Neurotherapeutics Cannabis Review

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Cannabinoids as Pharmacotherapies for Neuropathic Pain:From the Bench to the Bedside

Elizabeth J. Rahn and Andrea G. Hohmann

Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, Georgia 30602

Summary: Neuropathic pain is a debilitating form of chronicpain resulting from nerve injury, disease states, or toxic insults.Neuropathic pain is often refractory to conventional pharma-cotherapies, necessitating validation of novel analgesics. Can-nabinoids, drugs that share the same target as 9 -tetrahydro-cannabinol ( 9 -THC), the psychoactive ingredient in cannabis,have the potential to address this unmet need. Here, we reviewstudies evaluating cannabinoids for neuropathic pain manage-ment in the clinical and preclinical literature. Neuropathic painassociated with nerve injury, diabetes, chemotherapeutic treat-ment, human immunodeciency virus, multiple sclerosis, andherpes zoster infection is considered. In animals, cannabinoidsattenuate neuropathic nociception produced by traumatic nerveinjury, disease, and toxic insults. Effects of mixed cannabinoidCB 1 /CB 2 agonists, CB 2 selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or

degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoiddegradation on neuropathic nociception are described. Specicforms of allodynia and hyperalgesia modulated by cannabi-noids are also considered. In humans, effects of smoked mar-ijuana, synthetic 9 -THC analogs (e.g., Marinol, Cesamet) andmedicinal cannabis preparations containing both 9 -THC andcannabidiol (e.g., Sativex, Cannador) in neuropathic pain statesare reviewed. Clinical studies largely afrm that neuropathicpain patients derive benets from cannabinoid treatment.Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered.Finally, limitations of cannabinoid pharmacotherapies arediscussed together with directions for future research. KeyWords: Endocannabinoid, marijuana, neuropathy, multiplesclerosis, chemotherapy, diabetes.

NEUROPATHIC PAIN

Neuropathic pain is a debilitating form of treatment-resistant chronic pain caused by damage to the nervoussystem. Neuropathic pain may result from peripheralnerve injury, toxic insults, and disease states. Neuro-pathic pain remains a signicant clinical problem be-cause it responds poorly to available therapies. More-over, adverse side effect proles may limit therapeuticdosing and contribute to inadequate pain relief. Drugdiscovery efforts have consequently been directed to-ward identifying novel analgesic targets for drug devel-opment. This review will evaluate the efcacy of canna-binoids as analgesics for the treatment of neuropathicpain from the bench to the bedside.

CANNABINOID RECEPTOR PHARMACOLOGY

Evidence for the use of Cannabis sativa as a treatmentfor pain can be traced back to the beginnings of recordedhistory. The discovery by Gaoni and Mechoulam 1 of 9 -tetrahydrocannabinol ( 9 -THC), the primary psychoactiveingredient in cannabis, set the stage for the identication of an endogenous cannabinoid (endocannabinoid) transmittersystem in the brain. The endocannabinoid signaling systemincludes cannabinoid receptors (e.g., CB

1and CB

2), their

endogenous ligands (e.g., anandamide and 2-arachido-noylglycerol), and the synthetic and hydrolytic enzymesthat control the bioavailability of the endocannabinoids.Both CB 1

2 and CB 23 receptors are G-coupled protein

receptors that are negatively coupled to adenylate cy-clase. Activation of CB 1 receptors suppresses calciumconductance and inhibits inward rectifying potassiumconductance, thereby suppressing neuronal excitabilityand transmitter release. CB 2 receptor activation stimu-lates MAPK activity but does not modulate calcium orpotassium conductances. 4 The development of CB 1

5 and

CB 26

receptor knockout mice has helped elucidate the

Address correspondence and reprint requests to: Andrea G. Hohm-ann, Neuroscience and Behavior Program, Department of Psychology,Universi ty of Georgia, Athens, GA 30602-3013. E-mail: [email protected] .

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physiological roles of cannabinoid receptors in the ner-vous system. Generation of CB 1

/ mice that lack CB 1receptors in nociceptive neurons in the peripheral ner-vous system while retaining CNS expression (SNS-CB 1 ) has also docume nted a role for these receptors incontrolling nociception. 7

CB 1 and CB2 receptors exhibit disparate anatomicaldistributions. 3 CB 1 receptors are localized to the CNSand the periphery. CB 1 receptors are found in sites as-sociated wi th pain processing, including t he periaque -ductal gray, 8 rostral ventro me dial medul la,8 thalamus ,9

dorsal root ganglia (DRG), 10 amygdala, 8 and cortex. 8

Densities of CB 1 receptors are low in brainstem sitescritical for controlling heart rate and respiration. Thisdistribution explains the low toxicity and absence of lethality after marijuana intoxication. Activation of theCB 1 receptor also results in hyp othermia, sedation, cat-alepsy, and altered mental status. 11 Thus, it is critical for

any cannabinoid-based pharmacotherapy targeting CB 1receptors to balance clinically relevant therapeutic ef-fects with unwanted side effects. The CB 2 receptor wasoriginally believed to be restricted to th e periphery, pri-marily to immune cells (e.g., mast cells). 12 They may bepresent neuronally in some species. Th e CB 2 recept orprotein h as been reported in t he DRG, 13 brain stem, 14

thalamus, 15 periaqueductal gray, 15 and cerebellum 15,16 of naive rats. CB 2 receptor levels in most CNS sites arepresent at only low levels under basal conditions (or arebelow the threshold for detection). However, an upregu-lation of CB 2 receptor immunoreactivity or mRNA is

observed in sites implicated in nocice ptive processingunder conditions of induced neuropathy. 17,18 CB 2 recep-tors are localized to microglia, a resident population of macrophages within the CNS that are functionally andanatomically similar to mast cells. Microglia secrete pro-inammatory factors and induce the release of severalmediators (e.g., nitric oxide, neurotrophins, free radicals)that are associated with synaptogenesis and plasticity,leading to changes in neuronal excitability.

ENDOCANNABINOIDS

The rst endogenous ligand for cannabinoid recep-tors 19 was named anandamide (AEA) after the sankritword for bliss. Several other end ocan nabinoids incl uding2-arachydo noylglycerol (2-AG), 20,21 noladi n ether, 22 vi-rodhamine, 23 and N-arachidonoly-dopamine 24 have beendescribed. Fatty-acid amide hydrolase (FAAH) is theprinciple catabolic enzyme for fatty-acid amides includ-ing AEA and N -palmitoylethanolamine (PEA). 25 PEAdoes not bind cannabinoid receptors and has recentlybeen described as an endogenous ligand for peroxisomeproliferator receptor- (PPAR- ).26 PEA may indirectlyalter levels of endocannabinoids by competing withanandamide and other fatty-acid amides for degradation

by FAAH or by suppressing FAAH expression at thetranscriptional level. 27,28 FAAH / mice are hypoalge-sic in models of acute and inammatory pain; theseeffects are blocked by a CB 1 antagonist.

29,30 This basalhypoalgesia is absent in FAAH / mice subjected tonerve injury, where genotype differences in evoked neu-ropathic pain behaviors are not apparent. 30

Anandamide also acts as an endovanalloid at thetransient receptor potential cation channel (TRPV1)receptor. 31 AEA shows afnity for TRPV1 that is 5- to20-fold lower than its afnity for CB 1 . TRPV1 is notactivated by classical, nonclassical, or aminoalkylin-dole cannabinoid agonists. AEA can also activate theperoxisome proliferator receptor- (PPAR ) recep-tor. 32 Thus, not all effects of AEA are mediated bycannabinoid receptors.

The metabolic pathways responsible for endocannabi-noid degradation are well-characterized. Several FAAHinhibitors (e.g., OL135, URB597) have been developedand used to investigate physiological effects of in-creasing accumulation of AEA and other fatty-acidamides. Monoacylglycerol lipase (MGL) is a key en-zyme implicated in the hydrolysis of 2-AG. 33,34 MGLinhibitors (e.g., URB602, JZL184) have been devel-oped and can be used to selectively increase accumu-lation of this endocannabinoid. The endocannabinoidsystem has complex relationships with other metabolicpathways. Both AEA and 2-AG can be metabolized bycyclooxygenase-2, a phenomenon that may contributeto the antinociceptive properties of nonsteroidal anti-inammatory drugs that act through inhibition of cy-clooxygenase-2. 4 Table 1 provides a summary of can-nabinoids and related compounds that have beenevaluated for efcacy in preclinical and clinical stud-ies of neuropathic pain.

CANNABINOID MODULATION OFNEUROPATHIC NOCICEPTION IN

ANIMAL MODELS

W. E. Dixon 35 was the rst scientist to systematically

study the antinociceptive properties of Cannabis sativa .Dixon 35 reported that cannabis smoke delivered to dogsattenuated their responsiveness to pin pricks. He ob-served that normally evil-tempered and savage dogsbecame docile and affectionate after exposure to can-nabis, reecting the psychotropic and mood-altering ef-fects of cannabinoids. Motor effects observed after highdoses of cannabinoids included drowsiness, awkwardgate, and ataxia. Work by Walkers group subsequentlydemonstrated that cannabi noids suppress nociceptivetransmission (for review see 36 ). Early observations of theantinociceptive properties of cannabinoids laid a founda-tion for future research examining the impact of canna-

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binoids and modulation of the endocannabinoid systemon neuropathic pain.

Models of surgically-induced traumatic nerve injuryCannabinoids suppress neuropathic nociception in at

least nine different animal models of surgically-inducedtraumatic nerve or nervous system injury. Here, we re-

view the literature with a focus on uncovering effects of

different classes of cannabinoids on both neuropathicnociception and central sensitization in each model. Wealso consider the impact of nerve injury on the endocan-nabinoid signaling system. Where applicable, we revieweffects of neuropathic injury on levels of endocannabi-noids and related lipid mediators, and we describe reg-ulatory changes in CB 1 and CB 2 receptors induced bynerve injury. Finally, we will consider implications of the preclinical ndings for cannabinoid-based pharmaco-therapies for neuropathic pain in humans.

Chronic constriction injuryChronic constriction injury (CCI) produces mechani-

cal allodynia as well as thermal allodynia and hyper-algesia in the ipsilateral paw as early as 2 days post-surgery. 37 Initial reports failed to nd mechanicalhyperalgesia, although several of the reviewed articlesreport its presence after surgery. Very few studies haveinvestigated the presence of cold allodynia after thisnerve injury; however, those that have evaluated its pres-ence uniformly demonstrate efcacy of cannabinoids insuppressing cold allodynia. CB 1 receptors are upregu-lated in the spinal cord after CCI; these effects are be-lieved to be modulated by tyrosine kinase 38 and glu-cocorticoid 39 receptors. Not surprisingly, several classesof cannabinoids have been shown to suppress CCI-in-duced neuropathic nociception in rodents and includemixed cannabinoid agonists, which target both CB 1 andCB 2 receptors, CB 2 selective agonists, and modulators of the endocannabinoid system that inhibit FAAH or MGL(Tables 2 and 3).

Chronic administration of synthetic analogues of nat-ural cannabinoid ligands containing cannabidiol (CBD)attenuate or reverse established thermal and mechanicalhyperalgesia in the CCI model. However, anti-hyperal-gesic effects observed with these compounds are likelyto be independent of cannabinoid receptors, and may bemediated through TRPV1. Those studies investigatingpharmacological specicity have demonstrated blockadewith the TRPV1 antagonist capsazepine, but not a can-nabinoid CB 1 or CB 2 antagonist.

40,41 The CB 1 specicantagonist SR141716 has been tested in this model withdisparate results. SR141716, administered acutely, ispro-hyperalgesic and pro-allodynic in this model. 42

However, SR141716 (by mouth), administered chroni-cally, suppresses thermal and mechanical hyperalgesia inboth rats and CB 1

/ mice, while failing to produce aneffect in CB 1

/ mice. 43 These reports are interspersedwith a host of articles that indicate no antinociceptive orpro-nociceptive effects of either CB 1 or CB 2 antagonists,administered alone. Thus, it is important to emphasizethat the behavioral phenotype induced by antagonisttreatment may depend on the level of endocannabinoidtone present in the system, the injection paradigm (chronic

Table 1. Cannabinoids Evaluated for Suppression of Neuropathic Nociception

Natural cannabinoid ligands and synthetic analogues

9 -THC (Dronabinol/Marinol) Cannabidiol (CBD) Cannador (cannabis extract, 9 -THC:CBD,

2.5 mg:1.25 mg) Cannabis eCBD (Cannabis with high CBD content) Nabilone (Cesamet, 9 -THC analogue) Sativex (oral-mucosal spray, 9 -THC:CBD,

2.7 mg:2.5 mg)Endocannabinoids Anandamide (AEA) 2-arachydonoylglycerol (2-AG)Fatty acids L-29 N-arachidonoyl glycine (NaGly) Palmitoylethanolamine (PEA)CB 1 -selective agonists

ACEA Met-F-AEAMixed CB 1 /CB 2 agonists BAY59-3074 CP55,940 CT-3 (Ajulemic acid) HU-210 WIN55,212-2CB 2 -selective agonists A-796260 A-836339 AM1241 ((R,S)-AM1241) (R)-AM1241 (S)-AM1241 AM1714 Compound 27 GW405833 (L768242) JWH015 JWH133 MDA7 MDA19Endocannabinoid modulatorsUptake Inhibitors: AM404 VDM11FAAH inhibitors: Compound 17 OL135 URB597 MGL inhibitors: JZL184 URB602

FAAH fatty-acid amide hydrolase; MGL monoacylglycerollipase; THC tetrahydrocannabinol.

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although pharmacological specicity has not been con-sistently assessed ( Table 2 ). Thus, it is noteworthy thatCB 2 receptor mRNA is upregulated in the lumbar spinalcord after CCI. This u pregulation is restricted to nonneu-ronal cells (e.g., glia). 49 Interestingly, GW405833, a CB 2specic agonist, also reduces depression-like behaviorasso ciated with this mononeuropathy in the forced swimtest. 50 Tolerance, a feature that may contribute to loss of analgesic efcacy of currently available analgesics,failed to develop after repeated administration of the CB 2specic agonist, A-836339. Thus, CB 2 agonists mayshow therapeutic potential for suppressing neuropathicpain without producing tolerance when administ ered ei-ther alone or as adjuncts to exisiting treatments. 51

Endocannabinoid modulators suppress neuropathicpain symptoms associated with CCI ( Tables 2 and 3).AM404, an endocannabinoid transport inhibitor, in-creases accumulation and, hence, bioavailability, of

anandamide (and potentially other endocannabinoids)through a mechanism that remains incompletely under-stood. AM404 also n orma lizes CCI-induced changes in-nitric oxide activity, 52,53 cyclooxygenase-2 53 activity,cytokine l eve ls (e.g., tumor necrosis factor- and inter-leukin-10), 52 and nuclear factor- B52 levels. In CCI rats,chronic administration of either AM404 or URB597 sup-presses plasma extravasation, a condition a ssoci ated withneuropeptide release at peripheral levels. 54,55 AM404,administered chronically or acutely, does not affect lo-comotor behavior, indicating a low propensity of thisagent to produce unwanted motor side e ffect s associated

with direct activation of CB 1 receptors.52,53

CCI produces regulatory changes in endocannabinoidlevels. CCI increases AEA and 2-AG levels in the peri-aqueductal gray and rostral ventromedial medull a, sitesimplicated in the descending modulation of pain. 56 CCIalso increases levels of endogenous AEA, but not 2-AG,in the dorsal raphe, which was an observation that mayhelp explain the antihyperalgesic efca cy of an anand-amide transport inhibitor in this model. 57 CCI increasesserotonin (5-HT) levels in the dorsal raphe and this effectwas suppressed by both WIN55,212-2 and AM404 in aCB 1 dependent manner.

57 CCI-induced Fos expression

was observed in response to non-noxious mechanicalstimulation in spinal cord laminae I and II, the site of termination of A and C bers, which carry nociceptivesensory information from the periphery to the CNS.Lower levels of evoked Fos expression were observed inlaminae III and IV of CCI rats. Chronic administration of AM404 signicantly decreased CCI-induced Fos expres-sion in the lumbar spinal co rd through CB 1 /CB 2 andTRPV1-mediated mechanisms. 58 Antinociceptive effectsof FAAH inhibitors (OL135 and URB597) have alsobeen reported in mice after CCI. OL135 and URB597attenuate cold and mechanical allodynia in a manner thatis dependent on activation of both CB

1and CB

2recep- T

a b l e 3

. A n t i n o c i c e p t i v e E f f e c t s o f C a n n a b i n o i d s a f t e r C h r o n i c C o n s t r i c t i o n I n j u r y i n M i c e

M e c h a n i c a l

H y p e r a l g e s i a

M e c h a n i c a l A l l o d y n i a

M e c h a n i s m

C o m p o u n d

R o u t e

T h e r m a l

C B 1

C B 2

R e f N o .

E n d o c a n n a b i n o i d

M o d u l a t o r s

J Z L 1 8 4

i . p .

Y e s c o l d

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Y e s ( S R 1 i . p

. ) N o ( S R 2 i . p

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5 9

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a n d

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/ )

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a n d F A A H

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p e r o r e m ; S R 1

S R 1 4 1 7 1 6 ; S R 2

S R 1 4 4 5 2 8

.

* C h r o n i c p o s t i n j u r y ;

o n l y f o r t h e r m a l h y p e r a l g e s i a a n d m e c h a n i c a l a l l o d y n i a , n o b l o c k a d e o b s e r v e d f o r m e c h a n i c a l h y p e r a l g e s i a

.




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tors. 59 In addition, both OL135 and URB597 are antino-ciceptive in FAAH / mice, but fail to produce an effectin FAAH / mice. 59 The novel MGL inhibitor, JZL184,attenuates CCI-induced mechanical and cold allodyniathrough indirect activation of the CB 1 receptor; JZL184was efcacious in attenuating neuropathic nociception inboth FAAH / and FAAH / mice. 59 The fatty acidPEA, administered chronically, attenuated the develop-ment of thermal hyperalgesia and mechanical allodyniain the CCI model through CB 1 , PPAR , and TRPV1-mediated mechanisms. 60 Chronic administration of PEAalso normalized levels of three neutrophic factors (nervegrowth factor, glial cell line-derived neurotrophic factor,and neurotrophin-3) that were increased by CCI. 60 Thus,activation of CB 1 and CB 2 receptors, as well as pharma-cological manipulation of endocannabinoid accumula-tion or breakdown, suppresses neuropathic nociceptionin rodents.

Partial sciatic nerve ligation (Seltzer Model)Mechanical hyperalgesia and allodyn ia are observed

after partial ligation of the sciatic nerve. 61 Thermal hy-peralgesia was present in all studies review ed here thatevaluated this measure with one exception. 62 Only twostudies we reviewed examined the presence of cold al-lodynia after partial sciatic nerve ligation; the rst studyfound that both CB 2

/ and CB 2 / mice showed evi-

dence of cold allodynia after surgery. 63 Cold allodyniahas also been reported in rats after partial sciatic nerveligation. 64 All classes of cannabinoids evaluated pro-

duced anti-allodynic and antihyperalgesic effects in theSeltzer model ( Table 4 ).

