title: Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain.
abstract: Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain.
authors.affiliation: Department of Pharmacology, University of Arizona, N Campbell Ave, Tucson, 85724, USA.
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Marina N
authors.initials: MN
authors.lastname: Asiedu
authors.forename: Dipti V
authors.initials: DV
authors.lastname: Tillu
authors.forename: Raul
authors.initials: R
authors.lastname: Sanoja
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Arianna
authors.initials: A
authors.lastname: Lark
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.forename: Jessica
authors.initials: J
authors.lastname: Johnson
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Peebles
authors.forename: Talya
authors.initials: T
authors.lastname: Lepow
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use; D039562:Eukaryotic Initiation Factor-4F / Q000096:biosynthesis; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D058990:Molecular Targeted Therapy; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020536:Enzyme Activators; D039562:Eukaryotic Initiation Factor-4F; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases