ttOdtsiTuclssttsaptWi

E

aritsM

crpDntEtdtAa

ah

wfimdonot

ttloriddr

I

cTsacpttBhtitRhdmpcssi

I

remeeetussht


nhalation increases heart rate. Statistical indices of in-tantaneous heart rate variability based on the R-to-Rave interval estimate cardiac variability. Such estimatesre stress sensitive, and some investigators postulatehat early trauma may permanently diminish cardiacariability, leaving the individual less resilient futuretressors.23,155 High cardiac variability, or vagal tone,ay be an indirect marker of an individual’s ability to

espond effectively to a stressor and recover efficientlyrom it.

ensory DysregulationTracey and Mantyh201 postulate that chronic pain pa-

ients may have dysfunction in either the facilitatory sys-em or the inhibitory system for nociceptive modulation.ne can assess these processes by looking at windup andiffuse noxious inhibitory control (DNIC). Windup, oremporal summation, occurs when a subject undergoes aeries of identical noxious stimuli. Tracking the pain rat-ng across trials reveals increased pain or sensitization.his process may be abnormal in some chronic pain pop-lations.188 When the activation of 1 noxious stimulusauses a diminished response to a second noxious stimu-us, DNIC exists. In the laboratory, one measures the re-ponse to a phasic stimulus at baseline, applies a tonictimulus such as the cold pressor test, and then measureshe response to the phasic stimulus again. The responseo the phasic stimulus should diminish after the tonictimulus. This is independent of segment (hence diffuse)nd not being naloxone reversible in most reports it isrobably independent of the HPA axis. DNIC is a labora-ory predictor of clinical pain and quality of life.57

hether windup and DNIC are true opposing processess uncertain but worth exploration.

ndocrine DysregulationPotential trait measures exist for the HPA axis. DeKloet

nd Derijk45 postulated that MR and GR mediated stressesponses counterbalance: MR responses contribute tommediate arousal and coping whereas GR responses at-enuate emergency reactions and assist recovery fromtress. Normally, an individual possesses a characteristicR/GR balance that is largely genetically determined.Some approaches to diagnosing dysregulation involve

hallenging the HPA axis and looking for abnormal stateesponses to the challenges. The dexamethasone sup-ression test gauges HPA axis response in this way.159

examethasone is an exogenous steroid that providesegative feedback to the pituitary to suppress the secre-ion of ACTH. It does not cross the blood-brain barrier.xcessive CORT response to dexamethasone occurs in upo half of all severely depressed patients, indicating axisysregulation. Alternatively, the CRH challenge involveshe infusion of CRH and measurement of subsequentCTH and cortisol responses.51 It, too, can gauge HPAxis dysregulation.Detection of biorhythm dysregulation necessitates ex-

mination of diurnal or other chronological variation in
ormones. This typically requires multiple samples c
ithin a single day and examination of the resulting pro-le against a normal profile. CORT, for example, nor-ally peaks shortly after arising, and then blood levels

ecline and are very low late in the day and evening. Anyther pattern indicates dysregulation. In contrast, oppo-ent process dysregulation indicators derive from a ratiof opposing processes like the Th1/Th2 ratio. For this,here are many possibilities.In looking at the negative impact of sleep depriva-

ion35 Copinschi examined both types of dysregula-ion. Sleep deprived subjects had increased cortisolevels in the late afternoon and evening. Examinationf 2 brain-gut axis hormones related to appetite, gh-elin and leptin, also revealed dysregulation. Ghrelinncreases appetite while leptin decreases it. With sleepeprivation, the ghrelin-to-leptin ratio shifted in theirection of higher ghrelin and lower leptin; this cor-elated strongly with increased hunger.

mmune DysregulationFor the immune subsystem, Th1/Th2 balance has be-

ome a focus of attention in cytokine research.60,102

he general view holds that stress is immunosuppres-ive. However, it is becoming clear that glucocorticoidsnd catecholamines support inflammation locally inertain conditions; that is, they promote Th1 cytokineroduction. And yet, systemically these substances po-entiate Th2 production while inhibiting Th1 produc-ion, thereby exerting an anti-inflammatory effect.33

ecause cytokine activity depends heavily on stressormones, such localized targeting of proinflamma-ory processes could be advantageous in promotingncreased blood flow and cell trafficking to injuredissue. Th1/Th2 balance varies with the stress response.egardless of whether that response is hyperactive orypoactive, it may alter the course of immune-relatedisease. The Th1/Th2 ratio is skewed in several com-on diseases,60 and it is a useful parameter from a

sychosomatic perspective. For example, Glaser andolleagues examined Th1/Th2 balance in chronicallytressed caregivers of demented patients and found ahift in the Th2 direction, suggesting vulnerability tonfection.70

ndividual Differences and DiathesisInheritable individual differences in stress response/

ecovery stem from 2 causal mechanisms: Genetic andpigenetic. Noninheritable, environmentally deter-ined individual differences derive from previous life

xperiences including learning, culture, and experi-nce of trauma and the interactions of such experi-nces with genetic and epigenetic factors. Collectively,hese influences interact to determine an individual’snique vulnerability for developing chronic pain. Aevere stressor, a cascade of stressors, or continuedelf-generated stress-inducing thoughts can impose aeavy allostatic load that eventually causes dysregula-ion in one or another subsystem. Just as a metal link
hain subjected to tension will break at the weakest

leset

D

eatippfef

ptvsvctipi

G

aicdactsgcaii

tcafttatcpv

aPifgi

E

itDidiDpchsrvscsiTmlrtsi

C

wnsvtip

apdfbtsnoe


ink, a person with high, increasing allostatic load willxperience dysregulation in the most vulnerable organystem. Genetic and epigenetic factors interact withnvironmental factors to determine which organ sys-em is most vulnerable.

iathesisDiathesis refers to the vulnerability of an individual

xperiencing stress to a pathological consequence suchs organ pathology or system dysregulation. With tissuerauma, each individual carries a unique risk of develop-ng a chronic pain condition. For example, 22% to 67% ofatients who undergo a thoracotomy develop chronicain.198 The diathesis for each thoracotomy patient is aunction of genetic factors, epigenetic factors, and annsemble of other factors such as comorbidity, familialactors, psychological status and social support.The stress diathesis model is not new in the chronicain field, and psychologists in particular have called at-ention to individual differences in vulnerability to de-eloping disabling chronic pain.56,205 To date, paintress-diathesis has not extended beyond a psychologicaliew of nervous system function that lacks a physiologi-al explanatory framework. We suggest that stress dia-hesis is an essential construct for the development ofndividualized pain medicine. The supersystem conceptrovides a framework for studying chronic pain at the

ndividual level.

enetics

Genes determine both the morphology of an organismnd the processes by which it adapts to its environment,ncluding its capacity to mount a defense response. Onelinically important function of genetic profiling is toetermine who is at risk under stress for pathology, suchs disabling chronic pain. Another is to determine whoan and cannot benefit from a given type of pharmaco-herapy and at what dose. Moffit and colleagues141 de-cribe the joint influence of genes and environment asene-environment, or G � E, interaction, which stands inontrast to traditional assumptions of additive naturend nurture influences. The G � E interaction definesndividual differences in risk for a given pathology dur-ng sustained or severe stress.

