There is a great need for new
therapeutics for the treatment of
pain. A possible avenue to development of such
therapeutics is to interfere with signaling pathways engaged in peripheral nociceptors that cause these neurons to become hyperexcitable. There is strong evidence that
mitogen activated protein kinases (MAPKs) and
phosphoinositide 3-kinase (PI3K) / mechanistic target of
rapamycin (mTOR) signaling pathways are key modulators of nociceptor excitability in vitro and in vivo. Activation of
adenosine monophosphate activated
protein kinase (AMPK) can inhibit signaling in both of these pathways and AMPK activators have been shown to inhibit nociceptor excitability and
pain hypersensitivity in rodents. R419 is one of, if not the most potent AMPK activator described to date. We tested whether R419 activates AMPK in dorsal root ganglion (DRG) neurons and if this leads to decreased
pain hypersensitivity in mice. We find that R419 activates AMPK in DRG neurons resulting in decreased MAPK signaling, decreased nascent
protein synthesis and enhanced P body formation. R419 attenuates
nerve growth factor-(
NGF) induced changes in excitability in DRG neurons and blocks
NGF-induced mechanical
pain amplification in vivo. Moreover, locally applied R419 attenuates
pain hypersensitivity in a model of
post-surgical pain and blocks the development of hyperalgesic priming to both
NGF and incision. We conclude that R419 is a promising lead candidate compound for the development of potent and specific AMPK activation to inhibit
pain hypersensitivity as a result of injury.