Analgesic Systems: Roles of Stress

Analgesic Systems: Roles of Stress and Sex Differences

Analgesic systems

The sex differences in central nervous system (CNS) morphology and function is becoming more detailed every day, in both humans and animals. Sex differences in analgesia can be accredited to various factors, from reproductive hormones and genes to environmental and socio-cultural factors. This review will focus on the role of stress and sex differences in modulating a subject's response to pain and to analgesic manipulations. In addition to their well-known influence on reproductive physiology and behavior, gonadal hormones have widespread, multivariate actions from bones to muscles to neural structures that are compatible with the diffuse symptomatology of many chronic painful syndromes and stress Islam, Cooper and Bodnar ()

Specific principles of the three papers-Aging, gender, and gonadectomy effects upon morphine antinociception in rats highlight their interaction with each other in modulating morphine antinociception. This presents the alterations in morphine antinociception in rats as functions of age, gender (male, female), and gonadal status (intact, gonadectomized) across a dose range and time course on the tail-flick test. In gender-specific and gonadectomy-specific effects upon swim analgesia and the role of steroid replacement therapy, the study has based on the effects of testosterone propionate (TP) upon CCWS and ICWS analgesia in intact sham-operated rats and in gonadectomized rats and examined roles of steroid supplementation and steroid replacement. Modulation of gender-specific effects upon swim analgesia in gonadectomized rats thus looks at the effects of castration in adult male rats and ovariectomy in adult female rats upon the gender-specific differences observed in CCWS and ICWS analgesia. Several factors that might account for any gender-specific and gonadectomy-specific effects upon these analgesic responses are evaluated, including changes in either post-operative body weights or baseline responses of the two nociceptive tests employed: the tail-flick test which measures reactivity to heat and the jump test which measures reactivity to shock.

Interactions among aging, gender, and gonadectomy effects upon morphine antinociception in rats-aging have generally been one of the critical organismic variables in modulating morphine antinociception. This is because it decreases the binding characteristics and concentrations of opiate receptors and decreases levels of beta-endorphin Leuenkephalin, and Met-enkephalin. Previous studies revealed that aging produced reductions, reductions and increases, or increases in morphine antinociception. Some of these conflicting results appear to be because of differences in the maturity of animals and a lack of either dose-response or time-response analyses. Gender is a second critical organismic variable in modulating antinociceptive stimuli in animals, with males displaying significantly greater magnitudes of effects gender differences have been observed for basal nociceptive thresholds, morphine antinociception, stress-reduced antinociception, and antinociception induced by noradrenergic and cholinergic agonists.

Methodology

Albino Sprague-Dawley rats (60 days of age) are housed individually in polyethylene cages and maintained on a 12-h light: 12-h dark cycle with rat chow and water available ad lib. At 90 days of age, two groups of male rats and two groups of female rats are matched on the basis of body weight. All rats are then anesthetized with chlorpromazine (3 mg/kg, IP) followed by ketamine (100 mg/ml sterile water/kg body weight, IM). One group of male rats is castrated by removal of the testes and testicular fat with a single 2-cm midscrotal incision. One group of female rats is ovariectomized by removal of the ovaries and ovarian fat with a dorsal incision. The second groups of male and female rats then receive sham surgery in which the organs are exposed, but not removed. All rats are allowed a minimum of 3 months to recover from surgery to allow full development of gonadectomy-induced weight changes.

Results and findings

Aging produced significant differences in both the magnitude and potency of morphine antinociception. First, intact female rats displayed significant age-related decreases in morphine antinociception. Gender produced significant differences in the magnitude and potency of morphine antinociception, although not as one might have predicted in earlier studies in which young males display significantly greater magnitudes of effects relative to young females. The data indicate that such organismic variables as age, gender, and reproductive status all interact with one another to modulate rodent responsiveness to morphine antinociception. Such differentiation as functions of age, gender, and gonadectomy indicate that nociceptive reactivity and antinociceptive efficacy are not homogeneous, and that such variables may have chemical relevance for the treatment of different forms of pain. These variables include, the increased sensitivity observed in male rats and decreased sensitivity in female rats, the presence of gender differences in opiate antinociception in young animals for supra-spinally mediated nociceptive responses, but not spinally mediated nociceptive responses, and the ability of ovariectomy to mitigate age-related declines m morphine antinociception observed m female rats.

