Targeting AMPK for the Alleviation of Pathological Pain.
Chronic pain is a major clinical problem that is poorly treated with available therapeutics. Adenosine monophosphate-activated protein kinase (AMPK) has recently emerged as a novel target for the treatment of pain with the exciting potential for disease modification. AMPK activators inhibit signaling pathways that are known to promote changes in the function and phenotype of peripheral nociceptive neurons and promote chronic pain. AMPK activators also reduce the excitability of these cells suggesting that AMPK activators may be efficacious for the treatment of chronic pain disorders, like neuropathic pain, where changes in the excitability of nociceptors is thought to be an underlying cause. In agreement with this, AMPK activators have now been shown to alleviate pain in a broad variety of preclinical pain models indicating that this mechanism might be engaged for the treatment of many types of pain in the clinic. A key feature of the effect of AMPK activators in these models is that they can lead to a long-lasting reversal of pain hypersensitivity even long after treatment cessation, indicative of disease modification. Here, we review the evidence supporting AMPK as a novel pain target pointing out opportunities for further discovery that are likely to have an impact on drug discovery efforts centered around potent and specific allosteric activators of AMPK for chronic pain treatment.
University of Texas at Dallas, School of Behavioral and Brain Sciences, JO 4.212, 800 W Campbell Road, Richardson, TX, 75080, USA.
Marina N
MN
Asiedu
University of Texas at Dallas, School of Behavioral and Brain Sciences, JO 4.212, 800 W Campbell Road, Richardson, TX, 75080, USA.
Gregory
G
Dussor
University of Texas at Dallas, School of Behavioral and Brain Sciences, JO 4.212, 800 W Campbell Road, Richardson, TX, 75080, USA. theodore.price@utdallas.edu.
Theodore J
TJ
Price
D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000700:Analgesics / Q000627:therapeutic use*; D059350:Chronic Pain / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009020:Morphine / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000700:Analgesics; D007473:Ion Channels; D021122:Protein Subunits; D009020:Morphine; D055372:AMP-Activated Protein Kinases
AMPK; Cancer pain;; MAPK; Neuropathic pain; Postsurgical pain; mTOR