Role of gonadal hormones on mu-opioid-stimulated [ ³⁵S] GTPγS binding and morphine-mediated antinociception in male and female Sprague-Dawley rats

Rationale: Male rats are more sensitive to morphine-mediated antinociception than female rats. A role for gonadal hormones in this sex difference has not been clearly defined. Objectives: To test the hypothesis that in vivo manipulation of gonadal hormones alters morphine-mediated G protein activation and leads to changes in morphine-mediated antinociception. Methods: Adult male and female rats were gonadectomized and treated with either estradiol or testosterone in the females or testosterone in the male for up to 10 days. The ability of morphine and the peptidic mu-opioid agonist [D-Ala ², N-MePhe ⁴, Gly-ol]-enkephalin (DAMGO) to stimulate [ ³⁵S]GTPγS binding was measured in brain slices. In separate groups of identically treated rats, the antinociceptive response to morphine was determined using the warm-water tail-withdrawal assay. Results: In the thalamus, morphine- and DAMGO-stimulated [ ³⁵S]GTPγS binding was reduced by estradiol treatment of gonadectomized females compared to gonadectomized females treated with vehicle or testosterone. In the nucleus accumbens, the morphine-stimulated [ ³⁵S]GTPγS binding was increased by estradiol treatment of gonadectomized females. In males, castration caused an increase in agonist-stimulated binding in the thalamus and a reduction in the amygdala compared with intact males. No significant changes were seen in mu-opioid agonist-stimulated [ ³⁵S]GTPγS binding in other brain regions. There was no difference in antinociception following the systemic administration of morphine across the different hormonal manipulation conditions and the greater sensitivity of males was maintained irrespective of the treatment conditions. Conclusions: The modulation of mu-opioid receptor activation of G proteins by manipulation of sex hormones is region-specific and not reflected in antinociceptive responsiveness to morphine.