Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York.
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York..
J Pain. 2019 Feb;20(2):235-243. doi: 10.1016/j.jpain.2018.10.003. Epub 2018 Oct 23.
We showed previously that spinal metabotropic glutamate receptor 1 (mGluR) signaling suppresses or facilitates (depending on the stage of estrous cycle) analgesic responsiveness to intrathecal endomorphin 2, a highly mu-opioid receptor-selective endogenous opioid. Spinal endomorphin 2 antinociception is suppressed during diestrus by mGluR when it is activated by membrane estrogen receptor alpha (mERα) and is facilitated during proestrus when mGluR is activated by glutamate. In the current study, we tested the hypothesis that in female rats subjected to spinal nerve ligation (SNL), the inhibition of spinal estrogen synthesis or blockade of spinal mERα/mGluR would be antiallodynic during diestrus, whereas during proestrus, mGluR blockade would worsen the mechanical allodynia. As postulated, following SNL, aromatase inhibition or mERα/mGluR blockade during diestrus markedly lessened the mechanical allodynia. This was observed only on the paw ipsilateral to SNL and was eliminated by naloxone, implicating endogenous opioid mediation. In contrast, during proestrus, mGluR blockade worsened the SNL-induced mechanical allodynia of the ipsilateral paw. Findings suggest menstrual cycle stage-specific drug targets for and the putative clinical utility of harnessing endogenous opioids for chronic pain management in women, as well as the value of, if not the necessity for, considering menstrual cycle stage in clinical trials thereof. PERSPECTIVE: Intrathecal treatments that enhance spinal endomorphin 2 analgesic responsiveness under basal conditions lessen mechanical allodynia in a chronic pain model. Findings provide a foundation for developing drugs that harness endogenous opioid antinociception for chronic pain relief, lessening the need for exogenous opioids and thus prescription opioid abuse.
我们之前已经证明，脊髓代谢型谷氨酸受体 1（mGluR）信号会抑制或促进（取决于动情周期的阶段）鞘内内吗啡肽 2 的镇痛反应，内吗啡肽 2 是一种高度选择性μ-阿片受体的内源性阿片。当 mGluR 被膜雌激素受体 α（mERα）激活时，在动情期抑制脊髓内吗啡肽 2 的镇痛作用，而在动情前期，当 mGluR 被谷氨酸激活时，促进脊髓内吗啡肽 2 的镇痛作用。在目前的研究中，我们测试了以下假设：在接受脊神经结扎（SNL）的雌性大鼠中，在动情期抑制脊髓雌激素合成或阻断脊髓 mERα/mGluR 会产生抗痛觉过敏作用，而在动情前期，mGluR 阻断会加重机械性痛觉过敏。如假设的那样，在 SNL 后，在动情期抑制芳香酶或阻断 mERα/mGluR 明显减轻了机械性痛觉过敏。这种情况仅在 SNL 的同侧爪上观察到，并且被纳洛酮消除，这表明内源性阿片介导。相反，在动情前期，mGluR 阻断加重了 SNL 引起的同侧爪机械性痛觉过敏。研究结果表明，针对月经周期阶段的药物靶点和利用内源性阿片类药物进行女性慢性疼痛管理的潜在临床应用，以及在临床试验中考虑月经周期阶段的价值（即使不是必要性）。观点：在基础条件下增强脊髓内吗啡肽 2 镇痛反应的鞘内治疗减轻了慢性疼痛模型中的机械性痛觉过敏。这些发现为开发利用内源性阿片类药物缓解慢性疼痛的药物提供了基础，减少了对外源性阿片类药物的需求，从而减少了处方阿片类药物滥用的可能性。