Pro-hyperalgesic effects of SR141716 and SR144528have been reported in the Seltzer model, 65 indicating apotential alteration in endocannabinoid tone after nerveinjury. No other articles we reviewed reported similareffects of cannabinoid antagonists administered alone inthis model. Exogenously applied endocannabinoids,AEA and 2-AG, suppress changes in neuropathic noci-ception induced by partial sciatic nerve ligation. Inter-estingly, AEA produced anti-hyperalgesic and anti-allo-dynic effects through a CB 1 mechanism,

65,66 whereas

2-AG produced anti-hyperalgesic and anti-allodynic ef-fects thro ugh activation of both peripheral CB 1 and CB 2receptors. 67 AEA and PEA exerts effects, at least in part,through a peripheral mechanism; both fatty-acid amidessuppressed release of calcitonin gene-related peptide andsomatostatin evoked by the irritant resiniferotox in withoutaltering peptide release under basal conditions. 65 Antihy-peralgesic effects of AEA and PEA were blocked by a CB 1and CB 2 antagonist, respectively.

65 One limitation withstudies using exogenous administration of endocannabi-noids is that they do not imply that endocannabinoids arereleased under physiological conditions to produce theseeffects. Several studies report efcacy of mixed canna-

binoid CB 1 /CB 2 agonists in this model, although CNSside effects were nonetheless observed in the same doserange t hat resulted in full reversal of neuropathic noci-ception. 68 Ajulemic acid (CT-3), which was developedas a peripherally restricted cannabinoid analogue, alsoproduced activity in the tetrad, but antihyperalgesic ef-fects o ccu rred at doses lower than those producing sideeffects. 69

Structurally distinct CB 2 specic agonists are efca-cious in suppressing neuropathic nociception in thismodel. Moreover, CB 2 receptors in the spinal cord con-tribut e to CB 2 mediated suppression of mechanical allo-dynia. 70 CB 2

/ mice reportedly develop thermal hyper-algesia and mechanical allodynia in the contralateral pawafter surgery, whereas CB 2

/ do not. 63 Microglia andastrocyte expression in the spinal dorsal horn is observedin both CB 2

/ and CB 2 / mice ipsilateral to nerve

injury. However, CB 2 / mice notably exhibit increased

microglial and astrocyte expression in the contralateralspinal dorsal horn, a mechanism which may help toexplain differences in neu ropathic nociception betweenwild-types and knockouts. 63 Further support for this hy-pothesis is derived from the observation that overexpres-sion of the C B2 receptor attenuated enhanced expressionof microglia. 63 These results suggest that genetic disrup-tion of the CB 2 receptor has a disinhibitory effect on theresponses of glial cells after partial sciatic nerve ligation.The cytokine, interferon-gamma, is produced by astro-cytes and neurons ipsilateral to injury in both CB 2

/

and CB 2 / mice. However, CB 2

/ mice exposed to

partial sciatic nerve ligation exhibit interferon-gammaimmunoreactivity in the spinal dorsal horn contralateralto injury. Interferon- / /CB 2

/ mice showed no evi-dence of neuropathic nociception when the contralateralpaw was stimulated after surgery, suggesting that im-mune responses underlie neuropathic pain respons es ob-servable in the contralateral paw of CB 2

/ mice. 71 De-letion of a putative novel cannabinoid receptor, GPR55,is also associated with the failure to develop m ech anicalhyperalgesia after partial sciatic nerve ligation. 72

Compounds targeting three distinct mechanisms formodulating endocannabinoid levels also suppress neuro-

pathic nociception after partial sciatic nerve ligation. Thetransport inhibitor AM404, administered systemically,suppressed mechanical allodynia in a C B1 dependentmanner without producing motor effects. 73 The F AAHinhibitor URB59 7, administered locally in the paw, 67 butnot systemically, 62 suppressed both thermal hyperalgesiaand mechanical allodynia through a CB 1 mechanism.The MGL inhibitor URB602 (which can not be usedsystemically as a selective MGL inhibitor), administeredlocally in the paw, also suppressed neuropathic nocicep-tion in this m odel through activation of both CB 1 andCB 2 receptors.

67 The fatty-acid analogue of PEA, L-29,also suppressed thermal hyperalgesia and mechanical al-




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Table 4. Antinociceptive Effects of Cannabinoids after Partial Sciatic Nerve Ligation (Seltzer Model)

Compound Route ThermalMechanical

HyperalgesiaMechanicalAllodynia

Mechanis

CB 1

ExogenousEndocannabinoids

AEA i.p. Yes Yes (SR1 i.p.) i.paw Yes Yes Yes (AM251 i.paw) No

2-AG i.paw Yes Yes Yes (AM251 i.paw) YesMixed CB 1 /CB 2

AgonistsCT-3 (AJA) p.o. Yes Yes (SR1 s.c.) No

i.p. Yes CP55,940 s.c. Yes HU-210 s.c. Yes

i.p. NP Yes Yes

i.t. Yes Yes (AM251 i.t.) YesWIN55,212-2 s.c. Yes* Yes Yes

s.c. Yes Yes Yes (AM251 chronic s.c. ) Yi.t. Yes Yes (SR1 i.t.) i.pl. Yes Yes (blocked by SR1 s.c.,

but not i.t.)CB 2 Agonists GW405833 (L768242) i.p. Yes

Yes JWH133 i.p. No

i.t. Yes (CB 2 / )

No (CB 2 / )

i.paw No Endocannabinoid

ModulatorsAM404 i.p. Yes Yes (AM251 i.p.) URB597 i.p. NP No

i.paw Yes Yes Yes (AM251 i.paw) No URB602 i.paw Yes Yes Yes (AM251 i.paw) Yes

Fatty Acids L-29 i.p. Yes-heatNo-cold

Yes Yes (SR1 i.p.) Ye

NaGly s.c. No i.t. Yes No (AM251 i.t.) No

PEA i.p. Yes Ye

AEA anandamide; 2-AG 2-arachydonoylglycerol; AJA ajulemic acid; i.p. intraperitoneal; i.pl. intraplantar; i.paw intra-paw; i.t. intraNP not present; PEA palmitoylethanolamine; p.o. per orem; s.c. subcutaneous; SR1 SR141716; SR2 SR144528.White cells tested in rats. Shaded cells tested in mice.*Increased measurements in contralateral paw at dose(s) tested; Chronic pre-emptive/postinjury or both; Postinjury; Pre-emptive and postinjury cmechanical allodynia, not thermal hyperalgesia.

N e ur o t h er a p e u t i c s , V o l . 6 , N o .4 ,2 0 0 9


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lodynia in the Seltzer model. The L29-induced suppres-sion of thermal hyperalgesia was mediated by both theCB 1 receptor and PPAR- , whereas suppression of me-chanical allodynia was mediated by CB 1 /CB 2 andPPAR- receptors. 64 PEA abolished mechanical hyper-algesia after partial sciatic nerve ligation through amechanism that was blocked by a CB 2 antagonist. 65

When considering the effects of PEA, it is important toemphasize that PEA does not bind directly to CB 2 re-ceptors 74 ; therefore, blockade by a CB 2 specic antago-nist could indicate indirect modulation of receptor activ-ity (e.g., via activation of PPAR- or entourage effects)or blockade of an uncharacterized cannabinoid receptorthat binds the CB 2 antagonist SR144528. Intrathecal N-arachidonoyl glycine (NaGly), the arachodonic acid con- jugate, also attenuated mechanical allodynia in thismodel; however, the anti-hyperalgesic actions of thiscompound are independent of spinal cannabinoid recep-tors. 75 Locally injected (intra-paw) paracetamol sup-pressed mechanical allodynia and thermal hyperalgesiapresent after partial sciatic nerve ligation, and these ef-fects were blocked by local administration of either aCB 1 or a CB 2 antagonist.

76 Paracetomol may undergolocal metabolic transformation into AM404, resulting inincreased levels of endocannabiniods.

Spinal nerve ligation (SNL)All studies reviewed here docu mented the presence of

mechanical allod ynia after SNL. 77 All studies with theexception of one 78 indicated the presence of thermal

hyperalgesia when animals were tested. One study eval-uated the presence of cold allodynia and conrmed thatanimals with this injury display hyp ersensitivity to non-noxious levels of cold stimulation. 79 Gabapentin suc-cessfully attenuated mechanical allodynia in this model,however, several other commonly prescribed neuro-pathic pain medications, including amitriptyline, uo x-etine, and indomethacin failed to show similar effects. 80

Thus, it is noteworthy that mixed cannabinoid agonists,cannabinoid CB 2 selective agonists, and FAAH inhibi-tors all attenuated neuropathic nociception induced bySNL ( Table 5 ).

As with other nerve injury models, several mixed can-nabinoid CB 1 /CB 2 agonists suppress hyperalgesia andallodynia produced by SNL. Acute WIN55,212-2 sup-presses all forms of neuropathic nociception tested in thismodel. Chronic administration of WIN55,212-2 also at-tenuates the development of mechanical allodynia andsuppresses glial activation in the spinal cord after SNL,with no overt motor side effects. 81 Chronic administra-tion of WIN55,212-2 produced anti-allodynic effects forup to 6 days after the nal injection. A reappearance of glial activation was also associat ed with return of neu-ropathic nociception in this study. 81 CP55,940 producesantinociception in CB

1

/ , CB2

/ , CB2

/ , but not

CB 1 / mice subjected to SNL, suggesting that activity

at CB 1 dominates the antinocieptive prole of mixedCB 1 /CB 2 agonists after systemic administration.

