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

α3 甘氨酸受体的外周和中枢通路作为非阿片类药物分子靶点治疗疼痛

基本信息

批准号：
10445387
负责人：
YAN XU
金额：
$ 57.08万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445387
关键词：
2-tyrosine Absence of pain sensation Acute inflammatory pain Address American Analgesics Animals Behavior Binding Binding Sites Brain Brain region Cannabidiol Cannabinoids Chemosensitization Complement Coupling Data Dose Drug Addiction Drug Binding Site Drug Targeting Drug abuse Electrophysiology (science)Equilibrium Formalin Foundations Future Glycine Receptors Human Hypersensitivity In Situ Hybridization In Vitro Investigation Knock-out Knockout Mice Knowledge Laboratories Lead Legal patent Marijuana Mechanics Mediating Microinjections Midbrain structure Molecular Molecular Target Morphine Motivation Mus Names Neurons Neuropathy Nociception Nucleus Accumbens Operant Conditioning Opioid Opioid Receptor Pain Pain management Pathway interactions Peripheral Persistent pain Pharmaceutical Preparations Pharmacology Play Population Process Protein Family Rattus Regulation Research Personnel Rewards Risk Rodent Role Self Administration Side Signal Pathway Signal Transduction Site Specificity Spinal Spinal Cord Spinal cord posterior horn Substantia nigra structure Testing Time Transmembrane Domain Tyrosine 3-Monooxygenase United States National Institutes of Health Ventral Tegmental Area abuse liability behavior test cellular targeting chronic constriction injury chronic pain chronic pain management conditioned place preference cross reactivity design dopaminergic neuron dorsal horn drug candidate drug seeking behavior experience in silico in vivo inflammatory pain knockout animal morphine administration neurotransmission non-opioid analgesic novel therapeutics opioid epidemic pain model pain perception pain processing pain signal painful neuropathy positive allosteric modulator public health relevance receptor reconstitution scaffold screening side effect structural biology tool

项目摘要

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.

超过 1 亿美国人经历过某种形式的身体疼痛，其中四分之一每天都在努力应对慢性和持续性疼痛，这是与此相关的风险之一。现有的镇痛药物，除了一些可控制的副作用之外，是药物的潜力依赖性和滥用。甘氨酸能抑制在增强脊髓伤害感受中起着关键作用。正变构调节剂 (PAM) 的甘氨酸受体 (GlyR) 活性已得到认可通过结合结构生物学，作为治疗慢性疼痛的阿片类药物的有前途的替代品，电生理学和体内研究，我们在人体中发现了一个新的药物结合位点 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，可以增强 GlyR 且几乎没有交叉反应性与阿片受体和其他精神药物受体一起使用该支架的主要候选药物。被发现是含 α3 GlyR 的特异性正变构调节剂，并且具有更高的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。用于原位杂交的 RNAscope，我们还发现 α3GlyR 与这些有趣的发现使我们发现了中脑中特殊的投射神经元。 α3GlyRs 位于脊髓背角浅层和中脑发挥双重作用，作为镇痛的重要目标和奖励的抑制调节剂我们分别收集了充足的初步数据来支持以下三个电路。具体目标：目标 1：研究脊髓 α3GlyR 作为有效分子靶点的作用目标2：减轻神经性疼痛和炎性疼痛中的机械和热过敏；了解 α3GlyR 对中脑投射神经元作为关键细胞靶标的调节作用预期感受和抗精神运动刺激；以及目标 3：阐明甘氨酸能的耦合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 以镇痛和减少寻求奖励的行为，重点是这些机制引导的药物寻求和自我管理测试的工具学习。研究将补充并进一步加强新 α3GlyR 靶向药物的发现安全有效的疼痛治疗。