Organismic variables and pain inhibition: Roles of gender and aging

Brain Research Bulletin, Vol. 21, pp. 947-953. 0 Pergamon Press plc, 1988. Printed in the U.S.A. 0361-9230188 $3.00 + .OO

Organismic Variables and Pain Inhibition: Roles of Gender and Aging

RICHARD J. BODNAR, MARIA-TERESA ROMERO’ AND ELISSE KRAMER2

Department of Psychology and Neuro-Psychology Doctoral Sub-Program Queens College, CUNY, Flushing, NY 11367

BODNAR, R. J., M.-T. ROMERO AND E. KRAMER. Organismic variables and pain inhibition: Roles of gender and aging. BRAIN RES BULL 21(6) 947-953, 1988.-Multiple pain-inhibitory systems dependent upon both opioid and nonopioid mechanisms of action have been identified, particularly in the rodent. The experimental subject has typically been the young, adult male rat, and generalizations concerning these systems have been made from this subject pool. This review focuses upon the roles of two organismic factors, aging and gender, in the modulation of analgesic processes. Using an array of age cohorts (4, 9, 14, 19, 24 months), these data illustrate that aging produces differential decrements in the analgesic responses following morphine, different parameters of footshock, continuous cold-water swims (CCWS: a nonopioid stressor), intermittent cold-water swims (ICWS: an opioid stressor) and 2-deoxy-D-glucose (a mixed opioid/nonopioid stressor). In contrast, neither beta-endorphin nor food deprivation analgesia is affected by aging. This review identities that CCWS and ICWS analgesia are sensitive to gender differences, gonadectomy differences and steroid replacement differences such that females display less analgesia than males, gonadectomy reduces both analgesic responses, and that testosterone is most effective in reinstating gonadectomy-induced analgesic deficits. These data are considered in terms of therapeutic implications for the organismic variables under study as well as for the conceptual and methodological modifications that must be made in studying intrinsic pain inhibition.

Pain Analgesia Steroid replacement

Gender Aging Opioid response Nonopioid response Gonadectomy

OVER the past decade, multiple pain-inhibitory systems have been described for rodents which have applicability to primate and human systems as well. Although some of these systems [see reviews: (8, 41, 117, 118)] are activated by one or more of the endogenous opioid peptide families [see review: (6)], other pain-inhibitory systems appear to act inde- pendently of the opioid peptides. Three major techniques have been used to indicate differentiations between opioid and nonopioid analgesic systems: a) analgesia induced by nonopioid peptides, b) stimulation-produced analgesia, and c) environmental analgesia. Nonopioid peptide analgesia has been studied in terms of opioid and nonopioid mechanisms of action. For instance, while vasopressin and neurotensin analgesia are not mediated by the endogenous opioids (10, 11, 26,34,35,65,66,84,88), substance P analgesia is .dependent upon endogenous opioid systems (75,109). Since the initial discovery of stimulation-produced analgesia [e.g., (78,95)] corresponded closely with the discovery of the opiate receptor (91, 105, 1 lo), subsequent studies evaluated this relationship. Stimulation-produced analgesia was found to be blocked by opiate receptor antagonism in some (58,87), but not all (90,119) studies. These discrepancies were resolved by observations that stimulation-produced analgesia could be elicited from dorsal and ventral periaqueductal midbrain sites, but that only the latter was sensitive to both naloxone

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reversal (28) and nucleus raphe magnus lesions (93). The third means of distinguishing opioid and nonopioid systems is environmental analgesia. Acute exposure to certain stressful stimuli or environmental situations produces analgesia; repeated exposure to the same stimuli produces adapation to the stressful stimuli in some situations, but not others [see reviews: (1, 15, 17, 64, 71, 82)]. Varying the parameters of certain stressors was found to be a critical determinant of opioid or nonopioid modulation of these analgesic responses, especially for footshock analgesia (51, 70, 112, 114). Subsequently, a similar pattern of effects was demonstrated for analgesia following cold-water swims (20, 22, 25, 31-33, 45, 46, 88, 111). The physiological and pharmacological substrates of these opioid and nonopioid forms of analgesia have been described elsewhere [see reviews: (16, 70, 73, 115)].