45 Spi-nal, but not systemic, administration of HU-210 has beenreported to reduce A ber-evoked responses on spinalWDR neurons in both shams and SNL rats, whereasHU -21 0 showed no effect on C-ber responses of SNLrats. 82

SNL produces regulatory changes in CB 1 mRNA andendocannabinoid levels. Increases in CB 1 mRNA areobserved in the uninjured (but abnormal) L4 DRG ipsi-lateral to injury. 83 Increases in both AEA and 2-AG havealso been reported in the ipsilateral injured L5, but notthe uninjured L4 DRG. 83 These ndings collectivelydocument the presence of regulatory changes in endo-cannabinoid levels associated with SNL, a nding whichmay contribute to the efcacy of peripherally adminis-tered cannabinoid agonists that activate CB 1 receptors in

this model.Noxious stimulation (e.g., C-ber mediated activity)

induces phosphorylation of extracellular signal-regulatedprotein kinase (ERK) in dorsal horn neurons. The CB 1specic agonist ACEA inhibits pERK expression in-duced by in vitro application of capsaicin to the spinalcords of SNL rats. This observation contrasts with effectsof opioids (i.e., morphine and DAMGO), which lose theability to inhibit C-ber i nduced ERK activation in theL5 spinal cord after SNL. 84

Multiple CB 2 specic agonists suppress neuropathicnociception induced by SNL. The CB 2 agonist AM1241

suppresses both thermal hyperalge sia and mechanic alallodynia after SNL in both rats 17,44,85 and mice. 44

CB 1 / mice receiving AM1241 showed enhanced an-

tihyperalgesia. 44 An emerging body of literature nowsuggests that antinociceptive effects of CB 2 agonists ma ybe mediated by suppression of microglial activation. 4

Evidence for upregulation of CB 2 after SNL has beenreported by several groups. CB 2 mRN A was upregulatedin the lumbar spinal cord after SNL, 49 coincident withthe expression of activated microglia. Colocalizationstudies, however, were not performed. Upregulation of CB 2 receptor immunoreactivity on sensory afferent ter-

mina ls in the spinal cord has also been reported afterSNL. 18 This group failed to nd co-localization of CB 2with markers for glial cells in SNL rats, and concludedthat CB 2 receptors were u pregulated on sensory neuronsafter spinal nerve ligation. 18 CB 2 mRNA was also shownto be upregulated in the ipsilateral (vs the contralateral)spinal cord and DRG after SNL, and the presence of CB 2mRNA was conrmed in spinal cord microglial cells inculture. 17

The CB 2 specic agonist GW405833, administeredchronically, suppressed the development of mechanicalallodynia concomitant with suppress ion of glial activa-tion at the level of the spinal cord. 81 The structurally




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Table 5. Antinociceptive Effects of Cannabinoids after Spinal Nerve Ligation (Traditional and Modied)

Compound Route ThermalMechanical

Hyperalgesia Mechanical Allodynia CB

Mixed CB 1 /CB 2agonists

BAY 59-3074 p.o. NP Yes CP55,940 i.p. Yes No (SR1 i.p

Yes (CB 1 / )

No (CB 1 / )

Yes (CB 2 / and CB 2

/ ) i.t. Yes No (SR1 i.

WIN55,212-2 i.p. YesheatYescold

Yes* Yes (SR1

Yes

No i.p. Yes CB 2 Agonists AM1241 i.p. Yes Yes No (AM251

Yes (CB 1 / and CB 1

/ ) Yes (CB 1 / and CB 1

/ ) No (AM25 Yes

i.v. Yes Compound 27 i.p. Yes GW405833 (L768242) i.p. Yes L768242 (GW405833) i.p. Yes MDA19 i.p. Yes MDA7 i.p. Yes No (AM251

EndocannabinoidModulators

Compound 17 i.v. Yes OL135 i.p. Yes No (SR1 i.p

i.v. intravenous; i.p. intraperitoneal; p.o. per orem; i.t. intrathecal; NP not present; SR1 SR141716; SR2 SR144528.White cells tested in rats. Shaded cells tested in mice.*Increased measurements in contralateral paw at dose(s) tested; Only cold allodynia tested; Chronic postinjury.



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distinct CB 2 specic agonist, JWH133, also attenuatesmechanically-evoked responses of WDR neurons in bothnaive and spinal nerve ligated rats. 86 Local injection of JWH133 into the ventroposterolateral nucleus of thethalamus attenuated spontaneous and mechanically-evoked neuronal activity in SNL, but not sham rats, in aCB 2 dependent manner. 87 Thus, CB 2 receptor activationmay exert little functional control under nonpathologicalconditions. Systemic and spinal administration of thenovel CB 2 agonist, A-836339, also attenuates spontane-ous and mechanically-evoked neuronal ring of spinalWDR neurons in a CB 2 dependent manner in SNL, butnot sham rats. 88 Interestingly, pretreatment with the CB 1antagonist, SR141716, enhanced the effects of A-836339when applied to the L5 DRG, 88 indicating that blockadeof CB 1 receptors enhanced the antinociceptive effects of a CB 2 agonist, as previously reported.

89

Two endocannabinoid modulators have been evaluatedbehaviorally in this model. Compound 17, a novelFAAH inhibitor, reversed mechanical allodynia in SNLrats with the same potency as a 5-fold higher dose of gabapentin. 90 In addition, OL135, a compound that ac-cesses the CNS and inhibits FAAH, suppressed mechan-ical allodynia in a CB 2 dependent manner.

91 Low dosesof locally injected URB597 reduced mechanically-evoked responses of WDR neurons and increased endo-cannabinoid levels in ipsilateral paw tissue of sham-operated rats. 92 A 4-fold higher dose was required forreduction of mechanically-evoked WDR neuronal re-sponses in SNL rats; these rats showed no corresponding

increase in endocannabinoid levels, suggesting that con-tributions of FAAH to endocannabinoid metabolism maybe modied under conditions of neuropathic nocicep-tion. 92 The antinociceptive effects of URB597 wereblocked by a CB 1 specic antagonist in both sham andSNL rats. 92 In the same study, spinal administration of URB597 was equally efcacious at attenuating mechan-ically-evoked responses and increasing levels of endog-enous cannabinoids in SNL and sham rats, and theseeffects were CB 1 mediated.

92

Other nerve injury models

Cannabinoids alleviate neuropathic nociception in sev-eral other injury models. These studies support a role forCB 1 in the anti-hyperalgesic effects of cannabinoids,although pharmacological specicity has not been con-sistently assessed in the literature and high doses of cannabinoid agonists can produce motor side effects,which complicate interpretation of behavioral studies.Chronic constriction injury of the infraorbital nerve re-sults in thermal hyperalgesia and mechanical allodynia(as measu red by head withdrawals) ipsilateral to the siteof injury. 93 WIN55,212-2 and HU-210 increased me-chanical withdrawal responses and thermal withdrawallatencies on the ipsilateral side of the head in this mo-

del. 94 WIN55,212-2 was more efcacious in suppressingmechanical allodynia versus thermal hyperalgesia in thechronic constriction injury of the infraorbital nervemodel. High antihyperalgesic doses of WIN55,212-2 de-creased rotarod latencies and body temperature, whereasHU210, at the singular low dose used (10 g/kg), had noeffect on these dependent measures. CB 1 receptor up-regulation was observed in both the ipsilateral and con-tralateral supercial layer of the trigeminal caudal nu-cleus, and this effect was greater on the ipsilate ral side.These and earlier ndings from the same group 95 indi-cate that cannabinoids are negative modulators of noci-ceptive transmission at the supercial layer of the tri-geminal caudal subnucleus.

CB 2 receptor immunoreactivity96 is increased in the

ipsil ate ral dorsal horn after L5 spinal nerve transec-tion. 97 Importantly, co-localization of CB 2 immunoreac-tivity with markers of microglia a nd perivascular cells

was observed on day 4 postsurgery. 96 In this study, nei-ther neuronal cells nor ast rocyctes expressed immunore-activity for CB 2 receptors.

96 CP55,940 reversed mechan-ical allodynia in this model 1 h after a second intrathecalinjection, although this do sing paradigm was also asso-ciated with motor effects. 96 Intrathecal JWH015 dosedependently suppressed behavioral hypersensitivity aftera second injection, indicating a cumulative anti-allodyniceffect of this drug. Intrathecal JWH015 reduced spinalnerve transectioninduced increases in activated micro-glia in a CB 2 dependent manner, further supporting a rolefor nonneuronal CB2 receptors in antihyperalesic effects

of CB 2 agonists.96

Two models developed by Walczak et al. 98,99 involvedinjuries to the saphenous nerve in rats and mice, respec-tively. The advantage of injuring the saphenous nerve incomparison with other nerves is that the saphenous nerveis an exclusively sensory nerve, whereas other nerveinjury models typically target nerves that subserve bothsensory and motor functions. The rst model was pro-duced in rats by saphenous partial nerve ligation, whichinvolves trapping 30 % to 50% of the saphenous nervein a tight ligature. 98 Saphenous partial nerve ligationrats presented with all symptoms except mechanical

hyperalgesia , which was present inconsistently through-out testing. WIN55,212-2, administered systemically,suppres se d all forms of hyperalgesia and allodyniapresent. 98 In rats, saphenous partial nerve ligation in-creased -opioid, CB 1 , and CB 2 receptor protein in i p-silateral hind paw skin, DRG, and lumbar spinal cord. 98

In a second injury model, chronic constriction of thesaphenous nerve was accomplished by tyin g two looseligatures around the saphenous nerve in mice. 99 SystemicWIN55,212-2 suppressed all forms of neuropathic noci-ception present in this model, including thermal hyper-agesia, cold allody nia , mechanical hyperalgesia, and me-chanical allodynia. 99 Mu-opioid, CB

1and CB

2receptor




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protein was increased in the ipsilater al spinal cord andhind paw skin at 7 days postsurgery. 99 In addition, in-creased CB 1 receptor protein was observed in contralat-eral hind paw skin 7 days postsurgery and increased CB 2receptor expression was observed in the contralateralspinal cord 1 and 7 days postsurgery. The neurobiolog-ical rearrangement of cannabinoid and mu-opioid recep-tors may contribute to the antinociceptive efcacy of WIN55,212-2 and morphine in this model.

