MrgprC, A New Target for the Treatment of Neuropathic Pain

MrgprC，治疗神经性疼痛的新靶点

基本信息

批准号：
8233966
负责人：
Yun Guan
金额：
$ 28.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233966
关键词：
Absence of pain sensation Adverse effects Afferent Neurons Agonist Analgesics Animals Attenuated Behavioral Biological Calcium Caliber Development Dose Drug Delivery Systems Drug effect disorder Early treatment Family G-Protein-Coupled Receptors Gene Expression Heating Human Hyperalgesia In Vitro Infusion procedures Injury Intervention Intrathecal Injections Lead Ligands Ligation Long-Term Potentiation Maintenance Mechanics Mediating Messenger RNA Molecular Morphine Mus Mutant Strains Mice Neuraxis Neurons Non-Malignant Orthologous Gene Pain Pain Research Pathway interactions Peptides Peripheral Nervous System Peripheral nerve injury Persistent pain Pharmaceutical Preparations Population Postoperative Pain Process Quality of life Rattus Role Sensory Small Interfering RNA Spinal Spinal Cord Spinal Ganglia Spinal nerve structure Stimulus Surgical incisions System Tactile Therapeutic Time Wild Type Mouse Work attenuation base dorsal horn gain of function ganglion cell gene function in vivo injured loss of function mechanical allodynia member nerve injury neuronal excitability novel pain inhibition painful neuropathy patch clamp prevent public health relevance response selective expression small molecule spontaneous pain treatment strategy voltage

项目摘要

DESCRIPTION (provided by applicant): The treatment of neuropathic pain continues to challenge clinicians, in part because of limited efficacy of available treatments and a lack of pain-specific drug targets. Mas-related G-protein-coupled receptors (Mrgprs) represent a novel family of G-protein-coupled receptors (GPCRs) that are specifically expressed in small-diameter sensory neurons. Our preliminary work suggests that some Mrgprs, in particular MrgprC, may constitute a novel inhibitory system for persistent pain. Intrathecal administration of a peptide (BAM 8-22) and a small molecule non-peptide MrgprC agonist (compound 58) both attenuated neuropathic pain in rats and in wild type mice. However, BAM 8-22 lost this analgesic action on neuropathic pain in Mrpgr mutant mice. Using complementary behavioral, electrophysiological, and molecular biological approaches, we aim to assess the therapeutic value of MrgprC as a novel target in the treatment of neuropathic pain, and importantly, to examine the cellular and molecular mechanisms underlying MrgprC-mediated pain inhibition. Specifically, Aim 1 will characterize in detail the effects of intrathecal administration of the two MrgprC agonists on tactile allodynia, mechanical hyperalgesia, heat hyperalgesia and spontaneous pain in rats after an L5 spinal nerve injury. We will then examine whether MrgprC siRNA treatment reduces the analgesic efficacy of BAM 8-22. We will also investigate whether an early intervention with BAM 8-22 prolongs attenuation of neuropathic pain, enhances morphine analgesia in neuropathic pain, and prevents postsurgical pain in rats. In Aim 2, we will employ in vitro electrophysiological and molecular biological approaches to study the cellular and molecular mechanisms underlying MrgprC-mediated pain inhibition in the dorsal root ganglion (DRG) neurons. We will use both loss-of-function and gain-of-function strategies to determine if MrgprC activation attenuates high-voltage-gated (HVA) calcium current in DRG cells. We will further determine whether nerve injury up regulates the expression and function of MrgprC in uninjured DRG neurons. In Aim 3 we will study the neurophysiologic basis for MrgprC-mediated pain inhibition in the central nervous system. We will conduct in vivo electrophysiological studies to determine if MrgprC agonist attenuates dorsal horn neuronal sensitization to repetitive noxious inputs and normalizes the established neuronal hyperexcitability induced by the nerve injury. We will investigate whether nerve injury alters the expression of BAM 22, an endogenous Mrgpr ligand, in spinal cord and in DRGs. We postulate that MrgprC agonists may function as anti-hyperalgesic agents during the neuropathic pain state. Because MrgprC is an ortholog to the human MrgprX1, our findings may have important implications for developing new drug leads and mechanism-based treatment strategies for managing neuropathic pain with few side effects. PUBLIC HEALTH RELEVANCE: Our preliminary studies suggest that activation of an important member of Mas-related G protein-coupled receptors, MrgprC, may inhibit neuropathic pain. In this proposal, we will use complementary animal behavioral, electrophysiological, and molecular biological approaches to better assess the therapeutic utility of MrgprC agonist for the treatment of neuropathic pain and to understand the cellular and molecular mechanisms underlying the drug action. Current study may identify a new pain-specific treatment target and lead to a novel mechanism-based approach to the treatment of neuropathic pain.

