Dorsal root ganglion (DRG) sensory neurons play a critical role in processing and modulation of sensory information, including that experienced in peripheral neuropathy. In response to injury of peripheral nerves the DRG undergo changes in potassium channel (K+) function including KATP channels. KATP channels are integral in the regulation of membrane excitability and inhibited by physiological ATP and activated during events of energy depletion, such as metabolic stress. KATP activation plays a neuroprotective role in peripheral neuropathy via membrane hyperpolarization, decreased cell excitability and prevention of cell death. Similarly, the AMP-activated protein kinase (AMPK) signaling pathway enhances mitochondrial functioning and plays a neuroprotective role in peripheral neuropathy. Hypothesis: agonists of KATP channels enhance mitochondrial function and neurite outgrowth via the AMPK pathway and modulate neuronal excitability in DRG neurons. DRG neurons from adult Sprague-Dawley male rats were isolated and cultured under defined conditions. KATP channel openers pinacidil and VU0071063 increased levels of phosphorylated AMPK in a dose and time dependent manner. Additionally, opening of KATP channels augmented neurite outgrowth in the DRG neurons. Interestingly, pinacidil as well as VU0071063 treatment resulted in decreased ATP production as well as coupling efficiency and negatively impacted a plethora of other oxidative phosphorylation parameters. Lastly, pharmacological inhibition of AMPK via Compound C negated the enhancement effect of pinacidil and VU0071063 on neurite outgrowth. This data confirmed the ability of AMPK to act downstream of KATP channels and acts as a key mediator of KATP opening effects on neurite outgrowth. This study reveals for the first time that opening of KATP channels increases AMPK activity and augments neurite outgrowth. However, this mechanism of action of KATP activation did not positively effect mitochondrial respiration. The ability of pharmacological opening of KATP channels to drive neurite outgrowth indicate a potential therapeutic application in peripheral neuropathy.