The spared nerve injury (SNI) model reliably producesthermal hyperalgesia and mechanical allodynia in studiesthat tested for both measures. Initial reports of the SNImodel indicated the p resence of cold allodynia and me-chanical hyperalgesia, 100 but none of the articles reviewedhere assessed these behaviors in conjunction with cannabi-noid treatment. Standard analgesics (e.g., morphine, gaba-pentin, amitryptiline) are efcacious in treating neuropathicnociception resulting from a crush injury of the sciatic

nerve, but showed limited efcacy after SNI. 101 Two mixedcannabinoid CB 1 /CB2 agonists have been tested in thismodel. Acute WIN55,212-2 suppressed thermal hyperal-gesia and mechanical allodynia in both mice lacking CB 1receptors in primary nociceptors (SNS-CB 1 ) and theirwild-type controls; however, differences in the antinoci-ceptive effects of WIN55,212-2 were observed betweengenotypes, and these effects were greater with mechan-ical than thermal sensitivity. Comparable responses toWIN55,212-2 were only observed at doses high enoughto induce sedation and rigidity in all mice. SNS-CB 1mice showed exaggerated sensitivity to noxious levels of

mechanical stimulation and a cold plate relative to theirwild-type counterparts, whereas differential sensitivitywas not observed between genotypes with non-noxiouslevels of mechanic al stimulation and noxious levels of thermal stimulation. 7 Thus, CB 1 receptors on nociceptorsin the periphery account f or much of the antinociceptiveeffects of cannabinoids. 7 A dose-escalation study withBAY 59-3074 in the SNI model indicated that tolerancerapidly develops to side effects observed after chronicadministration (e.g., hypotherm ia), whereas no loss inanalgesic efcacy was obs erve d.78

Spinal cord injury (SCI) 102 produces mechanical hy-

peralgesia and allodynia. WIN55,212-2 is the only com-pound that has been evaluated in the SCI model. AcuteWIN55,212-2, administered systemically, suppressedSCI-induced mechanical allodynia in a CB 1 dependentmanner, although other parameters of neuropathic painwere not assessed. 103 Unlike morphine, chronic admin-istration of WIN55,212-2 reduced mechanical allodyniain the SCI model with no decrease in effectiveness overtime. 104

Tibial nerve injury is performed by unilaterally axoto-mizing the tibial branch of the sciatic nerve. Mechanicalallodynia and thermal hyperalgesia w ere present in theinitial study describing this technique, 105 as well as the

study we reviewed. Systemic BAY 59-3074 was shownto attenuate both forms of neuropathic nociception, a l-though pharmacological specicity was not assessed. 78

Tibial nerve injury injury resulted in an upregulation of CB 1 receptor mR NA in the contralateral thalamus on day1 postsurgery, 106 indicating cannabinoid receptor regu-lation within an important relay nucleus in the ascendingpain pathway.

Disease-related models of neuropathic painCannabinoid agonists have been evaluated in animal

models of disease-related neuropathic pain, althoughpharmacological specicity has not been consistently as-sessed. Herein, we review effects of cannabinoids inpreclinical models of neuropathic pain induced by diabe-tes, chemotherapeutic treatment, HIV/antiretroviral treat-ment, demyelination disorders, multiple sclerosis (MS), andpostherpetic neuralgia.

Single injection of streptozotocin-induced diabeticneuropathy

Diabetic neuropathy induced by a single injection of streptozotocin (STZ) resulted in increased sensitivity tonoxious and non-noxious levels of mechanical stimula-tion, and failed to induce thermal hyperalgesia in thestudies reviewed here ( Table 6 ). None of the studies wereviewed evaluated the presence of cold allodynia.2-Methyl-2-F-anandamide (Met-F-AEA), a CB 1 spe-cic agonist based on the structure of anandamide, themixed cannabinoid agonist WIN55,212-2, and the CB 2 spe-cic agonist AM1241, administered chronically, sup-

pressed mechanical hyperalgesia associated with STZ-induced diabetic neuropathy. However, mediation bycannabinoid receptors has not been assessed for agoniststested in this model. Daily pretreatment with indometh-acin (cyclooxygenase-1 inhibitor) or L-NG-nitro argi-nine ([L-NOArg] nonselective nitric oxide synthase in-hibitor) increased the antihyperalgesic actions of lowdoses of WIN55,212-2, AM1241, and Met-F-AEA inSTZ rats to a greater extent than the cannabinoid admin-istered alone, suggesting the presence of antinociceptivesynergism between cannabinoid and cyclooxygenasepathways. 107 Cyclooxygenase inhibitors may block oxi-

dative metabolism of endocannabinoids, thereby increas-ing endocannabinoids available to interact with cannabi-noid receptors.

Diabetic rats exhibit a dec rease in the density of CB 1receptor protein in DRG. 108 More work is necessary todetermine whether this loss of cannabinoid receptorscontributes to the neurodegenerative process in diabetes.Increased levels of endocannabinoids have be en found inobese patients suffering from type II diabetes, 109 and thiseffect is likely to result from downregulation of FAAHgene expression, an effect which has also bee n observedin adipocytes sampled from obese women. 110 Lean malessubjected to hyperinsulinemia show a 2-fold increase in




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Table 6. Antinociceptive Effects of Cannabinoids in Animal Models of Disease-Related Neuropathic Pain

Model Compound Route ThermalMechanical

HyperalgesiaMechanicalAllodynia

Me

CB 1

Diabetic Neuropathy Met-F-AEA i.p. Yes i.p.* Yes

WIN55,212-2 i.p. NP Yes Yes

NP Yes i.p.* Yes i.paw NP Yes

AM1241 i.p. Yes i.p.* Yes

Chemotherapy-inducedNeuropathy

CisplatinWIN55 ,212-2 i.p. Yes

Paclitaxel 118, 120

WIN55,212-2 i.p. Yes Yes Yes (SR1 i.p.) i.pl. Yes Yes

MDA7 i.p. NP Yes ( R,S)-AM1241 i.p. NP Yes No (SR1 i.p.) ( R)-AM1241 i.p. NP Yes

(S

)-AM1241 i.p. NP No AM1714 i.p. NP Yes No (SR1 i.p.) Vincristine 121

WIN55,212-2 i.p. NP Yes Yes (SR1 i.p.) i.t. NP Yes Yes (SR1 i.t.) i.pl. NP No

( R,S)-AM1241 i.p. NP Yes No (SR1 i.p.) Other HIV-SN

WIN55,212-2 i.p.* NP heatNPcold

Yes

L-29 i.p. NPheatNPcold

Yes Yes (SR1 i.p.)

LDPNWIN55,212-2 i.t. Yes Yes Yes (AM251 i.t.)

VZV

L-29 i.p. NP heatNPcold

Yes No (SR1 i.p.)

WIN55,212-2 i.p.* NP heatNPcold

Yes

ddc zalcitabine; HIV-SN HIV sensory neuropathy (includes antiretroviral treatment (ddc), HIV-gp120, and HIV-gp120 antiretroviral treatmeintraperitoneal; i.pl. intraplantar; LDPN lysolecithin-induced demyelination-associated peripheral neuropathy of saphenous nerve; NP

SR144528; VZV varicella zoster virus-induced neuropathy.White cells tested in rats. Shaded cells tested in mice.*Chronic postinjury; Chronic, pre-emptive and postinjury; Increased measurements in contralateral paw at dose(s) tested; In antiretroviral (ddc), HIV-(ddc) models; Only tested in the antiretroviral (ddc) model.



