Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Psychopharmacology (Berl). 2011 Dec;218(3):483-92. doi: 10.1007/s00213-011-2335-z. Epub 2011 May 24.
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.
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.
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 [(35)S]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.
In the thalamus, morphine- and DAMGO-stimulated [(35)S]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 [(35)S]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 [(35)S]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.
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.
雄性大鼠对吗啡介导的镇痛作用比雌性大鼠更为敏感。 但是，性腺激素在这种性别差异中的作用尚未明确界定。
测试以下假设，即体内操纵性腺激素会改变吗啡介导的 G 蛋白激活，并导致吗啡介导的镇痛作用发生变化。
对成年雄性和雌性大鼠进行性腺切除术，并对雌性大鼠进行雌激素或睾丸激素处理，或对雄性大鼠进行睾丸激素处理，最多持续 10 天。 在脑切片中测量吗啡和肽类μ阿片样激动剂[D-Ala(2)，N-MePhe(4)，Gly-ol]-enkephalin(DAMGO)刺激[(35)S]GTPγS 结合的能力。 在经过相同处理的大鼠的其他组中，使用温水尾巴撤离试验测定吗啡的镇痛反应。
在丘脑，与用载体或睾丸激素处理的去势雌性大鼠相比，用雌激素处理的去势雌性大鼠的吗啡和 DAMGO 刺激的[(35)S]GTPγS 结合减少。 在伏隔核中，用雌激素处理去势雌性大鼠会增加吗啡刺激的[(35)S]GTPγS 结合。 在雄性中，与完整雄性相比，去势导致丘脑内激动剂刺激结合增加，杏仁核减少。 在其他脑区，未见μ阿片样激动剂刺激的[(35)S]GTPγS 结合有明显变化。 在不同的激素操作条件下，吗啡的全身给药后镇痛作用没有差异，雄性的敏感性增加与治疗条件无关。
通过操纵性激素来调节μ阿片受体对 G 蛋白的激活作用是具有区域特异性的，并且不会反映在对吗啡的镇痛反应性上。