Young adult male rats were typically employed as subjects to characterize these multiple analgesic systems. How- ever, little was actually known about the effects of organismic variables upon the integrity of opioid and nonopioid analgesic responses. Our laboratory as well as others have focused upon two organismic factors, aging and gender, to determine whether these factors appreciably change opioid and nonopioid analgesic responses. Such considerations are essential since the pharmacological or physiological conse-

‘Present address: Department of Psychology, Barnard College of Columbia University, New York, NY. *Present address: Department of Geriatric Psychiatry, Mt. Sinai School of Medicine, New York, NY.

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94x BODNAR, ROMERO AND KRAMER

quences of development of new techniques to combat pain dependent (30, 60, PO, 180 min) analyses of morphine states must take these factors into account for obvious analgesia indicated that the three older cohorts (14, 19 and 24 therapeutic and clinical purposes. months) displayed equivalent reductions on the jump test

such that eliminations of morphine analgesia were observed

AGING AND OPIOID AND NONOPIOID ANALGESIC RESPONSES

Although several laboratories evaluated the effects of aging upon basal pain thresholds and analgesia induced by morphine, these studies had several disadvantages. First, systematic evaluation by a particular laboratory of aging across several dimensions of pain inhibition was typically not done. Second, highly-variable definitions of an aged animal (P-30 months) produced problems. Third, analyses of effects typically employed a bimodal (‘young’ versus ‘old’) dichotomy. Early studies reported both reductions [e.g., (29, 50, 113)] and increases [e.g., (57, 85, SP)] in basal pain thresholds that varied as functions of age cohort and pain test. Therefore, it became apparent that a systematic analysis of analgesic effects would require multiple pain tests to assess generalizability or specificity of actions. Changes in opiate mechanisms as a function of age were also reported. Decreases in the binding characteristics, affinity and concen- trations of opiate receptors were observed in regional and whole-brain assays (5781) as well as decreases in levels of beta-endorphin, leu-enkephalin and met-enkephalin (4, 39, 43, 44). Despite these consistent decreases in endogenous opioid function during aging, early reports of effects of aging upon morphine analgesia were more inconsistent, including reductions (29, 59, 113), reductions and increases (108), and increases (103). Again, these studies varied in different dimensions, including definitions of aging (10-28 months), the use of ‘young-old’ dichotomies, the use of single pain tests, and a consistent lack of either dose-response and/or time- response curves.

To evaluate systematically aging effects upon opioid and nonopioid forms of analgesia, our laboratory made the following adjustments. First, five cohorts of rats were tested: 4, 9, 14, 19 and 24 months of age. The use of multiple age cohorts allowed for the consideration as to whether any observed changes in analgesic effects were gradual and progressive rather than abrupt. Second, two nociceptive measures were evaluated: the tail-flick test which measures reactivity to heat and is considered to have primarily a spinal component (36), and the jump test which measures reactivity to shock and is considered to be primarily supraspinally- mediated (40). Third, since age-related effects upon analgesic processes could be due to specific changes in pain- inhibitory processes or due to an overall shift in many responses to the analgesia-producing agent, a second physiological response was also assessed. Fourth, where possible, both dose-response and time-response functions were ascer- tained.

Our laboratory evaluated four analgesic responses in this manner: morphine, 2-deoxy-D-glucose, cold-water swims and beta-endorphin. These responses were chosen to sam- ple: a) opioid analgesic responses which dissociate from each other [e.g., (24,106)], b) an analgesic response (continuous cold-water swims: CCWS) which is insensitive to opioid mediation across several dimensions (20,22,23,25,63, 120), and c) an analgesic response (2-deoxy-D-glucose: 2DG) which is partially mediated through opioid processes (19,107).

