Analgesic actions of adenosine A1 receptor along axonal tracts in chronic pain

腺苷 A1 受体沿轴突束对慢性疼痛的镇痛作用

• 批准号: 9101984
• 负责人: Takahiro Takano
• 金额: $ 29.17万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101984
• 关键词: Absence of pain sensation; Acid Phosphatase; Action Potentials; Acupuncture Analgesia; Acupuncture Points; Acupuncture Therapy; Acute; Address; Adenosine; Adenosine A1 Receptor; Adjuvant; Affect; Agonist; American; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biological; Caffeine; Characteristics; Chronic inflammatory pain; Clinical; Clinical Trials; Consumption; Data; Development; Experimental Models; Fiber; Future; Health; Hyperalgesia; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Institute of Medicine (U.S.); Knockout Mice; Lead; Link; Mediating; Modeling; Molecular; Mus; Pain; Pain Research; Pain management; Pathway interactions; Patients; Peripheral Nerves; Persistent pain; Process; Purinergic P1 Receptors; Receptor Signaling; Research Personnel; Series; Signal Pathway; Signal Transduction; Societies; Spinal Cord; Substance P; Testing; Therapeutic; United States; adenosine receptor activation; alternative treatment; ankle joint; attenuation; base; chronic pain; exhaust; human subject; in vivo; inflammatory pain; insight; mouse model; novel strategies; novel therapeutics; peripheral pain; receptor; receptor-mediated signaling; research study; sciatic nerve; transmission process; treatment strategy

DESCRIPTION (provided by applicant): More than 116 million Americans struggle with persistent pain. As current treatment options do not adequately address the wide spectrum of chronic pain presentations, acupuncture is a popular alternative. Yet, acupuncture remains controversial due to our incomplete understanding of its biological basis. In recent experiments we have shown that acupuncture is linked to an increase in the local concentration of adenosine at the acupoint, in both human subjects and in mice. Moreover, local administration of an adenosine A1 receptor agonist in the Zusanli acupoint in mice mimicked the analgesic actions of acupuncture. Other investigators have shown that local administration of PAP (an acid phosphatase that can convert AMP to adenosine) provides days of pain reduction. As most acupoints are located in close proximity to peripheral nerves, we speculate that local A1 receptor signaling in pain fibers can reduce the transmission of pro-algesic afferent input. Based on the findings that adenosine, delivered in the acupoint, potently reduces the conductance of A(delta) and C pain fibers in the sciatic nerve in mice with chronic pain, we propose to evaluate whether A1 receptor signaling in peripheral pain pathways constitutes a novel therapeutic strategy that could provide longer-lasting analgesia than acupuncture itself. Aim 1 will evaluate A1 receptor mediated signaling in mouse models of persistent inflammatory pain. The compound action potential will be recorded in the sciatic nerve before and after manipulation of adenosine signaling at the Zusanli acupoint. A1 receptor KO mice will serve as a negative control. Importantly, these experiments will also evaluate whether caffeine (an adenosine receptor antagonist) nullifies acupuncture induced analgesia. This issue is important because no clinical trials to date have considered that caffeine may directly counteract the clinical benefits of acupuncture. Aim 2 asks whether prolonged increases in adenosine A1 receptor signaling along axonal tracts can trigger a persistent suppression of pain in experimental models of chronic inflammatory pain. Preliminary data show that administration of CD73 (an ectonucleotidase that converts endogenous AMP to adenosine) in the Zusanli acupoint provides prolonged pain relief. Aim 3, we will build on preliminary data showing that administration of CD73 in the Zusanli acupoint reduced the level of substance P in spinal cord in mice with inflammatory pain. Given adenosine's endogenous anti-inflammatory profile, we will test the hypothesis that the adenosine signaling along afferent tracts suppresses hyperalgesia, leading to a reduction of inflammatory mediators in the spinal cord; then compare the observed anti-inflammatory action with long-term acupuncture. The proposed experiments will advance our understanding of the molecular pathways involved in acute and long-lasting analgesic actions of adenosine signaling along peripheral pain pathways. We hope these studies lead to the development of novel therapeutic strategies for the treatment of chronic pain, with the additional aim of providing insight into the biological basis of acupuncture.

描述（由申请人提供）：超过1.16亿美国人与持续性疼痛作斗争。由于目前的治疗方案不能充分解决广泛的慢性疼痛表现，针灸是一种受欢迎的选择。然而，由于我们对其生物学基础的不完全理解，针灸仍然存在争议。在最近的实验中，我们已经表明，针灸与穴位局部腺苷浓度的增加有关，在人类受试者和小鼠中。此外，在小鼠足三里穴位局部施用腺苷A1受体激动剂模仿针灸的镇痛作用。其他研究人员已经表明，局部施用PAP（一种酸性磷酸酶，可以将AMP转化为腺苷）可以减轻疼痛数天。由于大多数穴位位于靠近周围神经，我们推测，在疼痛纤维的局部A1受体信号可以减少传递的前痛觉传入输入。基于在穴位中递送的腺苷有效地降低慢性疼痛小鼠坐骨神经中A（δ）和C疼痛纤维的电导的发现，我们建议评估外周疼痛通路中的A1受体信号传导是否构成一种新的治疗策略，可以提供比针刺本身更持久的镇痛。目的1评价A1受体介导的持续性炎性疼痛小鼠模型的信号转导。在足三里穴位处操纵腺苷信号传导之前和之后，将在坐骨神经中记录复合动作电位。A1受体KO小鼠将作为阴性对照。重要的是，这些实验还将评估咖啡因（腺苷受体拮抗剂）是否会使针刺诱导的镇痛无效。这个问题很重要，因为迄今为止还没有临床试验认为咖啡因可能直接抵消针灸的临床益处。目的2：探讨在慢性炎症性疼痛的实验模型中，腺苷A1受体信号沿着轴突束的延长增加是否可以引发疼痛的持续抑制。初步数据显示，在足三里穴位施用CD73（将内源性AMP转化为腺苷的外核苷酸酶）提供了延长的疼痛缓解。目的3，我们将建立在初步数据显示，在足三里穴位注射CD73降低炎症疼痛小鼠脊髓中P物质的水平。鉴于腺苷的内源性抗炎的个人资料，我们将测试的假设，腺苷信号沿着传入束抑制痛觉过敏，导致脊髓中的炎症介质的减少，然后比较观察到的抗炎作用与长期针灸。 拟议的实验将推进我们的理解的分子途径参与急性和持久的镇痛作用的腺苷信号沿着外周疼痛通路。我们希望这些研究能为慢性疼痛的治疗带来新的治疗策略，并为针灸的生物学基础提供新的见解。