Sex differences in opioid antinociception.

Previous studies indicate that mu opioid agonists such as morphine may produce greater antinociception in male than in female rodents. The present study was designed to investigate the generality of this finding across dose, time and type of opioid agonist. In adult female and male Sprague-Dawley rats, time-effect curves were obtained for vehicle and three doses each of the mu agonists fentanyl and buprenorphine, the kappa agonists (5alpha,7alpha,8alpha)-(-)-N-methyl-[7-(1-pyrrolidinyl )-1-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593) and bremazocine and the delta agonists [D-Pen2,D-Pen5]enkephalin (DPDPE) and deltorphin on the 52 degrees C hot-plate and tail-withdrawal (immersion) assays. There were sex differences in the antinociceptive effects of the two kappa agonists and the two delta agonists, but the differences were assay-, dose- and/or time-dependent. Peak effects of U69,593 on tail withdrawal and DPDPE on hot plate tended to occur earlier in females than in males, and bremazocine produced greater tail-withdrawal antinociception in females than in males, whereas the highest doses of the two delta opioids produced greater hot-plate antinociception in males than in females. These results contrast with several previous reports showing that male rodents are more sensitive than females to the antinociceptive effects of mu and kappa (but not delta) opioids. These discrepancies may be caused by the more comprehensive examination of sex differences across dose and time used in the present study; sex differences that are dose- or time-dependent may not be apparent if a single dose or time point is examined. In addition, repeated testing procedures used in the present study may produce different results than acute testing procedures would, if female and male rats develop opioid tolerance at different rates.