Genetic contributions to individual differences includehe interactions of environment with individual genes,ombinations of genes, gene mutations, allelic variants,nd functional polymorphisms. Genetic factors may af-ect individual differences in pain sensitivity49: both syn-hesis and function of proteins affecting the plasticity ofhe CNS,69 tissue remodeling after injury,203 catechol-mine metabolizing enzymes such as catechol-O-methyl-ransferase or COMT,50 production of proinflammatoryytokines,14 tendency to high blood pressure and alteredain sensitivity79; thermal receptor sensitivity mediated
ia vanilloid receptors and opioid receptor subtypes,103 e
nd the efficacy of opioid and other analgesic drugs.166,173

athogenic mutations may be responsible for congenitalnsensitivity to painful events.139 In some cases, geneticactors influence individual differences only mar-inally,104 whereas in rare conditions such as congenital

nsensitivity, their effects are great.

pigeneticsEpigenetics has many definitions, but the basic concept

s that heritable traits exist, including transgenerationalraits, that do not stem from changes to the underlyingNA structure and are potentially reversible. Epigenetic

nfluences may reflect environmental pressure on an in-ividual or on an individual’s ancestors.222 Such changes

n gene expression occur through the methylation ofNA, the post-translational modifications of histoneroteins, and RNA-based silencing. Epigenetic factorsan exert heritable influence on both disease andealth.185 They determine opioid �-receptor expres-ion90 and influence the HPA axis aspects of the stressesponse.129 Many investigators focus on the role of en-ironment-driven maternal behavior as a determinant ofubsequent gene expression. For example, Zhang andolleagues229 demonstrated that environmental adver-ity affected mothers in a way that enhanced the capac-ty for a heightened defense response in the offspring.his increases the probably of offspring survival to sexualaturity but at the cost of multiple pathologies in later

ife. Epigenetic influences not only stem from the envi-onment; like genetic influences they may interact withhe environment. Unlike genetic influences, they are un-table and may alter with environmental change includ-ng in principle therapeutic intervention.

onclusionA human being is a complex adaptive system copingith a social and physical environment but possessingested subsystems. Wounding generates an allostatic re-ponse that involves an ensemble of interdependent ner-ous, endocrine and immune processes. We hypothesizehat these processes comprise a supersystem. Acute painn its multiple dimensions, and related symptoms, areroducts of the supersystem.The social system that encompasses the individual can

lso be a source of stressors. Social stressors can com-ound the allostatic load of a wound or act alone toysregulate the supersystem. When the supersystem suf-ers dysregulation, health, function, and sense of well-eing suffer. We propose that some chronic pain condi-ions and related multisymptom disorders stem fromupersystem dysregulation. Individuals vary and are vul-erable to dysregulation and dysfunction in particularrgan systems due to the unique interactions of genetic,pigenetic and environmental factors, and past experi-
nces that characterize each person.

R

1tkc6

2t

3n

4mh

5tr

6tf

7tnP

8t

9o2

1tC

12

1asR

1b

1omL

1ac

1m

1r1

1t

1i3


2nI2

2cfo2

2nen

2tP

2Jmc

2as

2MCnncB

2J

2lM

2cl1

3cDP

3H

3m

3he

3tt

3d

3Vfr

eferences

. Agelaki S, Tsatsanis C, Gravanis A, Margioris AN: Cortico-ropin-releasing hormone augments proinflammatory cyto-ine production from macrophages in vitro and in lipopolysac-haride-induced endotoxin shock in mice. Infect Immunol 70:068-6074, 2002

. Andersson J: The inflammatory reflex: Introduction. J In-ern Med 257:122-125, 2005

. Anisman H, Merali Z: Cytokines, stress and depressive ill-ess: brain-immune interactions. Ann Med 35:2-11, 2003

. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK: Hu-an brain mechanisms of pain perception and regulation in

ealth and disease. Eur J Pain 9:463-484, 2005

. Arjomand J, Cole S, Evans CJ: Novel orphanin FQ/nocicep-in transcripts are expressed in human immune cells. J Neu-oimmunol 130:100-108, 2002

. Aston-Jones G, Cohen JD: Adaptive gain and the role ofhe locus caeruleus-norepinephrine system in optimal per-ormance. J Comp Neurol 493:99-110, 2005

. Beauchaine T: Vagal tone, development, and Gray’s mo-ivational theory: Toward an integrated model of auto-omic nervous system functioning in psychopathology. Devsychopathol 13:183-214, 2001

. Bedi US, Arora R: Cardiovascular manifestations of post-raumatic stress disorder. J Natl Med Assoc 99:642-649, 2007

. Bella LD, Gualano L: Key Aspects of Melatonin Physiol-gy: Thirty Years of Research. Neuro Endocrinol Lett 27,006

0. Benarroch EE: The central autonomic network: func-ional organization, dysfunction, and perspective. Mayolin Proc 68:988-1001, 1993

1. Benarroch EE: Pain-autonomic interactions. Neurol Sci7(Suppl 2):S130-S133, 2006

2. Berridge CW, Waterhouse BD: The locus coeruleus-nor-drenergic system: modulation of behavioral state andtate-dependent cognitive processes. Brain Res Brain Resev 42:33-84, 2003

3. Besedovsky HO, del Rey A: The cytokine-HPA axis feed-ack circuit. Z Rheumatol 59(Suppl 2):II/26-II/30, 2000

4. Bessler H, Shavit Y, Mayburd E, Smirnov G, Beilin B: Post-perative pain, morphine consumption, and genetic poly-orphism of IL-1beta and IL-1 receptor antagonist. Neurosci

ett 404:154-158, 2006

5. Black PH: Central nervous system-immune system inter-ctions: Psychoneuroendocrinology of stress and its immuneonsequences. Antimicrob Agents Chemother 38:1-6, 1994

6. Blalock JE: The syntax of immune-neuroendocrine com-unication. Immunol Today 15:504-511, 1994

7. Blalock JE: Proopiomelanocortin and the immune-neu-oendocrine connection. Ann N Y Acad Sci 885:161-172,999

8. Blalock JE: The immune system as the sixth sense. J In-ern Med 257:126-138, 2005

9. Blalock JE, Smith EM: Conceptual development of themmune system as a sixth sense. Brain Behav Immunol 21:23-
3, 2007 2
0. Blandino P Jr, Barnum CJ, Deak T: The involvement oforepinephrine and microglia in hypothalamic and splenic

L-1beta responses to stress. J Neuroimmunol 173:87-95,006

1. Bliesener N, Albrecht S, Schwager A, Weckbecker K, Li-htermann D, Klingmuller D: Plasma testosterone and sexualunction in men receiving buprenorphine maintenance forpioid dependence. J Clin Endocrinol Metab 90:203-206,005

2. Borsody MK, Weiss JM: Alteration of locus coeruleuseuronal activity by interleukin-1 and the involvement ofndogenous corticotropin-releasing hormone. Neuroimmu-omodulation 10:101-121, 2002

3. Bracha HS: Can premorbid episodes of diminished vagalone be detected via histological markers in patients withTSD? Int J Psychophysiol 51:127-133, 2004

4. Brandao ML, Troncoso AC, de Souza Silva MA, HustonP: The relevance of neuronal substrates of defense in theidbrain tectum to anxiety and stress: empirical and con-

eptual considerations. Eur J Pharmacol 463:225-233, 2003

5. Brandman O, Ferrell JE Jr, Li R, Meyer T: Interlinked fastnd slow positive feedback loops drive reliable cell deci-ions. Science 310:496-498, 2005

6. Bremner JD, Vythilingam M, Anderson G, Vermetten E,cGlashan T, Heninger G, Rasmusson A, Southwick SM,

harney DS: Assessment of the hypothalamic-pituitary-adre-al axis over a 24-hour diurnal period and in response toeuroendocrine challenges in women with and withouthildhood sexual abuse and posttraumatic stress disorder.iol Psychiatry 54:710-718, 2003

7. Brown TT, Dobs AS: Endocrine effects of marijuana.Clin Pharmacol 42:90S-96S, 2002

8. Bruehl S, Burns JW, McCubbin JA: Altered cardiovascu-ar/pain regulatory relationships in chronic pain. Int J Behav

ed 5:63-75, 1998

9. Burstein R, Dado RJ, Cliffer KD, Giesler GJJ: Physiologicalharacterization of spinohypothalamic tract neurons in theumbar enlargement of rats. J Neurophysiol 66:261-284,991

0. Byers M, Bonica J: Peripheral pain mechanisms and no-iceptor plasticity, in Loeser J, Butler S, Chapman C and Turk(eds). Bonica’s Management of Pain, 3rd ed. Philadelphia,

A, Lippincott Williams & Wilkins, 2001, pp 26-72

1. Cabral GA, Staab A: Effects on the immune system.andb Exp Pharmacol 385-423, 2005

2. Cahalan MD, Gutman GA: The sense of place in the im-une system. Nat Immunol 7:329-332, 2006

3. Calcagni E, Elenkov I: Stress system activity, innate and Telper cytokines, and susceptibility to immune-related dis-ases. Ann N Y Acad Sci 1069:62-76, 2006

4. Ceciliani F, Giordano A, Spagnolo V: The systemic reac-ion during inflammation: The acute-phase proteins. Pro-ein Pept Lett 9:211-223, 2002

5. Copinschi G: Metabolic and endocrine effects of sleepeprivation. Essent Psychopharmacol 6:341-347, 2005

6. Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M:anilloid TRPV1 receptor mediates the antihyperalgesic ef-

ect of the nonpsychoactive cannabinoid, cannabidiol, in aat model of acute inflammation. Br J Pharmacol 143:247-
50, 2004

3C

3s1

3i

4t

4oa

4Hp2

4Cpp4

4A

4vda

4ptG

4Gt

4et1

4sMuc

5Mfp

5Otst

5c

5bs

5A

5I

c7

5tt

5uA

5ts5

5tA

6A

6Cr

6pA

6ta

6v

6ta

6cc

6a(n

6pt(

6c2

7Sta

7aF

7R

7i

7ft


7. Craig AD: Interoception: The Sense of the Physiologicalondition of the Body. Curr Opin Neurobiol 13:500-5, 2003

8. Cravatt BF, Lichtman AH: The endogenous cannabinoidystem and its role in nociceptive behavior. J Neurobiol 61:49-160, 2004

9. Czura CJ, Tracey KJ: Autonomic neural regulation ofmmunity. J Intern Med 257:156-166, 2005

0. Daniell HW: Hypogonadism in men consuming sus-ained-action oral opioids. J Pain 3:377-384, 2002

1. Daniell HW, Lentz R, Mazer NA: Open-label pilot studyf testosterone patch therapy in men with opioid-inducedndrogen deficiency. J Pain 7:200-210, 2006

2. De la Fuente M, Medina S, Del Rio M, Ferrandez MD,ernanz A: Effect of aging on the modulation of macro-hage functions by neuropeptides. Life Sci 67:2125-2135,000

3. deKloet CS, Vermetten E, Geuze E, Kavelaars A, HeijnenJ, Westenberg HG: Assessment of HPA-axis function inosttraumatic stress disorder: Pharmacological and non-harmacological challenge tests, a review. J Psychiatr Res0:550-567, 2005

4. deKloet ER: Hormones and the stressed brain. Ann N Ycad Sci 1018:1-15, 2004

5. deKloet ER, Derijk R: Signaling pathways in brain in-olved in predisposition and pathogenesis of stress-relatedisease: genetic and kinetic factors affecting the MR/GR bal-nce. Ann N Y Acad Sci 1032:14-34, 2004

6. Delgado M, Jonakait GM, Ganea D: Vasoactive intestinaleptide and pituitary adenylate cyclase-activating polypep-ide inhibit chemokine production in activated microglia.lia 39:148-161, 2002

7. Delgado M, Abad C, Martinez C, Juarranz MG, Leceta J,anea D, Gomariz RP: PACAP in immunity and inflamma-

ion. Ann N Y Acad Sci 992:141-157, 2003

8. Delgado M, Gonzalez-Rey E, Ganea D: VIP/PACAP pref-rentially attract Th2 effectors through differential regula-ion of chemokine production by dendritic cells. FASEB J8:1453-1455, 2004

9. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurds-on A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D,ax MB, Makarov SS, Maixner W: Genetic basis for individ-

al variations in pain perception and the development of ahronic pain condition. Hum Mol Genet 14:135-143, 2005

0. Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I,ax MB, Goldman D, Maixner W: Catechol-O-methyltrans-

erase gene polymorphisms are associated with multipleain-evoking stimuli. Pain 125:216-224, 2006

1. Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S,’Mahony L, O’Mahony S, Shanahan F, Keeling PW: Hypo-

halamic-pituitary-gut axis dysregulation in irritable bowelyndrome: Plasma cytokines as a potential biomarker? Gas-roenterology 130:304-311, 2006

2. Dubner R: The neurobiology of persistent pain and itslinical implications. Suppl Clin Neurophysiol 57:3-7, 2004

3. Dunn AJ, Wang J, Ando T: Effects of cytokines on cere-ral neurotransmission: Comparison with the effects oftress. Adv Exp Med Biol 461:117-127, 1999

4. Dunn AJ: Cytokine activation of the HPA axis. Ann N Ycad Sci 917:608-617, 2000

5. Dunn AJ: Effects of the IL-1 receptor antagonist on the
L-1- and endotoxin-induced activation of the HPA axis and 1
erebral biogenic amines in mice. Neuroimmunomodulation:36-45, 2000

6. Dworkin RH, Hetzel RD, Banks SM: Toward a model ofhe pathogenesis of chronic pain. Semin Clin Neuropsychia-ry 4:176-185, 1999

7. Edwards RR, Ness TJ, Weigent DA, Fillingim RB: Individ-al differences in diffuse noxious inhibitory controls (DNIC):ssociation with clinical variables. Pain 106:427-437, 2003

8. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES: The sympa-hetic nerve: An integrative interface between two super-ystems: The brain and the immune system. Pharmacol Rev2:595-638, 2000

