AMPK as a Novel Target for Treatment of Neuropathic and Post-Surgical Pain

Abstract

Chronic pain is a major health problem affecting more than 1.5 billion people worldwide. Specifically, neuropathic pain and chronic post-surgical pain are debilitating clinical conditions with few efficacious treatments, warranting development of novel therapeutics. Starting with the hypothesis that dysregulated translation regulation pathways may underlie these pain states, we demonstrated that there is a major reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity and increased phosphorylation of mTOR and ERK downstream targets in these persistent pain states. We also hypothesized that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the treatment of neuropathic and incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. The AMP activated protein kinase (AMPK) activators, metformin, resveratrol and A769662, inhibited translation regulation signaling pathways in sensory neurons, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. We have further demonstrated that local injection of resveratrol, metformin or A769662 and topical application of resveratrol, a potent AMPK activator, into the hindpaw following plantar incision dose-relatedly reverses incision-mediated mechanical hypersensitivity as well as hyperalgesic priming induced by incision. In addition, co-treatment with systemic metformin and local resveratrol at individually sub-efficacious doses at the time of incision blocked acute hypersensitivity and hyperalgesic priming suggesting potential super-additive effects of combined AMPK activator use. These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.