Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Pain. 2010 Dec;151(3):806-815. doi: 10.1016/j.pain.2010.09.018.
This investigation determined whether the activation of the kappa opioid receptor (KOR) in the spinal cord produces estrogen-dependent, sex-specific modulation of acute and inflammation-induced persistent nociception. We demonstrate for the first time that KOR antinociception and gene expression are enhanced by exogenous or endogenous estrogen in the female. The lack of KOR antinociception and KOR gene expression are not altered by the hormonal status (testosterone or estrogen) in males. Cannulae were implanted intrathecally in male, gonadectomized male (GDX), intact and ovariectomized female (OVX) Sprague-Dawley rats. Estradiol was injected subcutaneously, 48h before testing (GDX+E and OVX+E). Intrathecal injection of U50,488H, a selective KOR agonist, dose dependently increased heat-evoked tail flick latencies (TFLs) in proestrous and OVX+E groups, but not in male, GDX, GDX+E, OVX, and diestrous groups. Further, estrogen dose-dependently enhanced the effect of U50,488H in OVX rats. KOR selective antagonist, nor-binaltorphimine (Nor-BNI), blocked the antinociceptive effect of U50,488H. U50,488H reversed the carrageenan-induced thermal hyperalgesia in OVX+E rats, but not in male or OVX rats. However, U50,488H treatment did not alter mechanical thresholds in any group, with or without inflammation. KOR gene expression was enhanced in proestrous and OVX+E groups as compared to any other group. We conclude that selective activation of KOR in the spinal cord produces sex-specific, stimulus- and estrogen-dependent attenuation of acute and inflammatory pain in the rat via estrogen-induced upregulation of the KOR gene expression in the spinal cord. These findings may further implicate estrogen dependence of KOR effects in learning, epilepsy, stress response, addiction etc.
这项研究旨在探讨脊髓κ 阿片受体（KOR）的激活是否会产生雌激素依赖性、性别特异性的急性和炎症性持续性疼痛调节。我们首次证明，雌性动物中外源性或内源性雌激素增强了 KOR 的抗伤害作用和基因表达。而雄性动物的激素状态（睾酮或雌激素）并不改变 KOR 的抗伤害作用和基因表达。雄性、去势雄性（GDX）、完整和去势雌性（OVX）Sprague-Dawley 大鼠的鞘内置管。雌二醇皮下注射，测试前 48 小时（GDX+E 和 OVX+E）。鞘内注射 U50,488H，一种选择性 KOR 激动剂，剂量依赖性地增加发情期和 OVX+E 组的热诱发尾部拍打潜伏期（TFL），但不增加雄性、GDX、GDX+E、OVX 和间情期组。此外，雌激素剂量依赖性地增强了 U50,488H 在 OVX 大鼠中的作用。KOR 选择性拮抗剂诺布他林（Nor-BNI）阻断了 U50,488H 的抗伤害作用。U50,488H 逆转了 OVX+E 大鼠的角叉菜胶诱导的热痛觉过敏，但对雄性或 OVX 大鼠没有影响。然而，U50,488H 处理并未改变任何组的机械阈值，无论是否有炎症。与任何其他组相比，发情期和 OVX+E 组的 KOR 基因表达增强。我们的结论是，选择性激活脊髓中的 KOR 通过雌激素诱导脊髓中 KOR 基因表达的上调，产生性别特异性、刺激和雌激素依赖性的急性和炎症性疼痛减轻，这可能进一步暗示 KOR 效应的雌激素依赖性在学习、癫痫、应激反应、成瘾等方面的作用。