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FAAH mRNA expression, whereas obese males subjected to the same conditions failed to show similaralterations in gene expression. 111 These ndings are sug-gestive of a negative feedback mechanism that couldresult in downregulation of the endocannabinoid signal-ing system. The CB 1 antagonist rimonabant (Acomplia[Sano-Aventis, Montpellier, France]) ameliorates insu-lin resistance and decreases weight gain in patients suf-fering from metabolic syndromes. 112 In animal models,rimonabant improves resistance to insulin through path-ways that are both dependent and independent of adi-ponectin, a hormone important for the regulation of glu-cose and catabolism of fatty acids. 113 Although adverseside effects have limited the potential therapeutic ef-cacy of Acomplia, drugs modulating the endocannabi-noid system should not be disregarded as targets forpotential treatments of diabetes and its associated syn-dromes. STZ-diabetic mice showed a progressive declinein the radial arm maze and reduced neurological scores,both of which were recovered after treatment with HU-210. 114 However, these effects were not blocked by aCB 1 specic agonist. HU-210 did not alter the hypergly-cemia index; however, it did normalize cerebral oxida-tive stress present in diabetic mice. 114 An increase in thenumber of apoptotic cells and impaired neurite growthwas observed in PC12 cells cultured under hyperglyce-mic conditions, and these were effectively treated byHU-210. 114

Cannabinoids may show greater therapeutic potentialfor treating painful diabetic neuropathy compared to opi-

oids. Interestingly, 9 -THC exhibited enhanced antino-ciceptive efcacy in diabetic rats, whereas morphineshowed reduced antinociceptive efcacy. 115 Moreover, anon-nociceptive dose of 9 -THC, administered in conjunction with morphine, enhanced the antinociceptiveproperties of morphine in both diabetic and naivemice. 115 Thus, combinations of opioids and cannabinoidsmay show promise as adjunctive analgesics in humans.Diabetic rats exhibit lower levels of dynorphin and -en-dorphins in CSF relative to nondiabetic rats treated underthe same conditions. 115 Administration of 9 -THC todiabetic rats restored CSF levels of endogenous dynor-

phin and leu-enkephalin to levels observed after mor-phine administration to nondiabetic rats. 115 More work isnecessary to understand the mechanism underlying theseobservations.

Chemotherapy-induced neuropathyCannabinoid modulation of chemotherapy-induced

neuropathy has been evaluated with agents from threemajor classes of chemotherapeutic agents ( Table 6 ). Asingular study has evaluated cannabinoid modulation of neuropathic nociception induced by cisplatin, a plati-num-derived agent. WIN55,212-2 prevented the devel-opment of mechanical allodynia induced by cisplatin, but

failed to produce an anti-emetic benet in this study. 116

It is possible that the dose of cannabinoid employed, thespecies used (rat) or toxicity of cisplatin-dosing para-digms may prevent detection of anti-emetic effects inthis model. Cannabinoids have been shown to suppresscisplatin-induced emesis in the least shrew. 117

Paclitaxel has been most frequently studied in the can-nabinoid literature with three studies documenting can-nabinoid-mediated suppression of paclitaxel-inducedneuropathic nociception. In one study, paclitaxel 118 pro-duced mechanical allodynia starting on day 5 that con-tinued throughout the course of study, although thermalhyperalgesia was only present from days 18 to 21. 119

WIN55,212-2 suppressed neuropathic nociception in thismodel, but had no effect on body temperature or immo-bility. WIN55,212-2-induced decreases in spontaneousmotor activity were nonetheless observed. 119 A morerecent study using the same paclitaxel dosing para-digm 118 reported the presence of mechanical allodyniaand the absence of thermal hyperalgesia. 85 Naguib etal. 85 demonstrated that a novel CB 2 specic agonist,MDA7, suppressed paclitaxel-induced mechanical allo-dynia, although mediation by CB 2 receptors was notassessed. Using the paclitaxel dosing paradigm describedby Flatters and Bennett, 120 mechanical allodynia, but notthermal hyperalgesia, was observed. In this model, ratsshowed signs of mechanical allodynia up to 72 dayspost-paclitaxel. 89 Systemic administration of either theCB 2 agonist ( R,S)-AM1241 or its receptor-active enan-tiomer ( R)-AM1241 produced CB

2mediated suppres-

sions of paclitaxel-induced mechanical allodynia. ( S)-AM1241, the enantiomer exhibiting lower afnity for theCB 2 receptor, failed to produce an anti-allodynic ef-fect. 89 The novel cannabilactone, AM1714, also reversedmechanical allodynia associated with paclitaxel treat-ment in a CB 2 dependent manner.

89 Thus, both mixedCB 1 /CB 2 agonists and selective CB 2 agonists suppresspaclitaxel-evoked mechanical allodynia.

Cannabinoid modulation of neuropathic nociceptionhas also been evaluated with vincristine, an agent fromthe vinca-alkaloid class of chemotherapeutic agents. Vin-

cristine produced mechanical allodynia, but not thermalhyperalgesia, in a 10-day injection paradigm. 121 Sys-temic and intrathecal, but not intraplantar, WIN55,212-2suppressed vincristine-induced mechanical allodyniathrough activation of CB 1 and CB 2 receptors.

122 Thesendings implicate the spinal cord as an important site of action mediating anti-allodynic effects of cannabinoids.Systemic ( R,S)-AM1241 also partially reversed vincris-tine-ind uce d mechanical allodynia in a CB 2 dependentmanner. 122 The anti-allodynic effects of WIN55,212-2and ( R,S)-AM1241 were observed at doses that did notprod uce intrinsic effects on motor behavior in the bartest. 122 Our studies suggest that clinical trials of canna-




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binoids for the management of chemotherapy-evokedneuropathy are warranted.

HIV-associated sensory neuropathyThe mixed cannabinoid agonist WIN55,212-2 is an

effective anti-hyperalgesic agent in three distinct animal

models of HIV-associated sensory neuropathy ( Table 6 ).Rats treated with the antiretroviral agent zalcitabine(ddc) developed mechanical allodynia that persisted upto 43 d ays postinjection and peaked between days 14 and32. 123 No hypersensitivity to thermal stimuli or motordecits was observed after ddc treatment. HIV-1 hasindirect interactions with neurons through its bindingafnity to the external envelope binding protein gp120;researchers have exploited this mechanism to demon-strate development of peripheral neuropathy in rodentsafter exposure of the sciatic nerve to the HIV-1 gp120protein. Perineural HIV-gp120 together with ddc treat-

ment resulted in mechanical allodynia that was greaterthan either treatment alone; no changes in paw with-drawal la ten cies to thermal stimuli or motor decits werereported. 123 Thigmotaxis was present in animals receivingddc, either alone or in conjunction with HIV-gp120, in di-cating the presence of anxiety-like behavior in these rats. 123

Rats receiving ddc displayed modest levels of gliosis,whereas combined treatment with both HI V-g p120 and ddcincreased levels of microglial activation. 123 Importantly,chronic WIN55,212-2 reversed mechanical allodynia in-duce d by either ddc treatment 123 or HIV-gp120 expo-sure, 124 whereas animals subjected to both HIV-gp120

and ddc treatment exhibited a WI N5 5,212-2-inducedattenuation of mechanical allodynia. 123 Increases in thedensity of microglia and astrocytes were observed inthe ipsilateral dorsal horn after HIV-gp120 treatment.Thus, activated microglia may be a common targetunderlying cannabinoid-mediated suppressions of neuro-pathic nociception.

Demyelination-induced neuropathyWIN55,212-2 has been evaluated in the lysolecithin-in-

duced demyelination model ( Table 6 ). Heightened sensitiv-ity to both non-noxious and noxious mechanical stimulationis observed in lysolecithin-treated rats; this hypersensitivity

emerged 5 days po stexposure and peaked between 9 and 15days postexposure. 125 Recovery to baseline levels was ob-served by day 23 post-lysolecithin. WIN55,212-2 attenu-ated mechanical allodynia and thermal hyperalgesia in thismodel and remained efcacious for up to 1 hour postinjec-tion. 125 By contrast, DAMGO failed to produce an effect.Notably, the antihyperalgesic and anti-allodynic effects of WIN55,212-2 were reversed by a CB 1 specic antagonist inboth tests.

MS-associated neuropathyAnimal models of MS have been described, although

to our knowledge, no study to date has evaluated canna-

binoid-mediated suppressi on o f MS-induced neuropathicnociception. Lynch et al. 126 reported the presence of thermal hyperalgesia (tail immersion) and mechanicalallodynia in mice that were infected with Theilers mu-rine encephalomyelitis virus. Interestingly, female miceshowed an increased rate of development and greaterallodynia than their male counterparts, a nding whichmimics the greater prevalence of neuro pat hic pain symp-toms reported by female MS patients. 127 Cold and me-chanical allodynia, but not thermal hyperalgesia, havebeen reported in a model of autoimmune encephalomy-elitis in which mice were immunized w ith myelin oligo-dendrocyte glycoprotein (MOG[3555]) 128 ; autoimmuneencephalomyelitis has been postulated to underlie thedevelopment of neuropathic pain in MS. Interestingly, amouse model of MS (Theilers murine encephalomyelitisvirus infection) is also characterized by an upregulationof CB 2 recep tor mRNA and increases in levels of 2-AG

and PEA. 129 Animals treated subchronically with PEAshowed improvements in tests of motor performance,measures that were impaired aft er Theilers murine en-cephalomyelitis virus infection. 129 Thus, we postulatethat cannabinoid CB 2 agonists and modulators of endog-enous cannabinoids (e.g., MGL inhibitors) would exhibitanti-allodynic efcacy in this model.

