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: 8562613
• 负责人: Takahiro Takano
• 金额: $ 28.81万
• 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/8562613
• 关键词: Absence of pain sensation; Acid Phosphatase; Action Potentials; Acupuncture Analgesia; Acupuncture Points; Acupuncture procedure; 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; Hyperalgesia; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Institute of Medicine (U.S.); Lead; Link; Mediating; Modeling; Molecular; Mus; Pain; Pain Research; Pain management; Pathway interactions; Patients; Peripheral; 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; public health relevance; 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症状，针灸是一种流行的替代方法。然而，由于我们对其生物学基础的了解不完全，针灸仍然存在争议。在最近的实验中，我们发现，在人类受试者和小鼠体内，针灸与穴位局部腺苷浓度的增加有关。此外，在小鼠足三里穴位局部施用腺苷A1受体激动剂模拟了针灸的镇痛作用。其他研究人员表明，局部施用 PAP（一种可以将 AMP 转化为腺苷的酸性磷酸酶）可以减轻数天的疼痛。由于大多数穴位靠近周围神经，我们推测疼痛纤维中的局部 A1 受体信号传导可以减少促痛传入输入的传递。基于穴位注射腺苷可有效降低慢性疼痛小鼠坐骨神经中 A(δ) 和 C 疼痛纤维的电导的研究结果，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途径。可以提供比针灸本身更持久的镇痛的治疗策略。目标 1 将评估持续性炎性疼痛小鼠模型中 A1 受体介导的信号传导。在足三里穴位操作腺苷信号传导前后，将记录坐骨神经的复合动作电位。 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（一种腺苷受体拮抗剂）是否会抵消针灸引起的镇痛作用。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。目标 2 询问沿轴突束的腺苷 A1 受体信号传导的长期增加是否可以在慢性炎性疼痛的实验模型中引发持续的疼痛抑制。初步数据显示，在足三里穴位注射 CD73（一种将内源性 AMP 转化为腺苷的核酸外切酶）可长时间缓解疼痛。目标 3，我们将基于初步数据显示，在足三里穴位注射 CD73 降低了炎症性疼痛小鼠脊髓中 P 物质的水平。鉴于腺苷的内源性抗炎作用，我们将检验以下假设：沿着传入束的腺苷信号传导抑制痛觉过敏，从而导致脊髓中炎症介质的减少；然后将观察到的抗炎作用与长期针灸进行比较。 拟议的实验将增进我们对腺苷信号传导沿外周疼痛途径的急性和持久镇痛作用所涉及的分子途径的理解。我们希望这些研究能够开发出治疗慢性疼痛的新治疗策略，另外的目的是深入了解针灸的生物学基础。