Sex differences in opioid antinociception: kappa and 'mixed action' agonists

A number of investigators have shown that male animals are more sensitive t han females to the antinociceptive effects of mu -opioid agonists. The pres ent study was conducted to examine sex differences in opioid antinociceptio n in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu -receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine. (-)-bremazocine, (-)-pentazocine , butorphanol and nalbuphine on the 50 or 54 degreesC hotplate and warm wat er tail withdrawal assays; spontaneous locomotor activity was measured 32-5 2 min post-injection in the same rats. On the hotplate assay, only butorpha nol (54 degreesC) and nalbuphine (50 degreesC) were significantly more pote nt in males than females. On the tail withdrawal assay, all agonists were s ignificantly more potent or efficacious in males than females at one or bot h temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses t o drug (50 degreesC experiment). These results suggest that (1) sex differe nces in antinociceptive effects of opioids are not mu -receptor-dependent. as they may occur with opioids known to have significant kappa -receptor-me diated activity; (2) the mechanisms underlying sex differences in kappa -op ioid antinociception may be primarily spinal rather than supraspinal; (3) s ex differences in antinociceptive effects of opioid agonists are not second ary to sex differences in their sedative effects. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.