Peripheral and Central Pathways of α3 Glycine Receptors as Non-Opioid Molecular Targets to Treat Pain

超过1亿美国人经历过某种形式的身体疼痛，其中四分之一的人 每天都在努力科普慢性和持续性疼痛状况。与之相关的风险之一 现有的止痛药，除了一些可管理的副作用，是药物的潜力， 依赖和滥用。甘氨酸能抑制在脊髓伤害性感受中起关键作用。增强 甘氨酸受体（GlyR）活性通过正变构调节剂（PAM）已经被认识到 作为阿片类药物治疗慢性疼痛的有前途的替代品。通过结合结构生物学， 电生理学和体内研究，我们发现了一个新的药物结合位点，在人类 GlyRs介导大麻的镇痛作用，与其精神活性副作用无关。 我们进一步发现了一种新的分子支架，它可以增强GlyRs的交叉反应性， 与阿片受体和其他精神受体有关。这个支架的主要候选药物 被发现是含α3的GlyRs的特异性正变构调节剂， 在抑制啮齿动物的神经性疼痛和炎性疼痛方面比吗啡更有效。使用 在原位杂交中，我们还发现了α3GlyR与α3GlyR的大量共定位。 中脑中一组特殊的投射神经元。这些有趣的发现让我们 假设α3GlyRs在脊髓背角浅层和中脑中 作为镇痛的重要靶点和作为奖赏的抑制调节剂， 电路，分别。我们收集了大量的初步数据，以支持以下三个方面 具体目的：目的1：研究脊髓α3GlyR作为有效分子靶点的作用， 减轻神经性和炎性疼痛中的机械和热超敏反应;目的2： 了解α 3 GlyR对中脑投射神经元的调节作为关键细胞靶点 目的3：阐明甘氨酸能神经递质与神经递质的偶联， 和多巴胺能信号通路，以利用选择性正变构的双重作用， 调节α3GlyRs以镇痛和减少奖赏寻求行为，重点是 寻求药物和自我管理测试的工具学习。这些机制引导 研究将补充并进一步促进新的α 3GlyR靶向药物的发现 安全有效的疼痛治疗

Over 100 million Americans experience some forms of physical pain, a quarter of whom struggle daily to cope with chronic and persistent pain conditions. One of the risks associated with existing analgesic drugs, beyond some manageable side effects, is the potential for drug dependence and abuse. Glycinergic inhibition plays a pivotal role in spinal nociception. Enhancing glycine receptor (GlyR) activities by positive allosteric modulators (PAMs) has been recognized as a promising alternative to opioids for treating chronic pain. By combining structural biology, electrophysiology, and in vivo studies, we discovered a novel drug binding site in the human GlyRs that mediates marijuana’s analgesic action independent of its psychoactive side effects. We further discovered a new molecular scaffold that potentiates GlyRs with little cross reactivity with opioid receptors and other psychotropic receptors. A lead drug candidate from this scaffold was found to be specific positive allosteric modulators for α3-containing GlyRs and have higher potencies than morphine in suppressing neuropathic and inflammatory pain in rodents. Using RNAscope for in situ hybridization, we also discovered abundant colocalization of α3GlyR with a special group of projection neurons in the midbrain. These intriguing findings led us to hypothesize that α3GlyRs in the superficial layer of the spinal dorsal horn and in the midbrain play a dual role as important targets for analgesia and as inhibitory regulators for the reward circuits, respectively. We have collected ample preliminary data to support the following three specific aims: Aim 1: Investigate the role of spinal α3GlyR as an effective molecular target to alleviate mechanical and thermal hypersensitivity in neuropathic and inflammatory pain; Aim 2: Understand α3GlyR’s regulation of the midbrain projection neurons as a key cellular target for antinociception and anti-psychomotor stimulation; and Aim 3: Elucidate the coupling of glycinergic and dopaminergic signaling pathways to harness the dual action of selective positive allosteric modulation of α3GlyRs for both analgesia and reduction of reward-seeking behavior, focusing on drug-seeking and instrumental learning of self-administration tests. These mechanism-guided investigations will complement and further enhance the discovery of new α3GlyR-targeting drugs for safe and effective pain treatment.