Targeting Adenosine Monophosphate-Activated Protein Kinase (AMPK) in Preclinical Models Reveals a Potential Mechanism for the Treatment of Neuropathic Pain

Mol Pain. 2011 Sep 21;7:70. doi: 10.1186/1744-8069-7-70.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Enzyme Activators / pharmacology
  • Enzyme Activators / therapeutic use
  • Eukaryotic Initiation Factor-4F / biosynthesis
  • Hyperalgesia / complications
  • Hyperalgesia / drug therapy
  • Hyperalgesia / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Molecular Targeted Therapy*
  • Neuralgia / drug therapy*
  • Neuralgia / enzymology*
  • Neuralgia / physiopathology
  • Protein Biosynthesis / drug effects
  • Protein Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / injuries
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Sensory Receptor Cells / pathology
  • Signal Transduction / drug effects

Substances

  • Enzyme Activators
  • Eukaryotic Initiation Factor-4F
  • Protein Kinases
  • AMP-activated protein kinase kinase