Morphine analgesia displayed age-related decrements which differed as a function of the pain test employed (68). The dose-dependent (1, 2.5, 5 and 10 mgikg, SC) and time-

at doses as high as 10 mg/kg across ihe time course. A biphasic effect of aging upon morphine analgesia on the tail- flick test was observed with the three older groups showing significant declines in this response 30 min after drug administration and significant increases in this response 180 min after drug administration. That aging produced differential effects as a function of the pain test eliminated an explana- tion of age-related pharmacokinetic effects (e.g., differential drug sequestration) as a possible mechanism for the effects observed on the tail-flick test. Further, the changes in analgesic processes were not accompanied by a corresponding change in morphine hyperthermia. Interestingly, the age- related pattern of effects were not observed for analgesia induced by beta-endorphin (97). Rats aged 8, 18 and 30 months which received beta-endorphin (0.1, 0.5, 1 and 5 Kg, ICV) displayed similar analgesia of the tail-flick test for up to 60 min following injection. The insensitivity of beta- endorphin analgesia to aging is also striking given the age- related reductions in endogenous beta-endorphin (4, 5, 37, 39, 42, 44, 83). These data suggest striking differences in the ability of different opiate receptor agonists to elicit analgesic responses in the face of aging. Age-related declines have been demonstrated in only mu-sensitive assays (57, 80, 81). Since multiple opiate receptor subtypes [mu, delta, kappa, sigma, epsilon: (72, 77, 104, 116)] exist, it will be important to assess analgesia induced by agonists of different receptor subtypes across age groups. This might facilitate treatment of pain states in aging populations so that those agonists and receptor subtypes that are insensitive to the aging process, yet produce analgesia would be used preferentially in clinical settings.

Environmental analgesia is also sensitive to aging; both CCWS analgesia and 2DG analgesia displayed significant reductions in analgesic magnitude as a function of advancing age cohorts (67,69). However, the pattern of age-related declines differed between stressors and as compared to that observed for morphine (68). 2DG analgesia displayed a progressive decline in analgesic magnitude as a function of age on both tests. The tail-flick test showed significant correla- tions between the analgesic magnitude of 2DG and the age of the animal, accounting for up to 48% of the variance. Nota- bly, the decline in 2DG analgesia across cohorts was matched by a corresponding decline in 2DG hyperphagia such that the two oldest cohorts actually displayed significant hypophagia following 2DG. Thus the age-related declines in 2DG analgesia and hyperphagia might be related to overall age-related declines in glucoprivic responses noted through adulthood, including insulin release and glucose tolerance (27, 94, 102). CCWS analgesia also displayed age- related declines in analgesia; the pattern however appeared to be somewhat test-specific (67). On the tail-flick test, CCWS analgesia was intact in the four youngest cohorts, and eliminated in the oldest cohort. CCWS analgesia on the jump test displayed progressive age-related declines which were significantly lower in the three oldest cohorts. CCWS hypothermia was significantly potentiated in the three oldest cohorts, indicating both a progressive inability to cope with thermoregulation as a function of age as well as a clear dissociation between age-related effects upon analgesia and hypothermic responses following CCWS. Such dissociations between CCWS analgesia and hypothermia are quite com-

ANALGESIA, AGING AND GENDER 949

mon following a number of manipulations [see review: (16)], and suggest that the age-related effects upon analgesia induced by this nonopioid-mediated stressor may involve selective changes in nonopioid pain-inhibitory mechanisms.

Data from other laboratories also appear to support the observed general reduction in analgesic responsivity in aging. Shock delivered to either the forepaws or hindpaws produces opioid and nonopioid forms of analgesia respectively which are independent of ho~on~ mech~isms (79). Hamm and Knisely (5253) found that each of these forms of footshock analgesia was reduced in aged animals. Gimrdot and Holloway (4546) reported that while CCWS analgesia is mediated by nonopioid mechanisms, acute exposure to intermittent cold-water swims (ICWS) produced analgesia which is both cross-tolerant with morphine analgesia and blocked by naltrexone. This pattern is affected by aging. While young rats exposed to chronic ICWS displayed analgesic adaptation and analgesic cross-tolerance with morphine, aged rats exhibited marked impairments in adaptation to ICWS and a failure to develop cross-tolerance (47-49). There is one difference between our work and that of another laboratory (55): while we reported age-related declines in CCWS analgesia (67), they found that aging potentiated CCWS analgesia. However, a major procedural variable may account for such differences. In an effort to control for weight as a potential confounding variable in assessing age- related differences in analgesic magnitude, we employed female rats which displayed minimal weight fluctuations across cohorts. Hamm and co-workers employed two groups of males: 3-months (343 g) and 2fmonths (809 g). Our initial findings regarding CCWS analgesia (18) indicated that magnitude of CCWS analgesia and weight are positivety corre- lated. However, this may also represent an important gender difference (see following section). Finally, like the failure to observe age differences for beta-endorphin analgesia (97), Hamm and Knisely (54) failed to observe age-related decreases in analgesia following abrupt food deprivation (21, 56). Hence while the general trend in analgesic responsivity across age cohorts is a reduction in magnitude, there are some responses which appear insensitive to the aging process. These exceptions might represent an endogenous analgesic system insensitive to aging which might be sensitive to novel ph~acological or physiological activation. On the other hand, such responses may be due to some other un- known factor which may not be amenable to therapeutic intervention. It is clear at this juncture however that the major opioid-nonopioid and/or neural-neurohormonal characterizations of analgesic responses appear to decline as a function of age. Research at this point has systematically pinpointed the type and magnitude of decline in the rodent, which is merely suggestive of phylogeny in general How- ever, little has been done to determine whether such progressive declines can be retarded, stopped or even reversed. Elucidation of the endogenous mechanisms supposing these different forms of analgesia in young adult rodents may allow for clarification of changes in these systems across aging.

GENDER AND OPIOID AND NONOPIOID ANALGESIC RESPONSES

Like aging, gender differences in analgesic processes have largely not been considered. Young adult male rodents have typically been considered the ideal model for studies of intninSiC pain inhibition since estrous effects do not need to be controlled. Previous studies have focused upon changes in basal pain thresholds and morphine analgesia. Rats display gender-specific effects in their responsivity to noxious stim-

uh: shock thresholds of female rats are significantly lower than those of male rats [e.g., (7, 76, 89)l. Androgenized female rats display shock thresholds similar to that of intact male rats, while castrated male rats display shock thresholds similar to that of intact female rats (8,9), indicating a role for gonadal function in these responses. The gender differences in basal shock thresholds are accompanied by minor changes across the female estrous cycle. Flinch (detection) thresholds, but not jump (nociception) thresholds are altered in female rats with greatest sensitivity occurring during periods of greatest estrogen activity (38). Female rats and mice also display significantly less morphine analgesia following systemic administration than males (2,60-62). Again, gonadectomy produces parallel effects: castrated male rats display significantly less morphine analgesia than intact controls (30). Systemic morphine analgesia also appears sensitive to estrous influences in female rats with the greatest sensitivity observed in the late diestrous phase (3). The opioid-mediated analgesia induced by tailshock (74) is also sensitive to estrous influences: analgesia is greatest and smallest during estrous and metestrous respectively (101). Moreover, estradiol treatment alone, but not estradiol and progesterone combined to ovariectomized rats enhanced this form of shock analgesia.

Our laboratory again wished to ascertain whether there were similarities or differences in gender-specific effects upon opioid and nonopioid analgesic processes. In this re- gard, we chose the opioid analgesic response following ICWS (45,46) and the nonopioid analgesic response following CCWS (20, 22, 23, 25, 63, 120) as the basis for comparison. These paradigms again allowed the use of multiple nociceptive measures (tail-nick and jump tests) as well as a corresponding physiological measure (hypothe~ia). Our approach again attempted to be systematic: a) establishment of any gender-specific or estrous-specific effects, b) involvement of gonadal status through the use of gonadectomy, c) changes in opioid and nonopioid involvement as a function of gender or gonadal status, and d) involvement of gonadal steroids as possible modulators through supple- mentation in normal animals and replacement in gonadectomized animals.

The magnitudes of both CCWS and ICWS analgesia were signi~cantly lower in female rats than either age-matched or weight-matched male rats (96). Therefore, any changes in analgesic magnitude were not attributable to the positive correlation between analgesia and weight found earlier (18). Also, CCWS analgesia was not influenced by estrous factors in female rats, eliminating the possibility that fluctuations in circulating female gonadal steroids were causing the inherent gender difference. Therefore, analgesia induced by two swim stressors with different opioidnonopioid characterizations produced similar gender-specific patterns.