描述（由申请人提供）：神经性疼痛的治疗继续挑战临床医生，部分原因是可用治疗的疗效有限和缺乏疼痛特异性药物靶标。与MAS相关的G蛋白偶联受体（MRGPR）代表了一个新型的G蛋白偶联受体（GPCR）家族，该家族在小直径的感觉神经元中专门表达。我们的初步工作表明，一些MRGPR，尤其是MRGPRC可能构成了一种新型的持续抑制系统。鞘内给药肽（BAM 8-22）和小分子非肽MRGPRC激动剂（化合物58）均减轻大鼠和野生型小鼠的神经性疼痛。然而，BAM 8-22对MRPGR突变小鼠的神经性疼痛失去了这种镇痛作用。使用互补的行为，电生理学和分子生物学方法，我们旨在评估MRGPRC作为治疗神经性疼痛的新靶标的治疗价值，并且重要的是，重要的是检查MRGPRC介导的疼痛抑制作用的细胞和分子机制。具体而言，AIM 1将详细介绍两种MRGPRC激动剂对触觉异常性疾病，机械性痛觉过敏，热痛觉过敏和自发性疼痛的影响。然后，我们将检查MRGPRC siRNA处理是否降低了BAM 8-22的镇痛功效。我们还将研究BAM 8-22的早期干预是否会延长神经性疼痛的衰减，增强神经性疼痛中的吗啡镇痛，并防止大鼠的术后疼痛。在AIM 2中，我们将采用体外电生理和分子生物学方法来研究MRGPRC介导的背根神经节（DRG）神经元中MRGPRC介导的疼痛抑制的细胞和分子机制。我们将同时使用功能丧失和功能获得策略来确定MRGPRC激活是否减弱了DRG细胞中高压门控（HVA）钙电流。我们将进一步确定神经损伤是否可以调节MRGPRC在未受伤的DRG神经元中的表达和功能。在AIM 3中，我们将研究中枢神经系统中MRGPRC介导的疼痛抑制的神经生理基础。我们将进行体内电生理学研究，以确定MRGPRC激动剂是否减弱背角神经元敏化以重复性有害输入，并归一化神经损伤引起的已建立的神经元过度过敏性。我们将研究神经损伤是否会改变脊髓和DRG中内源性MRGPR配体BAM 22的表达。我们假设MRGPRC激动剂可能在神经性疼痛状态下起作用。由于MRGPRC是人类MRGPRX1的直系同源物，因此我们的发现可能对开发新药物铅和基于机制的治疗策略具有重要意义，用于管理神经性疼痛而副作用很少。公共卫生相关性：我们的初步研究表明，激活MAS相关G蛋白偶联受体的重要成员MRGPRC可能会抑制神经性疼痛。在该提案中，我们将使用互补的动物行为，电生理和分子生物学方法来更好地评估MRGPRC激动剂的治疗效用，以治疗神经性疼痛，并了解药物作用的细胞和分子机制。当前的研究可能会确定一个新的疼痛特异性治疗靶标，并导致一种基于机制的新方法来治疗神经性疼痛。