Receptor-selective antagonism of opioid antinociception in female versus male rats
Receptor-selective antagonism of opioid antinociception in female versus male rats
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DOI：
10.1097/00008877-200112000-00003
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发表时间：
2001-12-01
影响因子：
1.6
通讯作者：
Rice, KC
中科院分区：
文献类型：
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作者：
Craft, RM;Tseng, AH;Rice, KC
本研究旨在确定阿片受体激活的性别差异是否可以解释阿片抗痛觉的性别差异。在雌性和雄性spraguedawley大鼠中，使用52度热板试验比较了先前被证明在雄性动物中具有相对mu (-funaltrexamine, -FNA), kappa （norbinaltorphamine, norBNI）或delta （naltrindole， NTI）受体选择性的拮抗剂的时间过程，剂量效应和选择性。在两性中，脑室内β -FNA（10或20微克）。])剂量依赖性阻断芬太尼（0.056 mg/kg皮下注射）的抗痛觉作用；β -FNA后24 h观察到拮抗作用，并在7-14天内减弱。在两性中，norBNI（1 ~ 10杯c.c.v）剂量依赖性地阻断了U69,593 （1.0 mg/kg皮下注射）的抗伤害感受作用；拮抗作用在norbni后1 ~ 3 d达到最大，持续时间超过56 d。NTI（1杯或10杯i.c.v）剂量依赖性地阻断了[D-Pen(2), D-Pen(5)]脑啡肽（DPDPE, 100 nmol i.c.v）在两性中的抗伤害性作用；然而，NTI在女性中的作用时间比男性短。受体偏好激动剂芬太尼、吗啡和丁丙诺啡的抗伤感受作用被β -FNA显著且剂量依赖性地拮抗，但不被norBNI或NTI拮抗。与服用吗啡的男性相比，服用芬太尼或丁丙诺啡的女性对β -FNA的拮抗作用明显更大。kappa受体偏好激动剂U69,593和U50,488的抗感觉作用被norBNI显著且剂量依赖性地拮抗；在两性中，U50,488而不是U69,593也被NTI I和β -FNA在较小程度上拮抗。在两性中，δ受体偏好激动剂snc80的抗感觉作用被NTI显著拮抗，而不被norBNI或β -FNA拮抗。吗啡对β -FNA拮抗作用的性别差异提示在功能性mu阿片受体储备或信号转导方面可能存在性别差异；然而，所有受体激动剂缺乏一致性削弱了这一假设。总的来说，测试的阿片类药物在男性和女性受试者中具有非常相似的受体选择性。(C) 2001 Lippincott Williams & Wilkins。
This study was conducted to determine whether sex differences in opioid antinociception may be explained by sex differences in opioid receptor activation. The time course, dose-effect and selectivity of antagonists that have been previously shown to be relatively mu (beta -funaltrexamine, beta -FNA), kappa (norbinaltorphimine, norBNI), or delta (naltrindole, NTI) receptor selective in male animals were compared in female and male Sprague-Dawley rats using a 52 degreesC hotplate test. In both sexes, beta -FNA (10 or 20 mug intracerebroventricularly [i.c.v.]) dose-dependently blocked the antinociceptive effects of fentanyl (0.056 mg/kg subcutaneously); antagonism was observed 24 h after beta -FNA, and diminished within 7-14 days. In both sexes, norBNI (1 ou 10 mug i.c.v.) dose-dependently blocked the antinociceptive effects of U69,593 (1.0 mg/kg subcutaneously); antagonism was maximal by 1-3 days post-norBNI and lasted longer than 56 days. NTI (1 or 10 mug i.c.v.) dose-dependently blocked the antinociceptive effects of [D-Pen(2), D-Pen(5)]enkephalin (DPDPE, 100 nmol i.c.v.) in both sexes; however, the duration of action of NTI was shorter in females than in males. The antinociceptive effects of the mu receptor-preferring agonists fentanyl, morphine and buprenorphine were significantly and dose-dependently antagonized by beta -FNA, but not by norBNI or NTI, in both: sexes. beta -FNA antagonism was significantly greater in females compared with males given morphine, but not fentanyl:or buprenorphine. The antinociceptive effects of the kappa receptor-preferring agonists U69,593 and U50,488 were significantly and dose-dependently antagonized by norBNI; U50,488 but not U69,593 was also: antagonized to a lesser extent by NTI I and beta -FNA, in both sexes. The antinociceptive effect of the delta receptor-preferring agonist SNC 80 was significantly antagonized by NTI, but not by norBNI or beta -FNA, in both sexes. The sex difference in beta -FNA antagonism of morphine suggests that there may be sex differences in functional mu opioid receptor reserve or signal transduction; however, the lack of consistency across all mu agonists weakens this hypothesis. Overall, the opioids tested had very similar receptor selectivity in male and female subjects. (C) 2001 Lippincott Williams & Wilkins.