Endogenous Mechanisms of Electroacupuncture

电针的内源性机制

• 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
• 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

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)：在过去的二十年里，针灸和电针在北美越来越多地被用作慢性疼痛药物治疗的补充(1997年NIH关于针灸的共识声明)。至少三十年的研究表明，阿片能系统在针刺镇痛的机制中发挥了作用。然而，针灸治疗疼痛的有效性背后的机制(S)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而增强阿片类药物的镇痛作用已被明确。然而，NMDA受体系统的内源性调节剂在针刺镇痛中的作用一直被探讨得很少。Agmatine(脱羧化精氨酸)是一种内源性物质，能拮抗NMDA受体，抑制一氧化氮合酶。与合成的NMDA受体拮抗剂一样，胍丁胺也可以抑制阿片类药物的耐受和依赖。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电针发挥治疗益处的中枢神经系统区域的活性。这一应用的目的是确定胍丁胺对电针诱发镇痛的作用机制。中心假设是内源性胍丁胺通过抑制NR2B受体亚单位的NMDA受体发挥作用。这项研究的理论基础是，随着内源性胍丁胺参与电针诱导的镇痛并确定其机制，内源性胍丁胺可以在特定部位进行调节，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胺的能力。这一贡献将是重要的，因为了解胍丁胺是如何表现其效果的，是在非药理学和药理学疼痛治疗方法中优化其治疗应用的重要一步。这项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止痛，电针是一种普遍应用的非药物疼痛管理疗法，目前尚不清楚。这项研究的成功完成有望将电针和胍丁胺定位为改善疼痛管理和治疗的互补方法，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。 公共卫生相关性：针灸止痛技术是一种已知的激活自然(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努力，主要集中在阿片类神经递质(如内啡肽)上，尽管不是唯一的。这项拟议的研究将评估一种全新的脊椎疼痛控制系统(胍丁胺)对针灸效果的潜在贡献。胍丁胺阻断了一种具有良好特性的神经刺激剂谷氨酸的长期效果。本研究计划的目标是确定胍丁胺是否与其他天然止痛系统同时或协同作用，以提供通过 针灸的应用。