Postherpetic neuralgiaCannabinoids and fatty-acid amides suppress neuro-

pathic nociception in an animal model of postherpeticneuralgia ( Table 6 ). However, pharmacological specic-

ity has not been consistently assessed in this model.Approximately 50% of rats exposed to the varicella-zoster virus developed mechanical allodynia in the ipsi-lateral paw by 14 days postinfection; no t her mal hyper-algesia or cold allodynia was observed. 64 The PEAanalogue L-29 suppressed mechanical allodynia in thismodel with an earlier onset relative to gabapentin. How-ever, neither a CB 1 nor CB 2 specic antagonist blockedL-29 mediated suppression of varicella-zoster virus-in-duced mechanical allodynia. 64 This nding is perhapsunsurprising given that PPAR- med iate s effects of PEAin suppressing neuronal sensitization. 130 However, L-29,nonetheless, suppressed neuropathic nociception in theSeltzer model via activation of CB 1 and CB 2 receptors(see Table 4 ). Systemic WIN55,212-2, administeredfrom days 18 to 21 postinfection, fully reversed mechan-ical allodynia to baseline levels in this model of posther-petic neuralgia, alth ough pharmacological specicitywas not assessed. 131

CANNABINOID MODULATION OFNEUROPATHIC PAIN IN CLINICAL STUDIES

Cannabinoids have been evaluated in clinical studiesfor their suppression of acute, postoperative and neuro-




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Table 8. Effects of Cannabinoids in Injury-Related and Mixed Neuropathic Pain in Clinical Studies

Compound/Route Primary Outcome Measure Stimulus Evoked Pain Secondary O

Brachial PlexusAvulsion

Sativex/ 9 -THC* OralMucosal Spray

BS-11 (pain) Sativex reduced pain by0.58 boxes vs. placebo

9 -THC reduced pain by 0.64 boxes vs.

placebo

Pain reBS-1 Imp

GHQ-1SativSF-MP

VASTHC

PDI -Mixed

NeuropathyDronabinol (Marinol)

p.o.VAS daily pain ratings No effect Brush-induced mechanical allodynia

No effect MPQ/B

healtNabilone (Cesamet)/

DHC p.o.VAS daily pain ratings DHC better

than Nabilone SF-36

with impr

CT-3 (AJA)* p.o. VAS (pain) CT-3 reduced painratings in the morning (3 h postdrug), but not afternoon (8 hrs. postdrug) ; VRS (pain) No effect

Decrease in mechanical hypersensitivity(von Frey) in group receiving AJA prior to placebo (p 0.052)

TMT; A

Cannabis cigarettes(3.57% 9 -THC)*Smoking

Spontaneous pain relief VAS - Improved

Mechanical allodynia (foam brush)VAS; Thermal hyperalgesis VAS No effect

Pain UVAS

DegreePGICNeurGreaVAS

9 -THC/CBD/Sativex*Oral-Mucosal Spray

(Open-label phasewith Sativex priorto crossover)

VAS of 2 worst symptoms Decreasein symptoms following 9 -THC and Sativex relative to placebo

Qualitywith

DuratioBDI/G

impr follo

VAS daily ratings of target symptoms

CBD and 9

-THC improved pain;9 -THC and Sativex improved spasms; 9 -THC improved spasticity

Numeri

Spaswithmus

9 -TVAS da

imprimpr



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ministered for a 15-week treatment period, improvedoverall pain ratings, as well as sleep quality, spasms, andspasticity on category rating scales in patients sufferingfrom MS-related neuropathic pain. 143 A 1-year, double-blind, placebo-controlled follow-up study in MS patientsdemonstrated improved symptoms of pain, spasms, spas-ticity, sleep, shakiness, energy level, and tiredness afteradministration of either dronabinol or Cannador. 145 Thisstudy reported that 74% of the patients in the placebogroup, versus 45% of the patients receiving cannabinoid-based medications, cited a lack of benet derived fromexperimental medication as the reason for discontinua-tion of the trial. 145 MS patients receiving Sativex (amedicinal cannabis extract containing approximately a1:1 ratio of CBD: 9 -THC, administered as an oral-mu-cosal spray) reported signicant reductions in pain symp-toms, as measured with the NRS-11 and neuropathic painscale in a 4-week treatment period, double-blind, placebo-controlled study. 146 Ninety-ve percent of the patients inthe placebo-controlled study chose to enter a 2-yearopen-label study with Sativex. 147 Fifty-four percent of the patients completed 1 year and 44% of the patientscompleted 2 years of the study. Twenty-ve percentwithdrew due to adverse events, and 95% experiencedone or more adverse events during the course of treat-ment. The NRS-11, completed at the end of the trial, orupon withdrawal, was not different from the earlier ran-domized study indicating that Sativex was still suppress-ing pain. In addition, patients did not increase the titra-tion of their dose indicating that no tolerance developed

to Sativex. Most doses of Sativex were administeredbetween 6 PM and 12 AM, demonstrating that painsymptoms may be at their worst during normal sleepinghours for MS patients. A recent meta-analysis examiningsix studies of cannabinoid-based medications used forthe treatment of MS-related neuropathic pain revealedthat cannabis preparations were superior to a placebo. 148

Increased CB 2 immunoreactivity has been reported inspinal cords derived from MS patients. 149 Here, greaternumbers of microglia/macrophage cells expressing CB 2immunoreactivity were observed relative to controls. 149

Thus, cannabinoid-based pharmacotherapies consistently

show efcacy for suppressing pain due to MS, a diseasestate associated with an upregulation of CB 2 receptors inmicroglia.

Brachial plexus avulsion-induced neuropathyA single study has examined patients with neuropathic

pain resulting exclusively from a brachial plexus avul-sion ( Table 8 ). This study 150 used a 3-period crossoverdesign with patients self-administering 9 -THC, Sativex,or a placebo for 14 to 20 days per drug. Both 9 -THCand Sativex reduced the primary outcome measure (box-scale 11 ordinal rating scale) in patients suffering frombrachial plexus avulsion, indicating a reduction in pain T

a b l e 8

. C o n t i n u e d

C o m p o u n d / R o u t e

P r i m a r y O u t c o m e M e a s u r e

S t i m u l u s E v o k e d P a i n

S e c o n d a r y O u t c o m e M e a s u r e s R e f N o .

U n i l a t e r a l

M i x e d

N e u r o p a t h y

S a t i v e x

O r a l - M u c o s a l

S p r a y

N R S ( p a i n )

1 . 4 8 p t . r

e d u c t i o n ( 2 2 % )

i n S a t i v e x c o n d i t i o n v e r s u s

0 . 5 2 p t .

( 8 % ) r e d u c t i o n i n p l a c e b o c o n d i t i o n

M e c h a n i c a l d y n a m i c a l l o d y n i a N R S

R e d u c t i o n w i t h S a t i v e x

P u n c t a t e m e c h a n i c a l a l l o d y n i a

N o

e f f e c t

S l e e p d i s t u r b a n c e s N R S / N P S /

P D I / P G I C ( n e u r o p a t h i c p a i n ) /

P G I C ( p a i n a t a l l o d y n i c s i t e s )

I m p r o v e d w i t h S a t i v e x

G H Q - 1

2 / B R B - N

N o e f f e c t

1 3 3

U M N S

N a b i l o n e ( C e s a m e t ) *

p . o .

1 1 - P o i n t b o x t e s t o f s p a s t i c i t y - r e

l a t e d

p a i n

D e c r e a s e d a m e d i a n o f 2 p t .

w i t h N a b i l o n e v e r s u s a p l a c e b o

A s h w o r t h s c o r e / R i v e r m e a d

M o t o r A s s e s s m e n t / B a r t h e l

I n d e x

N o e f f e c t

1 6 0

A R C I - M

a d d i c t i o n r e s e a r c h c e n t e r i n v e n t o r y - m a r i j u a n a ; B D I

b o d y d i s a b i l i t y i n d e x ; B P I

W i s c o n s i n b r i e f p a i n i n v e n t o r y ; B R B - N

b r i e f r e p e a t a b l e b a t t e r y o f n e u r o p s y c h o l o g i c a l t e s t s ;

B S - 1

1

b o x s c a l e ; C B M

c a n n a b i n o i d b a s e d m e d i c i n e ; D H C

d i h y d r o c o d e i n e ; G H Q

g e n e r a l h e a l t h q u e s t i o n n a i r e ; H A D S

h o s p i t a l a n x i e t y a n d d e p r e s s i o n s c a l e ; M P Q

M c G i l l p a i n

q u e s t i o n n a i r e ; N P S

n e u r o p a t h i c p a i n s c a l e ; N R S

n u m e r i c a l r a t i n g s c a l e ; P D I

p a i n d i s a b i l i t y i n d e x ; P G I C

p a t i e n t g l o b a l i m p r e s s i o n o f c h a n g e ; p . o .

p e r o r e m ; p t .

p o i n t ; S F - 3

6

s h o r t f o r m h e a l t h q u e s t i o n n a i r e ; S F - M P Q

s h o r t f o r m o f M c G i l l q u e s t i o n n a i r e ; T M T

t r i a l m a k i n g t e s t ; U M N S

( c h r o n i c ) u p p e r m o t o r n e u r o n s y n d r o m e ; V A S

v i s u a l a n a l o g u e s c a l e ;

V R S

v e r b a l r a t i n g s c a l e .

* D o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d c r o s s o v e r ; o p e n - l a

b e l , n o p l a c e b o ;

d o u b l e - b

l i n d , c

r o s s o v e r ; D o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d .




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symptoms versus placebo. Sleep quality disturbancescores were improved in patients receiving either activedrug versus placebo. Eighty percent of the patients choseto enter an open-label study with Sativex after comple-tion of this randomized study.

CB 2 receptor immunoreactivity has been reported innormal and injured human DRG neurons, brachial plexusnerves, and neuromas, as well as peripheral nerve -bers. 151 However, upregulation of CB 2 receptor immu-noreactivity was specically observed in injured humannerve specimens and avulsed DRG obtained during sur-gery for brachial plexus repair. 151 These observationscorrespond to preclinical observations of cannabinoidreceptor upregulation after nerve injury. 18 However, pos-sible changes in CB 1 receptor immunoreactivity were notevaluated in the human tissue, and therefore can not beexcluded.

