Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: Estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male
Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: Estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male
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DOI：
10.1523/jneurosci.4783-06.2006
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发表时间：
2006-12-13
影响因子：
5.3
通讯作者：
Mokha, Sukhbir S.
中科院分区：
文献类型：
--
作者：
Claiborne, Jomo;Nag, Subodh;Mokha, Sukhbir S.
据报道，疼痛感知和调节方面存在性别相关差异。本研究首次以大鼠为实验动物，系统地研究孤啡肽 FQ (OFQ) 激活阿片样受体样 1 受体 (ORL1) 是否会产生性别特异性的脊髓伤害感受调节，以及雌激素或睾酮是否导致这些差异。两种行为模型，即 NMDA 和热诱导伤害性测试，用于检查脊髓伤害性的性别特异性调节。在雄性、卵巢切除 (OVX) 和绝情大鼠中鞘内显微注射 OFQ 在两项测试中均产生显着的镇痛作用。然而，OFQ 未能在发情前期大鼠（动情周期中循环雌二醇水平最高的阶段）中产生镇痛作用，并且在用 1 ng 至 100 μg 雌二醇治疗的 OVX 雌性大鼠中产生剂量依赖性作用。 OFQ 的镇痛作用在雄性和 OVX 动物中呈剂量依赖性，并被 ORL1 受体选择性拮抗剂 UFP-101（[Nphe(1)、Arg(14)、Lys(15)]N/OFQ(1-13)-NH2）可逆地拮抗。有趣的是，OFQ 对性腺切除 (GDX) 男性无效，而睾酮替代则恢复了 OFQ 对 GDX 男性的抗伤害作用。我们得出结论，OFQ 产生性别特异性的脊髓伤害感受调节；雌激素在雌激素水平正常循环的同时减弱女性的抗伤害作用，而睾酮是男性表达抗伤害作用所必需的；因此，雄性对 OFQ 的抗伤害作用的敏感性并不仅仅归因于这些动物内在的低雌激素水平。
Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL1) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 mu g of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe(1), Arg(14), Lys(15)]N/OFQ(1-13)-NH2), an ORL1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modulation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals.