Endogenous Mechanisms of Electroacupuncture

电针的内源性机制

基本信息

批准号：
8383006
负责人：
Carolyn A Fairbanks
金额：
$ 22.4万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383006
关键词：
Absence of pain sensation Acupuncture Analgesia Acupuncture procedure Address Adopted Affinity Agmatine Analgesics Area Arginine China Complement Consensus Data Dependence Development Drug Addiction Effectiveness Electroacupuncture Endorphins Genetic Glutamates Goals Hypersensitivity Immunoglobulin G Inflammatory Intrathecal Injections Japan Knowledge Learning Long-Term Effects Mediating Memory Microdialysis Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Neuraxis Neuronal Plasticity Neurotransmitters Nitric Oxide Synthase North America Opioid Outcome Pain Pain management Pharmacological Treatment Pharmacotherapy Physiological Play Positioning Attribute Publishing Regulation Research Rodent Model Role Site Spinal Spinal Cord Spinal cord posterior horn Synaptic Vesicles System Techniques Testing Therapeutic Translating United States United States National Institutes of Health Work addiction allodynia base chronic pain chronic stroke effective therapy expectation improved in vivo inhibitor/antagonist innovation mechanical allodynia nerve injury neuroadaptation novel novel therapeutic intervention preclinical study prevent programs receptor relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): Acupuncture and electroacupuncture have been increasingly adopted in North America as a complement to pharmacotherapy for chronic pain over the last twenty years (1997 NIH Consensus Statement on Acupuncture). At least thirty years of research indicate a role for opioidergic systems in the mechanisms underlying acupuncture-evoked analgesia. However, the mechanism(s) underlying the effectiveness of acupuncture for pain management remains only partially understood. In recent years a role for NMDA receptor antagonists to enhance opioid analgesia by inhibition of the development of analgesic tolerance has been clearly defined. However, the contribution of endogenous modulators of the NMDA receptor system to analgesia induced by acupuncture has been minimally explored. Agmatine (decarboxylated arginine) is an endogenous substance that antagonizes the NMDA receptor and inhibits nitric oxide synthase. Like synthetic NMDA receptor antagonists, agmatine also inhibits development of opioid tolerance and dependence. Since agmatine is expressed in the CNS, strategies could be used to optimize its activity in CNS regions where electroacupuncture exerts therapeutic benefit. The objective of this application is to determine the mechanism by which agmatine contributes to electroacupuncture-evoked analgesia. The central hypothesis is that endogenous agmatine exerts its effects through inhibition of the NMDA receptor at the NR2B receptor subunit. The rationale for the proposed research is that, with demonstration of endogenous agmatine participation in electroacupuncture-evoked analgesia and identification of the mechanism, endogenous agmatine could be regulated in site-specifically to optimize electroacupuncture therapy. Two specific aims are proposed: #1: Determine the extent to which and the mechanism by which endogenous agmatine contributes to electroacupuncture-induced pain control. #2: Determine the ability of electroacupuncture to release endogenous agmatine. This contribution will be significant because understanding how agmatine manifests its effects is an important step toward optimizing its therapeutic application in both non-pharmacological and pharmacological pain management approaches. The research proposed in this application is innovative because it represents a new mechanism to explain analgesia evoked by electroacupuncture, a commonly applied non-pharmacological pain management therapy that is not well understood. The successful completion of this research is expected to position both electroacupuncture and agmatine as complementary approaches to improve pain management and therapy that may translate to other therapeutic indications arising from maladaptive neuroplasticity. PUBLIC HEALTH RELEVANCE: The technique of acupuncture for analgesia is a system known to activate natural (endogenous) pain control systems. Endogenous pain control has motivated a multi-decade global research effort focused primarily, though not exclusively, on opioid neurotransmitters (e.g., endorphins). The proposed research would assess the potential contributions of an entirely novel spinal pain control system (agmatine) to acupuncture effects. Agmatine blocks the long-term effects of a well characterized nerve stimulant, glutamate. The goal of the present research program is to determine whether agmatine acts concurrently or synergistically with other natural pain control systems to provide the pain relief achieved through application of acupuncture.

描述（由申请人提供）：过去二十年来，针灸和电针疗法在北美已越来越多地被采用作为慢性疼痛药物治疗的补充（1997 年 NIH 针灸共识声明）。至少三十年的研究表明阿片类药物系统在针灸诱发镇痛的机制中发挥着重要作用。然而，针灸治疗疼痛的有效性背后的机制仍然只有部分被了解。近年来，NMDA 受体拮抗剂通过抑制镇痛耐受的发展来增强阿片类镇痛的作用已得到明确定义。然而，NMDA 受体系统内源性调节剂对针刺镇痛作用的研究却很少。胍丁胺（脱羧精氨酸）是一种内源性物质，可拮抗 NMDA 受体并抑制一氧化氮合酶。与合成 NMDA 受体拮抗剂一样，胍丁胺也抑制阿片类药物耐受和依赖性的发展。由于胍丁胺在中枢神经系统中表达，因此可以采用策略来优化其在中枢神经系统区域的活性，电针在这些区域中发挥治疗作用。本申请的目的是确定胍丁胺有助于电针诱发镇痛的机制。中心假设是内源性胍丁胺通过抑制 NR2B 受体亚基的 NMDA 受体发挥作用。本研究的基本原理是，通过证明内源性胍丁胺参与电针诱发镇痛并确定其机制，可以对内源性胍丁胺进行位点特异性调节以优化电针治疗。提出了两个具体目标：#1：确定内源性胍丁胺有助于电针引起的疼痛控制的程度和机制。 #2：确定电针释放内源性胍丁胺的能力。这一贡献将具有重要意义，因为了解胍丁胺如何发挥其作用是优化其在非药物和药物疼痛管理方法中的治疗应用的重要一步。本申请中提出的研究具有创新性，因为它代表了一种解释电针引起的镇痛的新机制，电针是一种常用的非药物疼痛管理疗法，但目前尚不清楚。这项研究的成功完成预计将使电针和胍丁胺成为改善疼痛管理和治疗的补充方法，这可能会转化为适应不良神经可塑性引起的其他治疗适应症。公共健康相关性：针灸镇痛技术是一种已知可以激活自然（内源性）疼痛控制系统的系统。内源性疼痛控制推动了数十年的全球研究工作，主要关注（但不限于）阿片类神经递质（例如内啡肽）。拟议的研究将评估一种全新的脊柱疼痛控制系统（胍丁胺）对针灸效果的潜在贡献。胍丁胺可阻断一种已明确描述的神经兴奋剂谷氨酸的长期作用。本研究计划的目标是确定胍丁胺是否与其他天然疼痛控制系统同时或协同作用，以提供通过以下方式实现的疼痛缓解：针灸的应用。