Mixed neuropathic painRecruitment of a patient population suffering from a

specic form of neuropathic pain can be a difcult pros-pect; therefore, several studies include patients in whichneuropathic pain is associated with different diseasestates or injuries ( Table 8 ). A 21-patient study reportedthat ajulemic acid (CT-3) suppressed mixed forms of neuropathic pain, as assessed with the VAS, in the morn-ing (3 h after drug administration), but not in the after-noon (8 h after drug administration). 152 Eighteen of thosesame patients participated in stimulus-evoked pain test-ing during the study, and those patients showed a trend

toward decr eas ed mechanical allodynia after CT-3 ad-ministration. 153 CT-3 binds with high afnity to bothCB 1 and CB 2 recept ors, and also binds with low afnityto PPAR receptors. 154 CT-3 has limited CNS availabil-ity, 69 which translates into fewer CB 1 -mediated side-effects.

Smoking cannabis cigarettes also improved spontane-ous pain relief and pain unpleasantness VAS ratings inpatients suffering from mixed forms of ne uro pathic pain,but failed to alter stimulus-evoked pain. 155 This studyreported that cannabinoids compounded the decreasedneurocognitive performance of patients that was present

at bas eline. Using an N of 1 preparation, Notcutt etal. 156 determined if patients experienced improvementsin pain after a 2-week open-label phase with Sativexprior to initiation of the double-blind, placebo-controlledcrossover phase of the study. 9 -THC and Sativex, butnot placebo or CBD, reduced the VAS rating of the t woworst pain symptoms during the crossover phase. 156

Quality of s leep was improved by all cannabinoid-basedmedications 156 and therefore may contribute to the ther-apeutic potential of the cannabinoids. By contrast, opioidanalgesics produce deleterious effects on sleep architec-ture, including reduct ions in slow wave sleep and pro-motion of sleep apnea. 157,158 A similarly structured study

reported improved pain ratings (VAS) and spasticity se-verity after CBD and 9 -THC in patients with mixedneuropathic pain. 159 9 -THC and Sativex also improvedmuscle spasms and spasticity severity. 159

Sativex improved pain ratings as measured with theNRS in a 5-week, double-blind, placebo-controlled studyperformed in patients experiencing unilateral neuro-pathic pain. 133 In this study, Sativex reduced mechanicaldynamic and punctate allodynia, and improved sleep dis-turbances. 133 Seventy-one percent of the patients testedchose to continue to the open-label study of Sativex with63% withdrawing by the end of the study for variousreasons. Nabilone (Cesamet) decreased measures of spasticity-related pain (11-point box test) in patients ex-periencing chronic upper motor neuron syndrome asso-ciated with a number of pain syndromes. 160 In a retro-spective review of patient charts at the Pain Center of theMcGill University Health Center from 1999 to 2003, 161

75% of patients received some benet from takingNabilone (whether it came in the form of pain relief,improved sleep, decreased nausea, or increased appetite).

Two studies have examined the effects of cannabinoid-based medications in patients suffering from spinal cordinjuries. An early case study reported pain relief andimprovement in spasticity in a patient with a spinal cordinjury after oral 9 -THC. 162 A later study reported that18% of the patients with spinal cord injuries reportedpain relief after treatment with oral dronabinol (mean, 31mg per day), whereas 23% experienced enhancement of pain resulting in subsequent withdrawal by several pa-

tients. 163 Changes in experimental design after initiationof the study complicate interpretation of these latter nd-ings. 163

CaveatsWe are aware of only two clinical studies that have

failed to report efcacy of cannabinoids, rela tive to pla-cebo, for treatment of mixed neuropathic pain. 164,165 Ouranalysis of the study by Clermont-Gnamien et al. 165 isrestricted to information provided in the abstract, pub-lished in English. Both of these studies used eight orfewer subjects and evaluated dronabinol titrated to a dose

of 25 mg/day (where tolerated). The me an dose was16.6 6.5 mg oral dron abin ol in one study 164 and 156 mg in the other study. 165 The two studies associatedwith negative outcomes for cannabinoids in managingneuropathic pain shared several common features: 1)evaluation of mixed neuropathic pain syndromes knownto be refractory to multiple analgesic treatments, 2) eval-uation of orally-administered 9 -THC (dronabinol) asopposed to mixtures of 9 -THC and CBD, or smokedmarijuana, 3) small numbers of subjects, and 4) obser-vation of prominent side effects (e.g., sedation) resultingin high dropout rates. One study reported side effects thatwere more prominent in older patients and did not cor-




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relate with analgesia. 164 Of course, one difculty in eval-uating efcacy of analgesics in patients with neuropathicpain refractory to all known treatments is that there is noindication that these patients would respond favorably toany analgesic under the study conditions. In a thirdstudy, effects of Nabilone were compared with dihydro-codeine in a randomized, crossover, double-blind studyof 3-months duration that did not include a pharmaco-logically inert placebo condition. In this latter study, 166 itwas concluded that the weak opioid dihydrocodeine wasa statistically better treatment for chronic neuropathicpain than Nabilone. 166 Patients in this study exhibited amean baseline VAS rating of 69.6 mm on a 0 to 100 mmVAS scale; mean VAS ratings were 59.93 24.42 mmand 58.58 24.08 mm for patients taking Nabilone anddihydrocodeine, respectively. However, the authorsnoted that a small number of subjects responded well toNabilone, and side effects were generally mild and in theexpected range. 166 Benets of an add-on treatment withNabilone have nonetheless been noted in patients withchronic therapy-resistant pain (observed in a causal re-lationship with a pathological status of the skeletal andlocomotor system). 167 Oral dronabinol produced signif-icant pain relief versus placebo when combined withopioid therapy in both a double-blind, placebo-controlledcrossover phase and a subsequent open-label exten-sion. 168 Patients also reported improvements in sleepproblems and disturbances while experiencing an in-crease in sleep adequacy in the open-label phase of thestudy. 168 Thus, caution should be exerted prior to con-cluding that side effects of cannabinoids seriously limitthe therapeutic potential of cannabinoid pharmacothera-pies for pain. Combination therapies, including a canna-binoid and opioid analgesic, show efcacy for treatment-resistant neuropathic pain and may be used to limit dosesof analgesics or adjuvants associated with adverse sideeffects.

Side effectsDiverse neuropathic pain states (characterized as

idiopathic, diabetic, immune-mediated, cobalamin-de-ciency related, monoclonal gammopathy-related, alco-hol abuse-related, and other) were recently examined ina prospective evaluation of specic chronic polyneurop-athy syndromes and their response to pharmacologicaltherapies. 169 Intolerable side effects were observed in allgroups of patients receiving either gabapentainoids, tri-cyclic antidepressants, anticonvulsants, cannabinoids(Nabilone or Sativex), or topical agents. 169 Notably, thepresence of intolerable side effects was similar amongthe different classes of medications. 169 In this study,most forms of neuropathic pain had similar prevalencerates and responsiveness to the different pharmacother-apies evaluated. 169

A recent systematic review of adverse effects of med-ical cannabinoids concluded that most adverse events(96.6%) were not serious and no serious adverse eventswere related exclusively to cannabinoid administration.Moreover, 99% of serious adverse events from rando m-ized clinical trials were reported in only two trials. 170

Greater numbers of nonserious adverse events wer e ob-served after cannabinoid treatment, as expected. 170 Sideeffects were equally associated with the different canna-binoid pharmacotherapies; the average rate of nonseriousadverse events was higher in pat ients receiving Sativexor oral 9 -THC than controls. 170 Thus, the main burdenfor the clinician is to balance therapeutic efcacy withthe r isk of intolerable side effects in the specic pa-tient. 169 High-quality trials of long-term exposure to can-nabinoids-based medications, together with careful mon-itoring of patients, are required to better characterizesafety issues related to the use of medical cannabi-

noids. 170

CONCLUSIONS

Cannabis has been used for pain relief for centuries,although the mechanism underlying their analgesic ef-fects was poorly understood until the discovery of can-nabinoid receptors, and their endogenous ligands in the1990s. During the last two decades, a large number of research articles have demonstrated the efcacy of can-nabinoids and modulators of the endocannabinoid sys-tem in suppressing neuropathic pain in animal models.

Cannabinoids suppress hyperalgesia and allodynia (i.e.,mechanical allodynia, mechanical hyperalgesia, thermalhyperalgesia, and cold allodynia where evaluated), in-duced by diverse neuropathic pain states through CB 1and CB 2 specic mechanisms. These studies have eluci-dated neuronal as well as nonneuronal sites (i.e., acti-vated microglia) of action for cannabinoids in suppress-ing pathological pain states and documented regulatorychanges in cannabinoid receptors and endocannabinoidaccumulation in response to peripheral or central nervoussystem injury. Clinical studies largely reafrm that can-nabinoids show efcacy in suppressing diverse neuro-

pathic pain states in humans. The psychoactive effects of centrally-acting cannabinoid agonists, nonetheless, rep-resent a challenge for pain pharmacotherapies that di-rectly activate CB 1 receptors in the brain. However, non-serious adverse events (e.g., dizziness), which pose themajor limitation to patient compliance with pharmaco-therapy, are not unique to cannabinoids. Approaches thatserve to minimize unwanted CNS side effects (e.g., bycombining 9 -THC with CBD, or by targeting CB 2 re-ceptors, peripheral CB 1 receptors, or the endocannabi-noid system) represent an important direction for futureresearch and clinical evaluation. The present review sug-gests that cannabinoids show promise for treatment of




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neuropathic pain in humans either alone or as an add-onto other therapeutic agents. Therefore, further evalua-tions of safety proles associated with long-term effectsof cannabinoids are warranted.

Acknowledgements: This work was supported by grants no.DA021644 and grant no. DA022478 (AGH). E.J.R. is sup-ported by an APS and a Psi Chi Graduate Research Grant.

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