Department of Pharmacology, The University of Arizona School of Medicine, United States; Bio5 Institute, The University of Arizona School of Medicine, United States; Graduate Interdisciplinary Program in Neuroscience, The University of Arizona School of Medicine, United States.
Neurosci Lett. 2013 Dec 17;557 Pt A(0 0):9-18. doi: 10.1016/j.neulet.2013.06.060. Epub 2013 Jul 3.
Chronic pain is a critical medical problem afflicting hundreds of millions of people worldwide with costly effects on society and health care systems. Novel therapeutic avenues for the treatment of pain are needed that are directly targeted to the molecular mechanisms that promote and maintain chronic pain states. Recent evidence suggests that peripheral pain plasticity is promoted and potentially maintained via changes in translation control that are mediated by mTORC1 and MAPK pathways. While these pathways can be targeted individually, stimulating the AMPK pathway with direct or indirect activators achieves inhibition of these pathways via engagement of a single kinase. Here we review the form, function and pharmacology of AMPK with special attention to its emerging role as a potential target for pain therapeutics. We present the existing evidence supporting a role of AMPK activation in alleviating symptoms of peripheral nerve injury- and incision-induced pain plasticity and the blockade of the development of chronic pain following surgery. We argue that these preclinical findings support a strong rationale for clinical trials of currently available AMPK activators and further development of novel pharmacological strategies for more potent and efficacious manipulation of AMPK in the clinical setting. Finally, we posit that AMPK represents a unique opportunity for drug development in the kinase area for pain because it is pharmacologically manipulated via activation rather than inhibition potentially offering a wider therapeutic window with interesting additional pharmacological opportunities. Altogether, the physiology, pharmacology and therapeutic opportunities surrounding AMPK make it an attractive target for novel intervention for chronic pain and its prevention.
慢性疼痛是一个严重的医学问题，困扰着全球数以亿计的人，给社会和医疗保健系统带来了巨大的经济负担。我们需要寻找新的治疗方法来治疗疼痛，这些方法应该直接针对促进和维持慢性疼痛状态的分子机制。最近的证据表明，外周疼痛可塑性是通过促进和维持慢性疼痛状态的分子机制来促进的。mTORC1 和 MAPK 途径介导的翻译控制的变化。虽然这些途径可以单独靶向，但通过直接或间接激活 AMPK 途径，通过单一激酶的参与来实现对这些途径的抑制。在这里，我们回顾了 AMPK 的形式、功能和药理学，特别关注其作为疼痛治疗潜在靶点的新兴作用。我们提出了现有的证据，支持 AMPK 激活在缓解周围神经损伤和切口引起的疼痛可塑性症状以及阻断手术后慢性疼痛发展中的作用。我们认为，这些临床前研究结果为目前可用的 AMPK 激活剂的临床试验以及更有效地在临床环境中操纵 AMPK 的新型药理学策略的进一步发展提供了强有力的理由。最后，我们认为 AMPK 代表了激酶领域中疼痛药物开发的独特机会，因为它可以通过激活而不是抑制来进行药理学操纵，从而提供更宽的治疗窗口，并带来有趣的额外药理学机会。总之，AMPK 的生理学、药理学和治疗机会使其成为治疗慢性疼痛及其预防的一种有吸引力的新干预靶点。
