AMPK ACTIVATORS FOR THE TREATMENT OF POST-SURGICAL PAIN

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。针对导致术后急性和慢性疼痛的分子事件的治疗可以更好地控制术后疼痛，并减少术后发生慢性疼痛的患者比例（高达50%）。本研究的重点是进一步开发两种潜在的疼痛药理控制机制：腺苷单磷酸活化激酶（AMPK）激活剂和破坏电压门控钠通道型1.7 (Nav1.7) /细胞外信号调节激酶（ERK）相互作用的肽。AMPK是一种能量感应激酶，内源性调节参与生长和增殖的细胞通路，新证据表明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蛋白（mTOR）和ERK信号通路来预防和逆转手术后疼痛。此外，AMPK激活剂抑制兴奋性并诱发感觉神经元的超兴奋性。Nav1.7主要在周围神经系统表达，对神经元的兴奋性起重要作用。人类基因研究已经证明了Nav1.7在疼痛加工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Nav1.7的调节机制直到现在才得到关注。我们的初步数据强烈表明AMPK激活因子与ERK介导的Nav1.7磷酸化干扰有关。这个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algogen引起的过度兴奋性。本课题旨在通过以下几个方面的研究，验证AMPK激活剂在术后疼痛行为模型中的药理学作用，AMPK调控感觉神经元mTOR和ERK的机制，以及AMPK介导的ERK与Nav1.7相互作用的调控，从而验证AMPK激活剂代表了一种治疗术后疼痛的新途径这一假说。根据该提案，我们期望为治疗疼痛的两种新治疗途径开发基本原理：1)AMPK激活剂和2)破坏ERK/Nav1.7相互作用的肽。因此，目前的应用将利用多学科的方法来解决手术后疼痛的问题，目标是向临床推进新的治疗方法。

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.