AMPK ACTIVATORS FOR THE TREATMENT OF POST-SURGICAL PAIN

用于治疗术后疼痛的 AMPK 激活剂

• 批准号: 8634807
• 负责人: GREGORY O DUSSOR
• 金额: --
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634807
• 关键词: 2' -adenylic acid; Acute; Acute Pain; Address; Adenosine; Adenosine Monophosphate; Afferent Neurons; Analgesics; Automobile Driving; Behavioral Model; Biological Factors; Cells; Clinic; Clinical; Clinical Management; Co-Immunoprecipitations; Data; Development; Event; Extracellular Signal Regulated Kinases; Generations; Goals; Growth; Healthcare Systems; Human Genetics; In Vitro; Interleukin-6; Lead; Link; MAPK3 gene; Maintenance; Mechanics; Mediating; Mediator of activation protein; Metformin; Modeling; Molecular Target; Mono-S; Nerve Growth Factors; Nervous system structure; Neuronal Plasticity; Neurons; Nutrient; Operative Surgical Procedures; Pain; Pain Disorder; Pain management; Pathway interactions; Patients; Peptides; Peripheral Nervous System; Persistent pain; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Play; Postoperative Pain; Process; Publications; Regulation; Research; Resveratrol; Role; Signal Pathway; Signal Transduction; Sodium Channel; Surgical incisions; Testing; Therapeutic; Translations; allodynia; chronic pain; design; drug discovery; inorganic phosphate; insight; interdisciplinary approach; mTOR protein; molecular pathology; novel; novel therapeutics; prevent; protein protein interaction; public health relevance; research clinical testing; research study; tool; voltage

DESCRIPTION (provided by applicant): Post-surgical pain represents an important clinical problem that is a major cause of chronic pain and a burden on healthcare systems. Treatments that target molecular events that underlie post-surgical acute and chronic pain may offer better management of post-surgical pain and reduce the proportion of patients (as high as 50%) that develop chronic pain after surgey. The focus of this research effort is to further develop two potential mechanisms for the pharmacological manipulation of pain: adenosine monophosphate activated kinase (AMPK) activators and peptides that disrupt voltage-gated sodium channel type 1.7 (Nav1.7) / extracellular signal regulated kinase (ERK) interactions. AMPK is an energy sensing kinase that endogenously regulates cellular pathways involved in growth and proliferation and emerging evidence suggests that activation of AMPK decreases the excitability of neurons. We have demonstrated that diverse AMPK activators prevent and reverse post-surgical pain via inhibition of mammalian target of rapamycin (mTOR) and ERK signaling pathways. Moreover, AMPK activators inhibit excitability and evoked hyperexcitability of sensory neurons. Nav1.7 is expressed primarily in the peripheral nervous system and plays an important role in setting the excitability of the neuron. Human genetic studies have demonstrated a crucial role for Nav1.7 in pain processing and recent evidence suggests that Nav1.7 also plays an important role in acquired pain disorders yet mechanisms through which Nav1.7 is regulated are only now coming into focus. Our preliminary data strongly suggest that AMPK activators are linked to interference with ERK mediated phosphorylation of Nav1.7. This process decreases the excitability of sensory neurons and reduces hyperexcitability induced by algogens linked to post-surgical pain. The goal of this proposal is to test the hypothesis that AMPK activators represent a new therapeutic avenue for the treatment of post-surgical pain through aims examining: 1) the pharmacology of AMPK activators in behavioral models of post-surgical pain, 2) mechanisms of AMPK regulation of mTOR and ERK in sensory neurons and 3) AMPK-mediated regulation of ERK interactions with Nav1.7. We anticipate developing a rationale for two novel therapeutic avenues for the treatment of pain under this proposal: 1) AMPK activators and 2) peptides that disrupt ERK/Nav1.7 interactions. Hence, the present application will utilize a multidisciplinary approach to tackle the problem of post-surgical pain with the goal of advancing novel therapies toward the clinic.

描述（由申请人提供）：术后疼痛是一个重要的临床问题，是慢性疼痛的主要原因，也是医疗保健系统的负担。针对术后急性和慢性疼痛的分子事件的治疗可以更好地管理术后疼痛，并减少术后出现慢性疼痛的患者比例（高达 50%）。这项研究工作的重点是进一步开发药物控制疼痛的两种潜在机制：单磷酸腺苷激活激酶 (AMPK) 激活剂和破坏电压门控钠通道 1.7 型 (Nav1.7)/细胞外信号调节激酶的肽（ ERK）相互作用。 AMPK 是一种能量感应激酶，可内源性调节参与生长和增殖的细胞通路，新出现的证据表明 AMPK 的激活会降低神经元的兴奋性。我们已经证明，多种 AMPK 激活剂通过抑制哺乳动物雷帕霉素靶点 (mTOR) 和 ERK 信号通路来预防和逆转术后疼痛。此外，AMPK 激活剂抑制感觉神经元的兴奋性并引起过度兴奋。 Nav1.7 主要在周围神经系统中表达，在设置神经元的兴奋性方面发挥重要作用。人类遗传学研究已经证明 Nav1.7 在疼痛处理中发挥着至关重要的作用，最近的证据表明 Nav1.7 在获得性疼痛障碍中也发挥着重要作用，但 Nav1.7 的调节机制现在才成为人们关注的焦点。我们的初步数据强烈表明 AMPK 激活剂与干扰 ERK 介导的 Nav1.7 磷酸化有关。这一过程降低了感觉神经元的兴奋性，并减少了与术后疼痛相关的痛觉原引起的过度兴奋。本提案的目的是通过以下目的检验 AMPK 激活剂代表治疗术后疼痛的新治疗途径的假设：1) AMPK 激活剂在术后疼痛行为模型中的药理学，2) 术后疼痛的机制AMPK 对感觉神经元中 mTOR 和 ERK 的调节，以及 3) AMPK 介导的 ERK 与 Nav1.7 相互作用的调节。我们预计根据该提案为两种治疗疼痛的新治疗途径建立一个基本原理：1) AMPK 激活剂和 2) 破坏 ERK/Nav1.7 相互作用的肽。因此，本申请将利用多学科方法来解决术后疼痛问题，目标是将新疗法推向临床。