Capsaicin-Induced Hyperalgesia and -Opioid-Induced Antihyperalgesia in Male and Female Fischer 344 Rats

The influence of sex in determining responses to opioid analgesics has been well established in rodents and monkeys in assays of short-lasting, phasic pain. The purpose of this investigation was to use a capsaicin model of tonic pain to evaluate sex differences in hyperalgesia and -opioid-induced antihyperalgesia in Fischer 344 (F344) rats. Capsaicin injected into the tail produced a dose-dependent thermal hyperalgesia in males and females, with the dose required to produce a comparable level of hyperalgesia being 3.0-fold higher in males than in females. These sex differences were modulated by gonadal hormones, inasmuch as gonadectomy increased the potency of capsaicin in males and decreased its potency in females. Morphine, buprenorphine, and dezocine administered by various routes [systemic (s.c.), local (in the tail), and central (i.c.v.)] generally produced marked antihyperalgesic effects in males and females. Although in most instances these opioids were equally potent and effective in males and females, selected doses of local and i.c.v. administered buprenorphine produced greater effects in females. When administered locally, the antihyperalgesic effects of morphine were mediated by peripheral opioid receptors in both males and females, since this effect was not reversed by i.c.v. naloxone methiodide. These data contrast with the finding that -opioids are more potent in male rodents in assays of phasic pain, thus suggesting that distinct mechanisms underlie male and female sensitivity to opioid antinociception in phasic and tonic pain models. These findings emphasize the need to test male and female rodents in tonic pain assays that may have greater relevance for human pain conditions. It is becoming increasingly clear that the sex of the organism is a critical determinant of responsiveness to nociceptive stimuli and opioid analgesics. In rodents and primates, for example, males are generally more sensitive to the acute antinociceptive effects of opioids than females in assays of thermal, electrical, and mechanical nociception (Kepler et al., 1991; Cicero et al., 1996; Negus and Mello 1999; Barrett et al., 2002). These findings do, however, contrast with those obtained in humans where the available data indicate that in the postsurgical setting, females are generally more sensitive than males to the antinociceptive effects of opioids (Gear et al., 1996, 1999). Nonhuman studies of sex differences have utilized acute, phasic pain tests (e.g., tail-flick, hot plate assay), in which a noxious stimulus is applied to a portion of the body for a brief period of time, and the trial is terminated when the animal executes an escape/withdrawal response (for a review, see Mogil et al., 2000). Animal models of tonic pain, in which nociception is prolonged and can be associated with inflammation and tissue damage, have been developed to model the profile of human clinical pain conditions, but not adapted to the study of sex differences in opioid antinociception. In these models, nociception is produced by the administration of one of a number of algogenic agents (e.g., formalin, capsaicin), and pain behaviors or responses to nociceptive stimuli are