Agonist/antagonist properties of nalbuphine, butorphanol and (−)-pentazocine in male vs. female rats

Abstract

To determine whether sex differences in the effects of mixed-action opioids could be due to differential activity at mu or kappa receptors, agonist/antagonist properties of nalbuphine, butorphanol and (−)-pentazocine were compared in male vs. female rats using a diuresis test. In water-loaded rats (2-h test), nalbuphine and (−)-pentazocine dose-dependently increased urination similarly in both sexes, whereas butorphanol increased urination more in females than in males on a ml/kg basis. The diuretic effects of all three opioids were at least partially blocked by the kappa receptor-selective antagonist nor-binaltorphimine (nor-BNI, 5 mg/kg) in both sexes. Kappa receptor-mediated antagonism of diuresis induced by U69,593 (0.56 mg/kg) was only observed with butorphanol in males. In water-loaded rats (1-h test), nalbuphine did not suppress, and butorphanol and (−)-pentazocine significantly suppressed urination in males only; all three mixed-action opioids dose-dependently blocked the antidiuretic effect of the selective mu agonist fentanyl (0.056 mg/kg) in both sexes. The ability of nalbuphine and (−)-pentazocine to block fentanyl-induced antidiuresis was not affected by pretreatment with nor-BNI in either sex. In contrast, the ability of butorphanol to block fentanyl-induced antidiuresis was attenuated by pretreatment with nor-BNI in males but not in females. These results suggest that sex differences in the effects of these mixed-action opioids are primarily due to their greater relative efficacy at the mu receptor in male than in female rats; butorphanol also may have greater efficacy at kappa receptors in females than in males.