Chronic pain affects more than 50 million Americans per year, resulting in extraordinary personal and societal costs. Adding to the dilemma, deaths involving prescription opiate analgesics have almost quadrupled in the last ten years. The clinical challenge of pain management is underscored by evidence that chronic pain is mechanistically distinct from acute pain, therefore a thorough understanding of the molecular and cellular mechanisms underlying the transition to chronic pain is fundamental to improving and expanding treatment options. Hyperalgesic priming is a compelling model of the transition to chronic pain in which an initial injury resolves, but leaves the animal in a primed state in which a second insult induces a greatly prolonged pain response. Experiments proposed here will examine the impact of mitochondrial dynamics on the development of acute and chronic inflammatory pain compared to a nerve injury model of neuropathic pain, and will explore molecular mechanisms mediating proposed anti-nociceptive actions of endogenous uncoupling mechanisms and mitochondrial uncoupling drugs. Specific Aim 1 will examine the how mitochondrial function changes in response to noxious insult and the impact of mitochondrial regulation on acute hyperalgesia in sensory ganglia. Specific Aim 2 will use patch clamp electrophysiology to demonstrate changes in electrical properties of sensory neurons in response to manipulation of mitochondrial function, and will identify cell signaling pathways that mediate mitochondrial effects on neuronal excitability. Specific Aim 3 will characterize changes in mitochondrial function unique to the transition to chronic pain, and will elucidate cell signaling pathways modulating the impact of mitochondrial function on inflammatory and neuropathic pain chronification. This proposal will use innovative approaches to explore novel mechanisms by which mitochondria influence the manifestation of acute and chronic pain, and test the therapeutic potential of targeting these mechanisms for pain relief.

PROJECT NARRATIVE Intractable pain is a major clinical challenge that poses a heavy societal burden and is driving a national controversy over the use of potentially dangerous opioid analgesics. This project explores novel endogenous mechanisms by which mitochondrial function regulates sensory neuron sensitization and excitability in preclinical models of acute and chronic inflammatory and neuropathic pain. Experiments proposed here will use mild mitochondrial uncoupling compounds as pharmacological tools to manipulate mitochondrial function in sensory neurons, and will test their efficacy as novel anti-nociceptive agents.