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1.16亿美国人在持续的痛苦中挣扎。由于当前的治疗选择不能充分解决慢性疼痛表现的广泛范围，因此针灸是一种流行的选择。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，针灸与在人类受试者和小鼠中的穴位点的局部腺苷浓度增加有关。此外，在小鼠Zusanli穴位中，局部给药模仿了针灸的镇痛作用。其他研究人员表明，局部给药PAP（可以将AMP转化为腺苷的酸性磷酸酶）提供了减轻疼痛的天数。由于大多数穴位都位于周围神经附近，因此我们推测疼痛纤维中的局部A1受体信号传导可以减少促脂传入输入的传播。基于以下发现的发现，腺苷在尖端中递送，有效地降低了患有慢性疼痛的小鼠坐骨神经中A（Delta）和C疼痛纤维的电导，我们建议评估A1受体信号在外周痛途径中是否可以构成更长的治疗策略的外周疼痛途径中是否可以提供更长的效果。 AIM 1将评估A1受体介导的信号在持续性炎症性疼痛的小鼠模型中。在操纵Zusanli穴位的腺苷信号传导之前和之后，复合动作电位将记录在坐骨神经中。 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）是否无效针灸诱导镇痛。这个问题很重要，因为迄今为止尚无临床试验认为咖啡因可以直接抵消针灸的临床益处。 AIM 2询问沿轴突区域腺苷A1受体信号传导的长时间增加是否会触发慢性炎性疼痛的实验模型中持续抑制疼痛。初步数据表明，Zusanli穴位中的CD73（将内源性AMP转化为腺苷的核苷酸酶的给药可长期缓解疼痛。 AIM 3，我们将基于初步数据，表明Zusanli穴位中CD73的给药降低了炎症性疼痛的小鼠脊髓中P的水平。鉴于腺苷的内源性抗炎概况，我们将检验以下假设：沿传入的腺苷信号传导抑制了痛觉过敏，从而导致脊髓中炎症介质的降低。然后将观察到的抗炎作用与长期针灸进行比较。 提出的实验将提高我们对沿周围疼痛途径腺苷信号传导涉及的分子途径的理解。我们希望这些研究能够发展出新的治疗策略来治疗慢性疼痛，并进一步洞悉针灸的生物学基础。