9. Elenkov IJ, Chrousos GP: Stress hormones, proinflamma-ory and antiinflammatory cytokines, and autoimmunity.nn N Y Acad Sci 966:290-303, 2002

0. Elenkov IJ: Glucocorticoids and the Th1/Th2 balance.nn N Y Acad Sci 1024:138-146, 2004

1. Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP:ytokine dysregulation, inflammation and well-being. Neu-oimmunomodulation 12:255-269, 2005

2. Eskandari F, Webster JI, Sternberg EM: Neural immuneathways and their connection to inflammatory diseases.rthritis Res Ther 5:251-265, 2003

3. Ferrell JE Jr: Self-perpetuating states in signal transduc-ion: positive feedback, double-negative feedback and bist-bility. Curr Opin Cell Biol 14:140-148, 2002

4. Fetler L, Amigorena S: Neuroscience. Brain under sur-eillance: the microglia patrol. Science 309:392-393, 2005

5. Fiset ME, Gilbert C, Poubelle PE, Pouliot M: Human neu-rophils as a source of nociceptin: A novel link between painnd inflammation. Biochemistry 42:10498-10505, 2003

6. Galati G, Committeri G, Sanes JN, Pizzamiglio L: Spatialoding of visual and somatic sensory information in body-entered coordinates. Eur J Neurosci 14:737-746, 2001

7. Ganea D, Delgado M: Vasoactive intestinal peptide (VIP)nd pituitary adenylate cyclase-activating polypeptidePACAP) as modulators of both innate and adaptive immu-ity. Crit Rev Oral Biol Med 13:229-237, 2002

8. Ganea D, Rodriguez R, Delgado M: Vasoactive intestinaleptide and pituitary adenylate cyclase-activating polypep-ide: Players in innate and adaptive immunity. Cell Mol BiolNoisy-le-grand) 49:127-142, 2003

9. Gjerstad J: Genetic susceptibility and development ofhronic non-malignant back pain. Rev Neurosci 18:83-91,007

0. Glaser R, MacCallum RC, Laskowski BF, Malarkey WB,heridan JF, Kiecolt-Glaser JK: Evidence for a shift in the Th-1o Th-2 cytokine response associated with chronic stress andging. J Gerontol A Biol Sci Med Sci 56:M477-M482, 2001

1. Goetzl EJ, Sreedharan SP: Mediators of communicationnd adaptation in the neuroendocrine and immune systems.ASEB J 6:2646-2652, 1992

2. Gosain A, Gamelli RL: A primer in cytokines. J Burn Careehabil 26:7-12, 2005

3. Goto T, Tanaka T: Tachykinins and tachykinin receptorsn bone. Microsc Res Tech 58:91-97, 2002

4. Gravanis A, Margioris AN: The corticotropin-releasingactor (CRF) family of neuropeptides in inflammation: Po-ential therapeutic applications. Curr Med Chem 12:1503-
512, 2005

7Lsic

7bPt

7acr1

7p6

7Mbp

8Whh2

8da

8sP

8o

8it

8Nn2

8tstr

8Lth

8teA

8abC

9WtC

9Hlg

9ag1

9du

9tn

9Tp

9i

9Smr

9Aon

9bR

1C1

1cce

1tR

1Ivsm

1psh

1w

1em

1Ft

1Gt


5. Grimm MC, Newman R, Hassim Z, Cuan N, Connor SJ,e Y, Wang JM, Oppenheim JJ, Lloyd AR: Cutting edge: Va-oactive intestinal peptide acts as a potent suppressor ofnflammation in vivo by trans-deactivating chemokine re-eptors. J Immunol 171:4990-4994, 2003

6. Grimm V, Revilla E, Berger U, Jeltsch F, Mooij WM, Rails-ack SF, Thulke HH, Weiner J, Wiegand T, DeAngelis DL:attern-oriented modeling of agent-based complex sys-ems: Lessons from ecology. Science 310:987-991, 2005

7. Grinevich V, Fournier A, Pelletier G: Effects of pituitarydenylate cyclase-activating polypeptide (PACAP) on corti-otropin-releasing hormone (CRH) gene expression in theat hypothalamic paraventricular nucleus. Brain Res 773:90-196, 1997

8. Gruys E, Toussaint M, Niewold T, Koopmans S: Acutehase reaction and acute phase proteins. J Zhejiang Univ SCIB:1045-1056, 2005

9. Guasti L, Gaudio G, Zanotta D, Grimoldi P, PetrozzinoR, Tanzi F, Bertolini A, Grandi AM, Venco A: Relationship

etween a genetic predisposition to hypertension, bloodressure levels and pain sensitivity. Pain 82:311-317, 1999

0. Hammack SE, Richey KJ, Schmid MJ, LoPresti ML,atkins LR, Maier SF: The role of corticotropin-releasing

ormone in the dorsal raphe nucleus in mediating the be-avioral consequences of uncontrollable stress. J Neurosci2:1020-1026, 2002

1. Hanley NR, Van de Kar LD: Serotonin and the neuroen-ocrine regulation of the hypothalamic-pituitary-adrenalxis in health and disease. Vitam Horm 66:189-255, 2003

2. Hansson E: Could chronic pain and spread of pain sen-ation be induced and maintained by glial activation? Actahysiol (Oxf) 187:321-327, 2006

3. Harleman JH: The immune system: Multiple sites butne system. Exp Toxicol Pathol 57:359-361, 2006

4. Harris J, Drew LJ, Chapman V: Spinal anandamide inhib-ts nociceptive transmission via cannabinoid receptor activa-ion in vivo. NeuroReport 11:2817-2819, 2000

5. Hassanzadeh P, Ahmadiani A: Nitric oxide and c-Jun-terminal kinase are involved in the development of darkeurons induced by inflammatory pain. Synapse 59:101-106,006

6. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Os-rander MM, Choi DC, Cullinan WE: Central mechanisms oftress integration: Hierarchical circuitry controlling hypo-halamo-pituitary-adrenocortical responsiveness. Front Neu-oendocrinol 24:151-180, 2003

7. Herman JP, Ostrander MM, Mueller NK, Figueiredo H:imbic system mechanisms of stress regulation: Hypo-halamo-pituitary-adrenocortical axis. Prog Neuropsychop-armacol Biol Psychiatry 29:1201-1213, 2005

8. Hollis JH, Lightman SL, Lowry CA: Integration of sys-emic and visceral sensory information by medullary cat-cholaminergic systems during peripheral inflammation.nn N Y Acad Sci 1018:71-75, 2004

9. Hosoi T, Okuma Y, Nomura Y: Electrical stimulation offferent vagus nerve induces IL-1beta expression in therain and activates HPA axis. Am J Physiol Regul Integromp Physiol 279:R141-R147, 2000

0. Hwang CK, Song KY, Kim CS, Choi HS, Guo XH, Law PY,ei LN, Loh HH: Evidence of endogenous mu opioid recep-

or regulation by epigenetic control of the promoters. Mol
ell Biol 27:4720-4736, 2007 3
1. Inoue A, Ikoma K, Morioka N, Kumagai K, Hashimoto T,ide I, Nakata Y: Interleukin-1beta induces substance P re-

ease from primary afferent neurons through the cyclooxy-enase-2 system. J Neurochem 73:2206-2213, 1999

