Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140, USA.
J Pharmacol Exp Ther. 2011 Nov;339(2):438-50. doi: 10.1124/jpet.111.183905. Epub 2011 Aug 12.
We examined whether sex differences in κ-opioid receptor (KOPR) pharmacology exist in guinea pigs, which are more similar to humans in the expression level and distribution of KOPR in the brain than rats and mice. The KOPR agonist trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzeneacetamide methanesulfonate (U50,488H) produced a dose-dependent increase in abnormal postures and immobility with more effects in males than females. Males also showed more U50,488H-induced antinociception in the paw pressure test than females. Pretreatment with the KOPR antagonist norbinaltorphimine blocked U50,488H-induced abnormal body postures and antinociception. In contrast, inhibition of cocaine-induced hyperambulation by U50,488H was more effective in females than males. Thus, sex differences in the effects of U50,488H are endpoint-dependent. We then examined whether sex differences in KOPR levels and KOPR-mediated G protein activation in brain regions may contribute to the observed differences using quantitative in vitro autoradiography of (3)H-(-)-N-methyl-N-(7-(1-pyrrolidinyl)1-oxaspiro(4,5)dec-8-yl)benzeacetamide ([(3)H]U69,593) binding to the KOPR and U50,488H-stimulated guanosine 5'-O-(3-[(35)S]thiotriphosphate ([(35)S]GTPγS) binding. Compared with females, males exhibited more [(3)H]U69,593 binding in the deep layers of somatosensory and insular cortices, claustrum, endopiriform nucleus, periaqueductal gray, and substantial nigra. Concomitantly, U50,488H-stimulated [(35)S]GTPγS binding was greater in males than females in the superficial and deep layers of somatosensory and insular cortices, caudate putamen, claustrum, medial geniculate nucleus, and cerebellum. In contrast, compared with males, females showed more U50,488H-stimulated [(35)S]GTPγS binding in the dentate gyrus and a trend of higher [(35)S]GTPγS binding in the hypothalamus. These data demonstrate that males and females differ in KOPR expression and KOPR-mediated G protein activation in distinct brain regions, which may contribute to the observed sex differences in KOPR-mediated pharmacology.
我们研究了在表达水平和脑内分布方面，豚鼠比大鼠和小鼠更类似于人类，κ-阿片受体（KOPR）药理学是否存在性别差异。KOPR 激动剂反式-（±）-3,4-二氯-N-甲基-N-[2-[1-吡咯烷基]-环己基]苯乙酰胺甲磺酸盐（U50,488H）在雄性和雌性动物中均引起剂量依赖性异常姿势和不动性增加，但在雄性中作用更强。雄性在爪压力试验中也表现出比雌性更强的 U50,488H 诱导的镇痛作用。KOPR 拮抗剂诺比那肽预处理可阻断 U50,488H 诱导的异常体位和镇痛作用。相反，U50,488H 抑制可卡因诱导的过度活动在雌性中的效果强于雄性。因此，U50,488H 作用的性别差异取决于终点。然后，我们使用定量体外放射自显影技术，通过 (3)H-(-)-N-甲基-N-(7-(1-吡咯烷基)-1-氧螺(4,5)癸-8-基)苯乙酰胺 ([(3)H]U69,593) 与 KOPR 的结合以及 U50,488H 刺激鸟苷 5'-O-(3-[(35)S]三磷酸 ([(35)S]GTPγS) 结合，研究了脑区 KOPR 水平和 KOPR 介导的 G 蛋白激活的性别差异是否可能导致观察到的差异。与雌性相比，雄性在感觉和岛叶皮质的深层、屏状核、内嗅核、导水管周围灰质和黑质中表现出更多的 [(3)H]U69,593 结合。同时，与雌性相比，U50,488H 刺激的 [(35)S]GTPγS 结合在感觉和岛叶皮质的浅层和深层、尾状核、屏状核、内侧膝状体核和小脑更强。相比之下，与雄性相比，雌性在齿状回中表现出更多的 U50,488H 刺激的 [(35)S]GTPγS 结合，并且在下丘脑中有更高 [(35)S]GTPγS 结合的趋势。这些数据表明，雄性和雌性在不同脑区的 KOPR 表达和 KOPR 介导的 G 蛋白激活存在差异，这可能导致观察到的 KOPR 介导的药理学性别差异。
