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: 8860362
• 负责人: GREGORY O DUSSOR
• 金额: $ 28.68万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 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 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860362
• 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; Health; 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; 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能会更好地管理术后疼痛，并减少术后发生慢性疼痛的患者比例（高达50%）。本研究工作的重点是进一步开发两种潜在的疼痛药理学操纵机制：腺苷一磷酸激活激酶（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（ERK）相互作用的肽。AMPK是一种内源性调节参与生长和增殖的细胞通路的能量感应激酶，并且新出现的证据表明AMPK的激活降低神经元的兴奋性。我们已经证明，不同的AMPK激活剂通过抑制哺乳动物雷帕霉素靶蛋白（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和诱发的过度兴奋性。Nav1.7主要在周围神经系统中表达，在设定神经元的兴奋性中起重要作用。人类遗传学研究已经证明了Nav1.7在疼痛处理中的关键作用，最近的证据表明Nav1.7在获得性疼痛疾病中也起着重要作用，但Nav1.7的调节机制现在才成为焦点。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致痛原诱导的过度兴奋性。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）AMPK调节感觉神经元中mTOR和ERK的机制，以及3）AMPK介导的ERK与Nav1.7相互作用的调节。我们预计将根据该提案为治疗疼痛的两种新型治疗途径开发理论基础：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的问题，目标是将新疗法推向临床。