2. Itoi K, Jiang YQ, Iwasaki Y, Watson SJ: Regulatory mech-nisms of corticotropin-releasing hormone and vasopressinene expression in the hypothalamus. J Neuroendocrinol6:348-355, 2004

3. Jedema HP, Grace AA: Corticotropin-releasing hormoneirectly activates noradrenergic neurons of the locus cer-leus recorded in vitro. J Neurosci 24:9703-9713, 2004

4. Ji RR, Kohno T, Moore KA, Woolf CJ: Central sensitiza-ion and LTP: Do pain and memory share similar mecha-isms? Trends Neurosci 26:696-705, 2003

5. Jiang W, Wallace MT, Jiang H, Vaughan JW, Stein BE:wo cortical areas mediate multisensory integration in su-erior colliculus neurons. J Neurophysiol 85:506-522, 2001

6. Joos GF, Germonpre PR, Pauwels RA: Role of tachykininsn asthma. Allergy 55:321-337, 2000

7. Jorgensen H, Knigge U, Kjaer A, Moller M, Warberg J:erotonergic stimulation of corticotropin-releasing hor-one and pro-opiomelanocortin gene expression. J Neu-

oendocrinol 14:788-795, 2002

8. Joseph J, Niggemann B, Zaenker KS, Entschladen F:nandamide is an endogenous inhibitor for the migrationf tumor cells and T-lymphocytes. Cancer Immunol Immu-other 53:723-728, 2004

9. Kalra PS, Dube MG, Kalra SP: The effects of interleukin 1eta on the hypothalamic tachykinin, neurokinin A. Braines 662:178-184, 1994

00. Karalis K, Muglia LJ, Bae D, Hilderbrand H, Majzoub JA:RH and the immune system. J Neuroimmunol 72:131-136,997

01. Kessler W, Kirchhoff C, Reeh PW, Handwerker HO: Ex-itation of cutaneous afferent nerve endings in vitro by aombination of inflammatory mediators and conditioningffect of substance P. Exp Brain Res 91:467-476, 1992

02. Kidd P: Th1/Th2 balance: The hypothesis, its limita-ions, and implications for health and disease. Altern Medev 8:223-246, 2003

03. Kim H, Neubert JK, San Miguel A, Xu K, Krishnaraju RK,adarola MJ, Goldman D, Dionne RA: Genetic influence onariability in human acute experimental pain sensitivity as-ociated with gender, ethnicity and psychological tempera-ent. Pain 109:488-496, 2004

04. Kim H, Lee H, Rowan J, Brahim J, Dionne RA: Geneticolymorphisms in monoamine neurotransmitter systemshow only weak association with acute post-surgical pain inumans. Mol Pain 2:24, 2006

05. Kin NW, Sanders VM: It takes nerve to tell T and B cellshat to do. J Leukoc Biol 79:1093-1104, 2006

06. Kinhult J, Egesten A, Uddman R, Cardell LO: PACAPnhances the expression of CD11b, CD66b and CD63 in hu-an neutrophils. Peptides 23:1735-1739, 2002

07. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L,riedman H: The cannabinoid system and immune modula-ion. J Leukoc Biol 74:486-496, 2003

08. Kodali S, Friedman I, Ding W, Seiffert K, Wagner JA,ranstein RD: Pituitary adenylate cyclase-activating polypep-

ide inhibits cutaneous immune function. Eur J Immunol 33:
070-3079, 2003

1Mr

1t

1DoN

1gas

1r2

1Pgi

1h2

1RC

1hci

1i2

1o

1b1

1rn4

1o2

1a

1oN

1m2

1s

1f2

1t

1sfD

1Dsm

1Dme

1aMCa3

1tt

1tb

1v

1t

1PtiE

1tC

1Mii9

1n

1mc

1p2

1DJmh2

1M2

1d


09. Kodounis A, Stamboulis E, Constantinidis TS, Liolios A:easurement of autonomic dysregulation in multiple scle-

osis. Acta Neurol Scand 112:403-408, 2005

10. Kohl J: The role of complement in danger sensing andransmission. Immunol Res 34:157-176, 2006

11. Korte SM, Koolhaas JM, Wingfield JC, McEwen BS: Thearwinian concept of stress: Benefits of allostasis and costsf allostatic load and the trade-offs in health and disease.eurosci Biobehav Rev 29:3-38, 2005

12. Kulkarni-Narla A, Beitz AJ, Brown DR: Catecholaminer-ic, cholinergic and peptidergic innervation of gut-associ-ted lymphoid tissue in porcine jejunum and ileum. Cell Tis-ue Res 298:275-286, 1999

13. Lambrecht BN: Immunologists getting nervous: neu-opeptides, dendritic cells and T-cell activation. Respir Res:133-138, 2001

14. Lazarus GS, Cooper DM, Knighton DR, Margolis DJ,ecoraro RE, Rodeheaver G, Robson MC: Definitions anduidelines for assessment of wounds and evaluation of heal-

ng. Arch Dermatol 130:489-493, 1994

15. Le Bars D: The whole body receptive field of dorsalorn multireceptive neurones. Brain Res Brain Res Rev 40:9-44, 2002

16. Ledberg A, Bressler SL, Ding M, Coppola R, Nakamura: Large-scale visuomotor integration in the cerebral cortex.ereb Cortex 17:44-62, 2006

17. Ledeboer A, Sloane EM, Milligan ED, Frank MG, Ma-ony JH, Maier SF, Watkins LR: Minocycline attenuates me-hanical allodynia and proinflammatory cytokine expressionn rat models of pain facilitation. Pain 115:71-83, 2005

18. Leonard BE: The HPA and immune axes in stress: Thenvolvement of the serotonergic system. Eur Psychiatry0(Suppl 3):S302-S306, 2005

19. Likhtik E, Pelletier JG, Paz R, Pare D: Prefrontal controlf the amygdala. J Neurosci 25:7429-7437, 2005

20. Lin YS, Lee LY: Stimulation of pulmonary vagal C-fibresy anandamide in anaesthetized rats: Role of vanilloid typereceptors. J Physiol 539:947-955, 2002

21. Maes M, Kenis G, Kubera M: In humans, corticotropineleasing hormone antagonizes some of the negative immu-oregulatory effects of serotonin. Neuro Endocrinol Lett 24:20-424, 2003

22. Maestroni GJ: Sympathetic nervous system influencen the innate immune response. Ann N Y Acad Sci 1069:195-07, 2006

23. Maggi CA: The effects of tachykinins on inflammatorynd immune cells. Regul Pept 70:75-90, 1997

24. Maier SF, Goehler LE, Fleshner M, Watkins LR: The rolef the vagus nerve in cytokine-to-brain communication. AnnY Acad Sci 840:289-300, 1998

25. Marchand F, Perretti M, McMahon SB: Role of the im-une system in chronic pain. Nat Rev Neurosci 6:521-532,

005

26. Marriott I: The role of tachykinins in central nervousystem inflammatory responses. Front Biosci 9:2153-65, 2004

27. McEwen BS: Allostasis and allostatic load: Implicationsor neuropsychopharmacology. Neuropsychopharmacology2:108-124, 2000

