AMPK ACTIVATORS FOR THE TREATMENT OF POST-SURGICAL PAIN

描述(由申请人提供)：手术后疼痛是一个重要的临床问题，是慢性疼痛的主要原因，也是医疗保健系统的负担。针对手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手术后疼痛，并减少手术后发生慢性疼痛的患者比例(高达50%)。这项研究的重点是进一步发展两种潜在的疼痛药物操纵机制：一磷酸腺苷激活的激酶(AMPK)激活剂和破坏电压门控钠通道1.7(Nav1.7)/细胞外信号调节激酶(ERK)相互作用的多肽。AMPK是一种内源性调节细胞生长和增殖途径的能量敏感蛋白，新的证据表明，AMPK的激活降低了神经元的兴奋性。我们已经证明，不同的AMPK激动剂通过抑制哺乳动物雷帕霉素靶标(MTOR)和ERK信号通路来预防和逆转手术后疼痛。此外，AMPK激动剂抑制感觉神经元的兴奋性和诱发的超兴奋性。Nav1.7主要在外周神经系统表达，在设定神经元的兴奋性方面起着重要作用。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在获得性疼痛障碍中也发挥着重要作用，但Nav1.7的调节机制直到现在才受到关注。我们的初步数据有力地表明，AMPK激活剂与干扰ERK介导的Nav1.7的磷酸化有关。这一过程降低了感觉神经元的兴奋性，并减少了与手术后疼痛有关的变应原诱导的过度兴奋性。本研究的目的是验证AMPK激动剂是治疗术后疼痛的一条新的治疗途径的假说，其目的在于研究：1)AMPK激活剂在术后疼痛行为模型中的药理学作用；2)AMPK对感觉神经元mTOR和ERK的调节机制；3)AMPK介导的ERK与Nav1.7相互作用的调节。根据这一建议，我们预计将为治疗疼痛的两种新的治疗途径提供理论基础：1)AMPK激动剂和2)破坏ERK/Nav1.7相互作用的多肽。因此，本申请将利用多学科方法来解决手术后疼痛问题，目标是将新的治疗方法推向临床。

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.