Endogenous Mechanisms of Electroacupuncture

描述（由申请人提供）：在过去的二十年里，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30年的研究表明阿片系统在针刺诱发镇痛的机制中发挥作用。然而，针灸治疗疼痛的有效性的机制仍然只有部分了解。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被明确定义。然而，NMDA受体系统的内源性调节剂对针刺镇痛的作用却很少被研究。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。与合成的NMDA受体拮抗剂一样，胍丁胺也抑制阿片类药物耐受性和依赖性的发展。由于胍丁胺在中枢神经系统中表达，因此可以使用策略来优化其在电针发挥治疗益处的中枢神经系统区域中的活性。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基丁胺通过抑制NR2B受体亚单位的NMDA受体发挥其作用。本研究的基本原理是，通过证明内源性胍丁胺参与电针镇痛并确定其机制，内源性胍丁胺可以在位点特异性地调节以优化电针治疗。提出了两个具体的目标：#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。这一贡献将是显着的，因为了解胍丁胺如何体现其效果是一个重要的一步，优化其在非药理学和药理学疼痛管理方法的治疗应用。本申请中提出的研究是创新的，因为它代表了一种新的机制来解释电针引起的镇痛，这是一种常用的非药物疼痛管理疗法，尚未得到很好的理解。这项研究的成功完成，预计将定位电针和胍丁胺作为补充方法，以改善疼痛管理和治疗，可能会转化为其他治疗适应症所产生的适应不良的神经可塑性。

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.