Endogenous Mechanisms of Electroacupuncture

描述（由申请人提供）：在过去的二十年中，针灸和电针在北美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能系统在针灸诱发镇痛机制中的作用。然而，针灸治疗疼痛的有效机制仍然只是部分被理解。近年来，NMDA受体拮抗剂通过抑制镇痛耐受性的发展来增强阿片镇痛的作用已被明确定义。然而，NMDA受体系统的内源性调节剂在针刺镇痛中的作用尚未得到充分探讨。Agmatine（脱羧精氨酸）是一种内源性物质，可以拮抗NMDA受体，抑制一氧化氮合酶。像合成的NMDA受体拮抗剂一样，胍丁氨酸也抑制阿片耐受性和依赖性的发展。由于胍丁氨酸在中枢神经系统中表达，因此可以使用策略来优化其在电针发挥治疗作用的中枢神经系统区域的活性。本应用的目的是确定其机制，agmatine有助于电针诱发镇痛。核心假设是内源性agmatine通过抑制NR2B受体亚基的NMDA受体发挥其作用。本研究的基本原理是，通过证明内源性agmatine参与电针诱发镇痛，并确定其机制，内源性agmatine可以通过部位特异性调节来优化电针治疗。提出了两个具体目标：#1：确定内源性胍丁氨酸在电针诱导的疼痛控制中的作用程度和机制。#2：测定电针释放内源性胍丁氨酸的能力。这一贡献将是重要的，因为了解胍丁氨酸如何表现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，因为它代表了一种新的机制来解释电针引起的镇痛，电针是一种常用的非药物疼痛管理疗法，但尚未得到很好的理解。这项研究的成功完成有望将电针和胍丁胺作为改善疼痛管理和治疗的互补方法，并可能转化为其他由神经可塑性不良引起的治疗适应症。

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.