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; 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）：手术后疼痛是一个重要的临床问题，是慢性疼痛和医疗保健系统负担的主要原因。靶向构成后手术后急性和慢性疼痛的分子事件的治疗方法可能会更好地治疗手术后疼痛，并减少患者的比例（高达50％），这些患者会在外科治疗后伴有慢性疼痛。这项研究工作的重点是进一步开发出两种潜在的疼痛操纵机制：腺苷单磷酸激活激酶（AMPK）活化剂和肽，这些激活剂和肽破坏了电压门控通道类型1.7（NAV1.7） /细胞外信号调节的激酶（ERK）相互作用。 AMPK是一种能量传感激酶，它可以内源调节与生长和增殖有关的细胞途径，并且新出现的证据表明AMPK的激活降低了神经元的兴奋性。我们已经证明，通过抑制雷帕霉素（MTOR）和ERK信号通路的哺乳动物靶标，可以通过抑制哺乳动物靶标，预防和反向手术后疼痛。此外，AMPK激活剂抑制了兴奋性和感官神经元的过度兴奋性。 NAV1.7主要在周围神经系统中表达，并在设定神经元的兴奋性方面起着重要作用。人类的遗传研究表明，NAV1.7在疼痛处理中起着至关重要的作用，最近的证据表明，NAV1.7在获得性疼痛障碍中也起着重要作用，但调节NAV1.7的机制才被关注。我们的初步数据强烈表明AMPK激活剂与ERK介导的NAV1.7的磷酸化有关。该过程降低了感觉神经元的兴奋性，并降低了与手术后疼痛相关的算法引起的过度兴奋性。该提案的目的是检验以下假说：AMPK激活剂代表了一种新的治疗途径，可通过旨在检查术后疼痛治疗后术后疼痛：1）AMPK激活剂在术后疼痛的行为模型中的药理学，2）MTOR和ERK调节MTOR和ERK在感官神经元中调节Ampk Neurons and ampk and ampk的机制。我们预计在此提案下为治疗疼痛治疗的两种新型治疗途径开发一个理由：1）AMPK激活剂和2）破坏ERK/NAV1.7相互作用的肽。因此，本应用将利用一种多学科的方法来解决术后疼痛的问题，目的是将新型疗法推向诊所。