Arbiters of endogenous opioid analgesia: role of CNS estrogenic and glutamatergic systems.
Arbiters of endogenous opioid analgesia: role of CNS estrogenic and glutamatergic systems.
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DOI：
10.1016/j.trsl.2021.02.002
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Liu NJ
中科院分区：
文献类型：
--
作者：
Gintzler AR;Liu NJ
女性的伤害感受和阿片类抗伤害感受是柔韧的过程，在生殖周期中发生质和量的变化。通过膜雌激素受体（mER）与多种其他信号分子[脊髓强啡肽、κ-阿片受体（KOR）、谷氨酸和代谢型谷氨酸受体1（mGluR 1）]结合的脊髓雌激素信号似乎起着主协调者的作用，在原伤害感受和抗伤害感受之间解析功能。这为药理学研究内在阿片类镇痛/抗异常性疼痛系统提供了一个窗口。在间情期，膜雌激素受体α（mERα）通过mGluR 1信号抑制脊髓内吗啡肽2（EM 2）镇痛。引人注目的是，在不存在外源性阿片类药物的情况下，在慢性疼痛模型中干扰这种抑制作用会增强阿片类药物的抗异常性疼痛作用，揭示了内源性阿片类药物的作用。在发情前期，强大的脊髓EM 2镇痛是明显的，但这需要脊髓强啡肽/KOR和谷氨酸激活的mGluR 1。此外，在发情前期慢性疼痛动物中的脊髓mGluR 1阻断（消除脊髓EM 2镇痛）加剧了机械性异常性疼痛，揭示了内源性阿片样物质的调节。含有μ-阿片受体、KOR、芳香化酶、mGluRs和mERα的复合物是引发内源性阿片类抗异常性疼痛的基础。芳香化酶-mER α寡聚体也很丰富，以中枢神经系统区域特异性的方式存在。这些可以独立调节，并允许雌激素在细胞内作用于它们合成的同一信号复合物中，解释了循环雌激素和中枢神经系统雌激素功能之间的异步关系。EM 2的观察结果突出了广泛表征外源性对内源性阿片类药物的反应性的翻译相关性，以及介导它们的神经元回路，沿着与生殖周期同相和异相的雌激素系统的多样性。
Nociception and opioid antinociception in females are pliable processes, varying qualitatively and quantitatively over the reproductive cycle. Spinal estrogenic signaling via membrane estrogen receptors (mERs), in combination with multiple other signaling molecules [spinal dynorphin, kappa-opioid receptors (KOR), glutamate and metabotropic glutamate receptor 1 (mGluR1)], appears to function as a master coordinator, parsing functionality between pronociception and antinociception. This provides a window into pharmacologically accessing intrinsic opioid analgesic/anti-allodynic systems. In diestrus, membrane estrogen receptor alpha (mERα) signals via mGluR1 to suppress spinal endomorphin 2 (EM2) analgesia. Strikingly, in the absence of exogenous opioids, interfering with this suppression in a chronic pain model elicits opioid anti-allodynia, revealing contributions of endogenous opioid(s). In proestrus, robust spinal EM2 analgesia is manifest but this requires spinal dynorphin/KOR and glutamate-activated mGluR1. Furthermore, spinal mGluR1 blockade in a proestrus chronic pain animal (eliminating spinal EM2 analgesia) exacerbates mechanical allodynia, revealing tempering by endogenous opioid(s). A complex containing mu-opioid receptor, KOR, aromatase, mGluRs, and mERα are foundational to eliciting endogenous opioid anti-allodynia. Aromatase-mERα oligomers are also plentiful, in a central nervous system region-specific fashion. These can be independently regulated and allow estrogens to act intracellularly within the same signaling complex in which they are synthesized, explaining asynchronous relationships between circulating estrogens and central nervous system estrogen functionalities. Observations with EM2 highlight the translational relevance of extensively characterizing exogenous responsiveness to endogenous opioids and the neuronal circuits that mediate them along with the multiplicity of estrogenic systems that concomitantly function in phase and out-of-phase with the reproductive cycle.
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DOI：
10.1073/pnas.1009923107
发表时间：
2010-11-16
影响因子：
11.1
作者：
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DOI：
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影响因子：
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