28. McEwen BS: The End of Stress as We Know It. Washing-
on, DC, Joseph Henry Press, 2002 c
29. Meaney MJ, Szyf M: Environmental programming oftress responses through DNA methylation: Life at the inter-ace between a dynamic environment and a fixed genome.ialogues Clin Neurosci 7:103-123, 2005

30. Merali Z, Michaud D, McIntosh J, Kent P, Anisman H:ifferential involvement of amygdaloid CRH system(s) in the

alience and valence of the stimuli. Prog Neuropsychophar-acol Biol Psychiatry 27:1201-1212, 2003

31. Merali Z, Khan S, Michaud DS, Shippy SA, Anisman H:oes amygdaloid corticotropin-releasing hormone (CRH)ediate anxiety-like behaviors? Dissociation of anxiogenic

ffects and CRH release. Eur J Neurosci 20:229-239, 2004

32. Meunier JC, Mollereau C, Toll L, Suaudeau C, Mois-nd C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P,onsarrat B, Mazarguil H, Vassart G, Parmentier M,

ostentin J: Isolation and structure of the endogenousgonist of opioid receptor-like ORL1 receptor. Nature77:532-535, 1995

33. Mignini F, Streccioni V, Amenta F: Autonomic innerva-ion of immune organs and neuroimmune modulation. Au-on Autacoid Pharmacol 23:1-25, 2003

34. Miksa M, Wu R, Zhou M, Wang P: Sympathetic excito-oxicity in sepsis: Pro-inflammatory priming of macrophagesy norepinephrine. Front Biosci 10:2217-2229, 2005

35. Millan MJ: The induction of pain: An integrative re-iew. Prog Neurobiol 57:1-164, 1999

36. Miller DB, O’Callaghan JP: Neuroendocrine aspects ofhe response to stress. Metabolism 51:5-10, 2002

37. Milligan E, Zapata V, Schoeniger D, Chacur M, Green P,oole S, Martin D, Maier SF, Watkins LR: An initial investiga-ion of spinal mechanisms underlying pain enhancementnduced by fractalkine, a neuronally released chemokine.ur J Neurosci 22:2775-2782, 2005

38. Millington GW: Proopiomelanocortin (POMC): The cu-aneous roles of its melanocortin products and receptors.lin Exp Dermatol 31:407-412, 2006

39. Miranda C, Selleri S, Pierotti MA, Greco A: The581V mutation, associated with a mild form of congen-

tal insensitivity to pain with anhidrosis, causes partialnactivation of the NTRK1 receptor. J Invest Dermatol 119:78-979, 2002

40. Misslin R: The defense system of fear: Behavior andeurocircuitry. Neurophysiol Clin 33:55-66, 2003

41. Moffitt TE, Caspi A, Rutter M: Measured gene-environ-ent interactions in psychopathology. Perspectives on Psy-

hological Science 1:5-27, 2006

42. Mueller DL: Tuning the immune system: Competingositive and negative feedback loops. Nat Immunol 4:210-11, 2003

43. Muller MB, Zimmermann S, Sillaber I, Hagemeyer TP,eussing JM, Timpl P, Kormann MS, Droste SK, Kuhn R, Reul

M, Holsboer F, Wurst W: Limbic corticotropin-releasing hor-one receptor 1 mediates anxiety-related behavior andormonal adaptation to stress. Nat Neurosci 6:1100-1107,003

44. Nagy A, Eordegh G, Paroczy Z, Markus Z, Benedek G:ultisensory integration in the basal ganglia. Eur J Neurosci

4:917-924, 2006

45. Neumeister A, Daher RJ, Charney DS: Anxiety disor-ers: Noradrenergic neurotransmission. Handb Exp Pharma-
ol 2005:205-223, 2005

1ri

1lS

1m

1n

1L

1pieA

1Fg

1m

1mT

1v

1m1

1a

1mtd

1tp1

1n1

1cp

1tnp

1tc

1pd1

1i

tl

1BgO

1Jtc1

1r1

1k9

1cP

1Mp

1RmA

1Mgip

1Ttv2

1da

1J

1e1

1E

1a

1Joea

1ecJ

1h


46. Nussdorfer GG, Malendowicz LK: Role of VIP, PACAP, andelated peptides in the regulation of the hypothalamo-pitu-tary-adrenal axis. Peptides 19:1443-1467, 1998

47. Pacak K: Stressor-specific activation of the hypotha-amic-pituitary-adrenocortical axis. Physiol Res 49(Suppl 1):11-S17, 2000

48. Padgett DA, Glaser R: How stress influences the im-une response. Trends Immunol 24:444-448, 2003

49. Pare D, Quirk GJ, Ledoux JE: New vistas on amygdalaetworks in conditioned fear. J Neurophysiol 92:1-9, 2004

50. Parkin J, Cohen B: An overview of the immune system.ancet 357:1777-1789, 2001

51. Patwardhan AM, Jeske NA, Price TJ, Gamper N, Ako-ian AN, Hargreaves KM: The cannabinoid WIN 55,212-2

nhibits transient receptor potential vanilloid 1 (TRPV1) andvokes peripheral antihyperalgesia via calcineurin. Proc Natlcad Sci U S A 103:11393-11398, 2006

52. Pennefather JN, Lecci A, Candenas ML, Patak E, PintoM, Maggi CA: Tachykinins and tachykinin receptors: Arowing family. Life Sci 74:1445-1463, 2004

53. Pezet S, McMahon SB: Neurotrophins: Mediators andodulators of pain. Annu Rev Neurosci 29:507-538, 2006

54. Pinter E, Helyes Z, Szolcsanyi J: Inhibitory effect of so-atostatin on inflammation and nociception. Pharmacol

her 112:440-456, 2006

55. Porges SW: Vagal tone: A physiologic marker of stressulnerability. Pediatrics 90:498-504, 1992

56. Pozo D, Delgado M: The many faces of VIP in neuroim-unology: A cytokine rather a neuropeptide? FASEB J 18:

325-1334, 2004

57. Price DD: Psychological and neural mechanisms of theffective dimension of pain. Science 288:1769-1772, 2000

58. Raffin-Sanson ML, de Keyzer Y, Bertagna X: Proopio-elanocortin, a polypeptide precursor with multiple func-

ions: From physiology to pathological conditions. Eur J En-ocrinol 149:79-90, 2003

59. Raison CL, Miller AH: When not enough is too much:he role of insufficient glucocorticoid signaling in the patho-hysiology of stress-related disorders. Am J Psychiatry 160:554-1565, 2003

60. Ralevic V: Cannabinoid modulation of peripheral auto-omic and sensory neurotransmission. Eur J Pharmacol 472:-21, 2003

61. Rashid S, Lewis GF: The mechanisms of differential glu-ocorticoid and mineralocorticoid action in the brain anderipheral tissues. Clin Biochem 38:401-409, 2005

