Abstract
Increased mRNA translation in sensory neurons following peripheral nerve injury contributes to the induction and maintenance of chronic neuropathic pain. Metformin, a common anti-diabetic drug and an activator of AMP-activated protein kinase (AMPK), inhibits cap-dependent mRNA translation and reverses mechanical hypersensitivity caused by a neuropathic injury in both mice and rats. P-bodies are RNA granules that comprise sites for metabolizing mRNA through the process of de-capping followed by RNA decay. These RNA granules may also sequester mRNAs for storage. We have previously demonstrated that induction of cap-dependent translation in cultured trigeminal ganglion (TG) neurons decreases P-body formation and AMPK activators increase P-body formation. Here we examined the impact of AMPK activation on protein synthesis and P-body formation in vitro and in vivo on mouse dorsal root ganglion (DRG) neurons. We demonstrate that AMPK activators inhibit nascent protein synthesis and increase P-body formation in DRG neurons. We also demonstrate that mice with a spared-nerve injury (SNI) show decreased P-bodies in the DRG, consistent with increased mRNA translation resulting from injury. Metformin treatment normalizes this effect in SNI mice and increases P-body formation in sham animals. These findings indicate that P-bodies are dynamically regulated by nerve injury in vivo and this effect can be regulated via AMPK activation.