Opioid Antinociception in Ovariectomized Monkeys: Comparison with Antinociception in Males and Effects of Estradiol Replacement

• Published in: The Journal of pharmacology and experimental therapeutics 1999-09, Vol.290 (3), p.1132-1140
• Main Authors: Negus, S S, Mello, N K
• Format: Article
• Language: English
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer - pharmacology; Analgesics, Non-Narcotic - pharmacology; Analgesics, Opioid - pharmacology; Animals; Dose-Response Relationship, Drug; Estradiol - analogs & derivatives; Estradiol - therapeutic use; Estrogen Replacement Therapy; Female; Hot Temperature; Macaca mulatta; Male; Nociceptors - drug effects; Ovariectomy; Pain - physiopathology; Receptors, Opioid, kappa - agonists; Receptors, Opioid, mu - agonists; Sex Factors
• ISSN: 0022-3565; 1521-0103

Baseline nociception and opioid antinociception were compared in male and ovariectomized female rhesus monkeys. Females were studied without estradiol replacement or during treatment with estradiol benzoate at doses (0.002 and 0.01 mg/kg/day) designed to mimic 17β-estradiol blood levels observed during different phases of the menstrual cycle and during pregnancy. Baseline sensitivity to thermal stimuli (42–54°C) was similar in male and ovariectomized female monkeys. The antinociceptive effects of the μ-opioid agonists fentanyl, morphine, butorphanol, and nalbuphine were examined at 50 and 54°C. There were no sex-related differences in the antinociceptive effects of the high-efficacy μ agonist fentanyl; however, the lower-efficacy μ agonists morphine, butorphanol, and nalbuphine produced greater antinociceptive effects in males than in untreated ovariectomized females. Because butorphanol and nalbuphine have low selectivity for μ versus κ receptors and may produce κ-agonist effects under some conditions, the high-efficacy, κ-selective agonist U50,488 was also studied. U50,488 also produced greater antinociceptive effects in males. Treatment with estradiol benzoate tended to enhance opioid antinociception in the ovariectomized females; however, this effect was significant only for butorphanol and U50,488 during treatment with the highest dose of estradiol benzoate. These findings suggest that opioid agonists usually produce greater antinociception in male monkeys than in females, and the magnitude of these sex-related differences may be inversely related to efficacy at μ receptors or selectivity for μ versus κ receptors. Estradiol appears to have little effect on μ-agonist antinociception in primates but may enhance the antinociceptive effects of κ agonists.