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Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain

Ohannes K Melemedjian1, Marina N Asiedu1, Dipti V Tillu1, Raul Sanoja1, Jin Yan1, Arianna Lark1, Arkady Khoutorsky23, Jessica Johnson1, Katherine A Peebles1, Talya Lepow1, Nahum Sonenberg23, Gregory Dussor14 and Theodore J Price145*

Author Affiliations

1 Department of Pharmacology, University of Arizona, N Campbell Ave, Tucson, 85724, USA

2 Department of Biochemistry, McGill University, Sir William Osler, Montreal, H3G 1Y6, Canada

3 Goodman Cancer Research Centre, McGill University, McGill University, Sir William Osler, Montreal, H3G 1Y6, Canada

4 Graduate Interdisciplinary Program in Neuroscience, University of Arizona, N Campbell Ave, Tucson, 85724, USA

5 Bio5 Institute, University of Arizona, N Campbell Ave, Tucson, 85724, USA

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Molecular Pain 2011, 7:70  doi:10.1186/1744-8069-7-70

Published: 21 September 2011

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.