Comparison of Antinociceptive Effects Induced by Kappa Opioid Agonists in Male and Female Mice

Abstract

A recent clinical report suggested that kappa opioids such as nalbuphine and butorphanol produced greater pain relief in women than in men. However, both compounds have been characterized as partial agonists with mixed mu/kappa opioid actions in animal studies. The aim of this study was to evaluate whether there is a sex difference in antinociception caused by nalbuphine and butorphanol as well as more selective kappa opioid agonists including U50,488 and Cl-977 in mice. In the acid-induced writhing assay, all compounds (U50,488: 1-10 mg/kg; Cl-977: 0.01-0.1 mg/kg; nalbuphine: 1-320 mg/kg; butorphanol: 0.032-0.32 mg/kg) dose-dependently inhibited writhing, but there were no sex-related differences found when comparing ED(50) values in male and female mice. In the warm water (48°C) tail withdrawal assay, U50,488 (10-100 mg/kg) and Cl-977 (0.1-3.2 mg/kg) also dose-dependently produced antinociception, although there were no sex-related differences observed. Nalbuphine (10-320 mg/kg) did not have antinociceptive effects under this condition. On the other hand, butorphanol (0.32-32 mg/kg) produced greater antinociception in male (50% MPE) than female mice (20% MPE). Further antagonist studies revealed that butorphanol is a mixed mu/kappa opioid with low efficacy. In summary, there were no sex-related differences in response to more selective kappa opioid agonists on antinociception in mice under these conditions.