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

超过1亿美国人经历着某种形式的身体疼痛，其中四分之一 每天都要努力应对慢性和持续性的疼痛状况。与此相关的风险之一是 现有的止痛药，除了一些可控的副作用外，是有潜力的药物 依赖和虐待。甘氨酸能抑制在脊髓伤害性感受中起着关键作用。增强 正变构调节剂(PAM)的甘氨酸受体(GlyR)活性已被公认 作为治疗慢性疼痛的阿片类药物的一种有前途的替代品。通过结合结构生物学， 电生理学和活体研究，我们在人类体内发现了一个新的药物结合部位 调节大麻的止痛作用的GlyRs，独立于其精神活性副作用。 我们进一步发现了一种新的分子支架，它可以增强GlyRs，而交叉反应性很小 阿片受体和其他精神药物受体。从这个断头台上找到了一个主要的候选药物 被发现是含有α3的GlyRs的特异性正变构调节剂，并且具有更高的 比吗啡更能抑制啮齿动物的神经性和炎症性疼痛。vbl.使用 RNAS镜下原位杂交，我们还发现α3GlyR与 中脑中有一组特殊的投射神经元。这些耐人寻味的发现让我们 假设α3GlyRs位于脊髓背角浅层和中脑 作为镇痛的重要靶点和奖赏的抑制调节器的双重作用 分别是电路。我们已经收集了充足的初步数据来支持以下三个方面 具体目标：目标1：研究脊髓α3GlyR作为有效分子靶点的作用 减轻神经性和炎症性疼痛的机械和热过敏；目标2： 了解α3GlyR对作为关键细胞靶点的中脑投射神经元的调节 目标3：阐明甘氨酸能的偶联作用 和多巴胺能信号通路利用选择性正变构的双重作用 α3GlyRs对镇痛和减少奖赏行为的调节作用 寻求毒品和自我管理测验的工具性学习。这些机制引导 调查将补充并进一步加强发现新的α3GlyR靶向药物 用于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.