Spinal and supraspinal N-methyl-D-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia
Spinal and supraspinal N-methyl-D-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia
复制标题
DOI：
10.1016/j.physbeh.2015.05.006
复制
发表时间：
2015-08-01
影响因子：
2.9
通讯作者：
Kest, Benjamin
中科院分区：
文献类型：
--
作者：
Arout, Caroline A.;Caldwell, Megan;Kest, Benjamin
吗啡引起一种矛盾的状态，即疼痛敏感度增加，称为吗啡诱导的痛觉过敏(MIH)，这使其临床疗效复杂化。我们先前已经证明，在吗啡注射(40 mg/kg/24小时)过程中，全身注射N-甲基-D-天冬氨酸受体(NMDAR)和黑素皮质素-1受体(MC1R)拮抗剂分别对雄性和雌性小鼠的MIH具有性别依赖性逆转作用。这种质的性别差异是卵巢激素依赖的，因为NMDAR拮抗剂逆转了去卵巢女性的MIH，但在去卵巢小鼠注射黄体酮后无效。在这里，我们利用鞘内和脑室内注射的范例来评估脊髓和棘上受体对雄性和雌性CD-1小鼠性别差异的贡献。具体地说，我们在吗啡注射过程中分别注射了NMDAR和MC1R选择性拮抗剂MK-801和MSG606。结果表明，在吗啡注射过程中，脊髓和棘上MK-801和MSG606分别选择性地逆转男性和女性的MIH。此外，虽然MK-801逆转了卵巢切除(OVX)女性的MIH，但MSG606在同一组中是在急性皮下注射黄体酮后最有效的。因此，目前的研究表明，脊髓和脊髓上的NMDAR和MC1R是吗啡注射过程中观察到的定性性别差异的基础，这些基因座上的受体也对性类固醇调节敏感。(C)2015 Elsevier Inc.保留所有权利。
Morphine elicits a paradoxical state of increased pain sensitivity, known as morphine-induced hyperalgesia (MIH), which complicates its clinical efficacy. We have previously shown that systemic injections of N-methyl-D-aspartate receptor (NMDAR) and melanocortin-1 receptor (MC1R) antagonists sex-dependently reverse MIH during morphine infusion (40 mg/kg/24 h) in male and female mice, respectively. This qualitative sex difference is ovarian hormone dependent, as NMDAR antagonists reverse MIH in ovariectomized females but are rendered ineffective following progesterone injection in OVX mice. Here, we utilized intrathecal and intracerebroventricular injection paradigms to assess the contribution of spinal and supraspinal receptors to this sex difference in male and female CD-1 mice. Specifically, we injected NMDAR and MC1R selective antagonists, MK-801 and MSG606 respectively, during morphine infusion. Results illustrated that both spinal and supraspinal MK-801 and MSG606 selectively reversed MIH in males and females, respectively, during morphine infusion. Furthermore, while MK-801 reversed MIH in ovariectomized (OVX) females, MSG606 was most effective in doing so in this same group following an acute subcutaneous progesterone injection. The present studies thus indicate that both spinal and supraspinal NMDARs and MC1Rs underlie the qualitative sex difference observed during morphine infusion in mice, and that the receptors in these loci are also sensitive to sex steroidal modulation. (C) 2015 Elsevier Inc. All rights reserved.