Steroids can act in two fund~ent~ly different modes: they can organize neural pathways responsible for repro- ductive and other steroid-sensitive behaviors, and/or they can activate these behaviors (92). While adult gonadectomy typically interferes with the latter effects, perinatal gonadectomy interferes with the former effect. The studies reported here (100) employed adult gonadectomy ; perinatal gonadectomy studies are currently underway in our laboratory. Rats received gonadectomy or sham surgery at least 1 month be- fore testing. Both castration in males and ovariectomy in females significantly reduced the magnitude of both CCWS and ICWS analgesia relative to same-sex sham-operated counterparts. Both forms of analgesia were significantly re-

BODNAR, ROMERO AND KRAMER

duced in castrated males to the level observed in sham females, an effect reminiscent for both basal thresholds (8,9) and morphine analgesia (30). Changes in neither CCWS nor ICWS hypothermia could account for the analgesic effects. Intact females displayed significantly greater CCWS and ICWS hypothermia than intact males; gonadectomy reduced the magnitude of both hypothermic responses. Further, neither activity during the swim nor changes in either body weight or basal thresholds could account for the analgesic patterns. The effectiveness of the gonadectomies was con- firmed by reductions (7792%) in male seminal vesicles and prostate glands, and in female uterine tissue. Therefore, it appears that gonadal steroids are necessary as m~uIating influences in both males and femates for the full expression of both opioid and nonopioid forms of analgesia. Further, the gender differences in analgesia also appear attributable to circulating male steroids given the lack of differences in CCWS and ICWS analgesia between castrated males and intact females.

The opioidinonopioid distinction between ICWS and CCWS analgesia respectively was formulated by studies using male rats as subjects. In examining opioid and nonopioid mediation of ICWS and CCWS analgesia respectively, we (99) found that this differentiation was dependent upon gender and not affected by gonadectomy. While both age-matched male and female rats failed to display changes in CCWS anaigesia following naloxone (14 mgikg, SC), only male rats displayed significant reductions in ICWS analgesia following opiate receptor antagonism. Naloxone failed to alter significantly ICWS analgesia in age-matched female rats. This effect was not due to weight differences since weight-matched male rats also displayed a significant dose- dependent (I-14 mgkg, SC) reversal of ICWS analgesia by naloxone. Gonadectomy failed to alter this relationship: castrated male rats, but not ovariectomized female rats, exhibited significant reductions in ICWS analgesia following naloxone. This indicates that the opioid modulation of ICWS analgesia is not linked through circulating male gonadai steroids, but that the gender differences in opioid mechanisms may be due to other factors. One prospective candi- date is the organizational role of perinatal steroids.

Steroid replacement in ovariectomized rats was differen- tialiy effective in enhancing analgesia induced by taiishock (101). Given the dramatic adult gonadectomy-induced reductions of both CCWS and ICWS analgesia, this suggested that circulating gonadal steroids played an activational role in these analgesic responses. Which steroids alone or in combination were responsible for such mediation was un- known. Testosterone proprionate (TP) and estradiol ben- zoate (EB) are highly effective in reinstating sexual behavior following gonadectomy [e.g., (12-14)]; therefore. we used these steroids to examine whether they would reinstate analgesic magnitudes in castrated rats following replacement therapy and/or potentiate analgesic magnitudes in intact rats following suppIementat~on. Effects upon the former, but not the latter paradigm would speak to an activational modulatory influence. Effects upon both paradigms would only speak to steroid effects as ‘drugs,’ that is, absolute levels as the important variable. Thus our laboratory (98) evaluated the effects of TP and EB administered over a chronic injection regimen upon CCWS and ICWS analgesia in intact and gonadectomized rats. The doses and injection regimens of TP (2 mg/kg, IP, 2 weeks prior to and during testing) and EB (4 &kg. IP. 1 week prior to and during testing) were chosen for their ability to fully reinstate sexual behavior in gonadec-