Gender-Specific and Gonadectomy-Specific effects upon Swim Analgesia: Role of Steroid Replacement Therapy-Variations in the patterning of cold-water swims results in differential opioid and non-opioid modulation of subsequent analgesic responses in male rats similar to that observed for foot shock analgesia Romero, Cooper, et al.()

. Continuous cold-water swim (CCWS) analgesia in male rats is unaffected by either morphine tolerance or naloxone antagonism, is potentiated by the irreversible mu1 antagonist, naloxazone, and is reduced by the putative antienkephalinase, D-phenylalanine. In contrast, intermittent cold-water swim (ICWS) analgesia in male rats is both cross-tolerant with morphine analgesia and blocked by naltrexone. Both forms of analgesia decline as a function of age. Female rats displayed significantly less CCWS and ICWS analgesia than either age matched or weight-matched male rats.

Methodology

Albino Sprague-Dawley rats (90-100 days of age) are housed in same-sex pairs in wire mesh cages, and are maintained on a 12hr light: 12hr dark cycle. Purina rat chow and water are available ad lib. Male (450g) and female (280g) rats are matched into sham and gonadectomy groups on the basis of preoperative body weights. All rats are anesthetized with ketamine (100 mg/ml sterile water/kg body weight, IM). Castrations are performed by removing the testis and testicular fat following a single 2-cm mid scrotal incision. Ovariectomies are performed by removing the ovaries and ovarian fat through a dorsal approach. Sham surgeries for each gender occurred in which the organs are exposed, but not removed. All rats are allowed four weeks to recover from surgery to allow full development of any gonadectomy-induced weight changes which are monitored during the experimental period.

Results and findings

Although baseline tail-flick latencies failed to differ between males and females irrespective of treatment, jump thresholds of sham-operated males were significantly higher than those of females irrespective of treatment, confirming previous reports. Significant CCWS and ICWS analgesia were observed in all groups on both tests relative to no swim values. Naive sham-operated male rats displayed significantly greater CCWS analgesia on the tail flick and jump tests than naive females. The loss of gender differences was attributable to a decrease in analgesic magnitude on the tail-flick test in vehicle-treated males, and an increase in analgesic magnitude on the jump test in vehicle-treated females. The study produced two major sets of findings that include; gender-specific effects, but not gonadectomy-specific effects upon CCWS and ICWS analgesia were sensitive to a chronic regimen of chronic vehicle injections, and TP appeared to be effective in reversing gonadectomy-specific analgesic deficits Romero, Kepler, et al.()

Modulation of Gender

Specific Effects upon Swim Analgesia in Gonadectomized Rats-Rodents displays gender-specific effects both in their reactivity to noxious stimuli and in responses to certain analgesic manipulations. The significant hyper reactivity to shock observed in female rats appears to be mediated by gonadal function since androgenized females and normal males display similar shock threshold responses and since castrated males and normal females display similar shock threshold responses. Similarly both normal female rats and castrated male rats display significantly less morphine analgesia than normal male rats.

Methodology

Albino Sprague-Dawley rats (90-100 days of age) are housed in same-sex pairs in wire mesh cages and are maintained on a 12hr light: 12hr dark cycle. Purina rat chow and water are available ad lib. Seventeen male rats (range: 485-580 g) and 17 female rats (range: 234-320 g) are divided into groups matched on the basis of body weight. Rats are anesthetized with ketamine (100 mg/ml sterile water/kg body weight, IM). Ten male rats are castrated in which the testis and testicular fat are removed following a single 2-cm mid scrotal incision. Ten female rats are ovariectomized in which the ovaries and ovarian fat are removed through a dorsal approach. Seven male and seven female rats received sham surgery in which the organs are exposed, but not removed. Rats are allowed four weeks to recover from surgery to allow full development of any gonadectomy-induded weight changes which are monitored during the experimental period.