Capsaicin-induced hyperalgesia and μ-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 mu-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 mu-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.