tomized animals (12-14). In intact male rats, TP only significantly enhanced CCWS analgesia on the tail-flick test; EB was without effect in intact males. However, both steroids reinstated both CCWS and ICWS analgesia in castrated males to levels observed in intact males. In intact females, EB only significantly decreased CCWS analgesia on the tail-flick test; TP was without effect in intact females. TP reinstated both CCWS and ICWS analgesia in ovariectomized females to levels observed in intact females. EB only reinstated ICWS analgesia in ovariectomized females on the jump test, but was otherwise ineffective. The steroid repIacement effects could not be explained by corresponding changes in CCWS and ICWS hypothe~ia. Thus, TP was far more effective than EB in reinstating both forms of analgesia in gonadectomized rats, while generally failing to alter analgesic magnitudes in intact rats. This is interesting since both steroids were capable of increasing the sizes of accessory sexual organs in gonadectomized rats. These data suggest that TP is implicated in the modulation of these gender- sensitive and gonadectomy-sensitive responses.

The ability of adult gonadectomy to reduce opioid and nonopioid analgesia, together with the ability of gonadal steroid replacement therapy to reinstate the analgesic deficits in gonadectomized rats without consistently affecting intact rats, indicates that the gonadal system is involved in activational modulation of intrinsic pain-inhibition. The specificity of this response is evident by the failure of gonadectomy and/or replacement therapy to produce corresponding changes in CCWS and ICWS hyperthermia. Moreover, there was correspondence between the loss of analgesia and the decrease in accessory sexual organ size following gonadectomy, and the reinstatement of both parameters following steroid replacement, particularly with TP. These studies thus have identified gender, gonadectomy and steroid factors in analgesic responses, but have not elucidated a mechanism and/or site of action. In terms of gonadal modulation of these analgesic responses, three sites are apparent: a) a spinal locus, particularty since vaginal stimulation anaigesia appears to be modulated at this level isee review: (a)], b) a hypothalamic locus. particularty since CCWS analgesia is dependent upon the medial-basal hypothalamus for its full expression (2,16), or c) a peripheral locus since CCWS analgesia is dependent upon peripheral factors [e.g., pituitary-adrenal axis: (16)] for its full expression. Therefore, future studies need to pinpoint the site of action of gonadal modulation so as to then determine mechanism of action. As indicated earlier, steroids can conceivably exert activational and organizational effects upon gender-sensitive and gonadal-sensitive behaviors (92). The studies reported herein illustrate the importance of activational mechanisms. Our laboratory is currently examining organizational mechanisms by using perinatai gonadectomy to determine changes in analgesic responses, and if so, the effectiveness and timing of steroid replacement therapy. Finally, the use of TP and EB as prototypical gonadal steroids is not exhaus- tive, and further studies employing other gonadal steroids. alone or in combination will be necessary to elucidate mechanisms of action.

IMPLICATIONS

This review, as well as the developmental and phylogenetic approaches taken by others in the Omnitech Symposium at the Society for Neuroscience meeting, stress the emerging importance of organismic variables in the study of pain-inhibitory mechanisms. This review has indicated

ANALGESIA, AGING AND GENDER

how these emerging research concepts have explored differences as a function of either aging or gender, and thereby provide suggestions of potential clinical and/or therapeutic importance. However, these differences are equally important on a conceptual and methodological basis. The description of some of the endogenous opioid systems in pain inhibition is becoming more and more complete [e.g., (6,41, 117, 118)]. However, it is clear that much further work is necessary to delineate the precise mechanisms of action of other endogenous opioid systems, as well as identifying and describing the sites and mechanisms of action of nonopioid peptides and transmitters in analgesia. To accomplish this, one must often encounter subtle organismic variable differences which may change interpretation of the essential fea- tures of these latter systems. It is important to isolate those variables which are descriptive of the intrinsic system or

9.51

systems to be studied, from those modulatory variables which may or may not have direct relevance to the analgesia function, but rather may modify it under particular circum- stances. Hopefully, a full parametric analysis of each and every organismic variable on each aspect of pain inhibition will not have to be done, but given the effects reported herein, they certainly bear scrutiny in making interpretations and generalizations about data.

ACKNOWLEDGEMENTS

This research was supported by PSCiCUNY Grants 6-66351 and 6-67241 and NIH BRSG RR07064. The authors wish to thank Drs. M. Kavaliers and K. P. Ossenkopp for their kind invitation to par- ticipate in the symposium from which this review was derived.

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Organismic variables and pain inhibition: Roles of gender and aging