62. Rasmussen DD, Marck BT, Boldt BM, Yellon SM, Ma-sumoto AM: Suppression of hypothalamic pro-opiomela-ocortin (POMC) gene expression by daily melatonin sup-lementation in aging rats. J Pineal Res 34:127-133, 2003

63. Rassnick S, Sved AF, Rabin BS: Locus coeruleus stimula-ion by corticotropin-releasing hormone suppresses in vitroellular immune responses. J Neurosci 14:6033-6040, 1994

64. Reiche EM, Morimoto HK, Nunes SM: Stress and de-ression-induced immune dysfunction: Implications for theevelopment and progression of cancer. Int Rev Psychiatry7:515-527, 2005

65. Reubi JC, Horisberger U, Kappeler A, Laissue JA: Local-
zation of receptors for vasoactive intestinal peptide, soma- n
ostatin, and substance P in distinct compartments of humanymphoid organs. Blood 92:191-197, 1998

66. Reyes-Gibby CC, Shete S, Rakvag T, Bhat SV, Skorpen F,ruera E, Kaasa S, Klepstad P: Exploring joint effects ofenes and the clinical efficacy of morphine for cancer pain:PRM1 and COMT gene. Pain 130:25-30, 2007

67. Ribeiro SC, Kennedy SE, Smith YR, Stohler CS, ZubietaK: Interface of physical and emotional stress regulationhrough the endogenous opioid system and mu-opioid re-eptors. Prog Neuropsychopharmacol Biol Psychiatry 29:264-1280, 2005

68. Rittner HL, Machelska H, Stein C: Leukocytes in theegulation of pain and analgesia. J Leukoc Biol 78:1215-222, 2005

69. Rittner HL, Stein C: Involvement of cytokines, chemo-ines and adhesion molecules in opioid analgesia. Eur J Pain:109-112, 2005

70. Rivest S: How circulating cytokines trigger the neuralircuits that control the hypothalamic-pituitary-adrenal axis.sychoneuroendocrinology 26:761-788, 2001

71. Robinson DA, Calejesan AA, Wei F, Gebhart GF, Zhuo: Endogenous facilitation: from molecular mechanisms to

ersistent pain. Curr Neurovasc Res 1:11-20, 2004

72. Robison CL, Meyerhoff JL, Saviolakis GA, Chen WK,ice KC, Lumley LA: A CRH1 antagonist into the amygdala ofice prevents defeat-induced defensive behavior. Ann N Ycad Sci 1032:324-328, 2004

73. Rode F, Thomsen M, Brolos T, Jensen DG, Blackburn-unro G, Bjerrum OJ: The importance of genetic back-

round on pain behaviours and pharmacological sensitivityn the rat spared serve injury model of peripheral neuro-athic pain. Eur J Pharmacol 564:103-111, 2007

74. Romeo HE, Tio DL, Rahman SU, Chiappelli F, Taylor AN:he glossopharyngeal nerve as a novel pathway in immune-o-brain communication: relevance to neuroimmune sur-eillance of the oral cavity. J Neuroimmunol 115:91-100,001

75. Rosen JB: The neurobiology of conditioned and uncon-itioned fear: A neurobehavioral system analysis of themygdala. Behav Cogn Neurosci Rev 3:23-41, 2004

76. Ross FP, Christiano AM: Nothing but skin and bone.Clin Invest 116:1140-1149, 2006

77. Sandkuhler J: The organization and function of endog-nous antinociceptive systems. Prog Neurobiol 50:49-81,996

78. Schafer M: Cytokines and peripheral analgesia. Advxp Med Biol 521:40-50, 2003

79. Selye H: A syndrome produced by diverse nocuousgents. Nature (London) 138:32, 1936

80. Seres J, Herichova I, Roman O, Bornstein S, Jurcovicova: Evidence for daily rhythms of the expression of pro-opi-melanocortin, interleukin-1-beta and interleukin-6 in ad-nopituitaries of male long-evans rats: Effect of adjuvantrthritis. Neuroimmunomodulation 11:316-322, 2004

81. Serhan CN, Fierro IM, Chiang N, Pouliot M: Cuttingdge: Nociceptin stimulates neutrophil chemotaxis and re-ruitment: Inhibition by aspirin-triggered-15-epi-lipoxin A4.Immunol 166:3650-3654, 2001

82. Siau C, Bennett GJ: Dysregulation of cellular calciumomeostasis in chemotherapy-evoked painful peripheral
europathy. Anesth Analg 102:1485-1490, 2006

1vTs

1ma

1me2

1tnc2

1ih

1Ap9

1Oa

1ge

1m

1(P

1rl

1cpp

1tr

1uBp

1tr

1as

1vdn1

2R

i2

2p

28

2i

2a8

2d2

2po

2eSt

2t4

2nrir7

2i2

2cs

2Sllf

2D

2t

2gm

2cU

2nl

2m2

2


83. Siegelaar SE, Olff M, Bour LJ, Veelo D, Zwinderman AH,an Bruggen G, de Vries GJ, Raabe S, Cupido C, Koelman JH,ijssen MA: The auditory startle response in post-traumatictress disorder. Exp Brain Res 174:1-6, 2006

84. Silverman MN, Pearce BD, Biron CA, Miller AH: Immuneodulation of the hypothalamic-pituitary-adrenal (HPA)

xis during viral infection. Viral Immunol 18:41-78, 2005

85. Sinclair SK, Lea RG, Rees WD, Young LE: The develop-ental origins of health and disease: Current theories and

pigenetic mechanisms. Soc Reprod Fertil Suppl 64:425-443,007

86. Singh Tahim A, Santha P, Nagy I: Inflammatory media-ors convert anandamide into a potent activator of the va-illoid type 1 transient receptor potential receptor in noci-eptive primary sensory neurons. Neuroscience 136:539-548,005

87. Staines DR: Postulated vasoactive neuropeptide auto-mmunity in fatigue-related conditions: A brief review andypothesis. Clin Dev Immunol 13:25-39, 2006

88. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD:bnormal sensitization and temporal summation of secondain (wind-up) in patients with fibromyalgia syndrome. Pain1:165-175, 2001

89. Stefanova I, Dorfman JR, Tsukamoto M, Germain RN:n the role of self-recognition in T-cell responses to foreignntigen. Immunol Rev 191:97-106, 2003

90. Stein BE, Wallace MW, Stanford TR, Jiang W: Cortexoverns multisensory integration in the midbrain. Neurosci-ntist 8:306-314, 2002

91. Steinman L: Elaborate interactions between the im-une and nervous systems. Nat Immunol 5:575-581, 2004

92. Stone EA: Stress and catecholamines, in Friedhoff AJed). Catecholamines and Behavior. Vol 2. New York, NY,lenum Press, 1975, pp 31-72

93. Sung CP, Arleth AJ, Feuerstein GZ: Neuropeptide Y up-egulates the adhesiveness of human endothelial cells foreukocytes. Circ Res 68:314-318, 1991

94. Svensson TH: Peripheral, autonomic regulation of lo-us coeruleus noradrenergic neurons in brain: putative im-lications for psychiatry and psychopharmacology. Psycho-harmacology 92:1-7, 1987

95. ten Bokum AM, Hofland LJ, van Hagen PM: Somatosta-in and somatostatin receptors in the immune system: Aeview. Eur Cytokine Netw 11:161-176, 2000

96. Terman G, Bonica J: Spinal mechanisms and their mod-lation, in Loeser J, Butler S, Chapman C and Turk D (eds).onica’s Management of Pain, 3rd ed. Philadelphia, PA, Lip-incott Williams & Wilkins, 2001, pp 73-132

97. Thayer JF, Brosschot JF: Psychosomatics and psychopa-hology: Looking up and down from the brain. Psychoneu-oendocrinology 30:1050-1058, 2005

98. Tiippana E, Nilsson E, Kalso E: Post-thoracotomy painfter thoracic epidural analgesia: A prospective follow-uptudy. Acta Anaesthesiol Scand 47:433-438, 2003

99. Tognetto M, Amadesi S, Harrison S, Creminon C, Tre-isani M, Carreras M, Matera M, Geppetti P, Bianchi A: Anan-amide excites central terminals of dorsal root ganglioneurons via vanilloid receptor-1 activation. J Neurosci 21:104-1109, 2001

00. Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon
S, Matthews PM: Imaging attentional modulation of pain b
n the periaqueductal gray in humans. J Neurosci2:2748-2752, 2002

01. Tracey I, Mantyh PW: The cerebral signature for painerception and its modulation. Neuron 55:377-391, 2007

02. Tracey KJ: The inflammatory reflex. Nature 420:853-59, 2002

03. Travis EL: Genetic susceptibility to late normal tissuenjury. Semin Radiat Oncol 17:149-155, 2007

04. Tsigos C, Chrousos GP: Hypothalamic-pituitary-adrenalxis, neuroendocrine factors and stress. J Psychosom Res 53:65-871, 2002

05. Turk DC: A diathesis-stress model of chronic pain andisability following traumatic injury. Pain Res Manag 7:9-19,002

06. Turnbull AV, Rivier CL: Regulation of the hypothalamic-ituitary-adrenal axis by cytokines: Actions and mechanismsf action. Physiol Rev 79:1-71, 1999

07. van Hagen PM, Hofland LJ, ten Bokum AM, Licht-nauer-Kaligis EG, Kwekkeboom DJ, Ferone D, LambertsW: Neuropeptides and their receptors in the immune sys-em. Ann Med 31(Suppl 2):15-22, 1999

08. Vanegas H, Schaible HG: Descending control of persis-ent pain: inhibitory or facilitatory? Brain Res Brain Res Rev6:295-309, 2004

09. Viveros-Paredes JM, Puebla-Perez AM, Gutierrez-Coro-ado O, Sandoval-Ramirez L, Villasenor-Garcia MM: Dys-egulation of the Th1/Th2 cytokine profile is associated withmmunosuppression induced by hypothalamic-pituitary-ad-enal axis activation in mice. Int Immunopharmacol 6:774-81, 2006

10. Vizi ES, Elenkov IJ: Nonsynaptic noradrenaline releasen neuro-immune responses. Acta Biol Hung 53:229-244,002

11. Vogeser M, Groetzner J, Kupper C, Briegel J: The serumortisol:cortisone ratio in the postoperative acute-phase re-ponse. Horm Res 59:293-296, 2003

12. von Horsten S, Ballof J, Helfritz F, Nave H, Meyer D,chmidt RE, Stalp M, Klemm A, Tschernig T, Pabst R: Modu-ation of innate immune functions by intracerebroventricu-arly applied neuropeptide Y: Dose and time dependent ef-ects. Life Sci 63:909-922, 1998

13. Wallengren J: Vasoactive peptides in the skin. J Investermatol Symp Proc 2:49-55, 1997

14. Walter L, Stella N: Cannabinoids and neuroinflamma-ion. Br J Pharmacol 141:775-785, 2004

15. Wang F, Millet I, Bottomly K, Vignery A: Calcitoninene-related peptide inhibits interleukin 2 production byurine T-lymphocytes. J Biol Chem 267:21052-21057, 1992

16. Watkins LR, Maier SF: Implications of immune-to-brainommunication for sickness and pain. Proc Natl Acad Sci

S A 96:7710-7713, 1999

17. Watkins LR, Maier SF: Immune regulation of centralervous system functions: From sickness responses to patho-

ogical pain. J Intern Med 257:139-155, 2005

18. Weber KT: A neuroendocrine-immune interface: The im-unostimulatory state of aldosteronism. Herz 28:692-701,

003

19. Weidenfeld J, Feldman S, Mechoulam R: Effect of the
rain constituent anandamide, a cannabinoid receptor ag-

oN

2baN

2pN

2e1

2hiI

2a

2

bPI

2fl1

2li1

2a

2Cpf

2n


nist, on the hypothalamo-pituitary-adrenal axis in the rat.euroendocrinology 59:110-112, 1994

20. Wenger T, Ledent C, Tramu G: The endogenous canna-inoid, anandamide, activates the hypothalamo-pituitary-drenal axis in CB1 cannabinoid receptor knockout mice.euroendocrinology 78:294-300, 2003

21. Westland K: Neurophysiology of nociception, in Pap-agallo M (ed). The Neurological Basis of Pain. New York,Y, The McGraw-Hill Companies, Inc, 2005, pp 3-19

22. Whitelaw NC, Whitelaw E: How lifetimes shape epig-notype within and across generations. Hum Mol Genet5(Spec No 2):R131-R137, 2006

23. Wieczorek M, Dunn AJ: Relationships among the be-avioral, noradrenergic, and pituitary-adrenal responses to

nterleukin-1 and the effects of indomethacin. Brain Behavmmun 20:477-487, 2005

24. Wieseler-Frank J, Maier SF, Watkins LR: Glial activationnd pathological pain. Neurochem Int 45:389-395, 2004

25. Wieseler-Frank J, Maier SF, Watkins LR: Immune-to- i

rain communication dynamically modulates pain:hysiological and pathological consequences. Brain Behav

mmun 19:104-111, 2005

26. Wieseler-Frank J, Maier SF, Watkins LR: Central proin-ammatory cytokines and pain enhancement. Neurosignals4:166-174, 2005

27. Xu Y, Day TA, Buller KM: The central amygdala modu-ates hypothalamic-pituitary-adrenal axis responses to systemicnterleukin-1beta administration. Neuroscience 94:175-183,999

28. Zhang JH, Huang YG: The immune system: A new lookt pain. Chin Med J (Engl) 119:930-938, 2006

29. Zhang TY, Bagot R, Parent C, Nesbitt C, Bredy TW,aldji C, Fish E, Anisman H, Szyf M, Meaney MJ: Maternalrogramming of defensive responses through sustained ef-ects on gene expression. Biol Psychol 73:72-89, 2006

30. Zukowska Z, Pons J, Lee EW, Li L: Neuropeptide Y: Aew mediator linking sympathetic nerves, blood vessels and

mmune system? Can J Physiol Pharmacol 81:89-94, 2003

Documents

Focus Article · mitters, peptides, endocannabinoids, cytokines, and hormones, an ensemble of interdependent nervous, endocrine, and immune processes operates in concert to cope with