Chronic pain is common among Veterans and remains an unmet medical need. Voltage-gated sodium channels (NaVs) that are expressed preferentially in primary afferents play a critical role in human pain disorders, and present opportune targets for the development of novel pain treatments that carry minimal CNS side effects and addictive potential. NaV1.7 is a peripheral threshold channel that regulates action potential firing and neurotransmitter release. Our work for the past 15 years has linked NaV1.7 to human pain disorders, e.g., inherited erythromelalgia, small fiber neuropathy, painful diabetic neuropathy, and validated NaV 1.7 as a highly attractive target for the treatment of pain. Although considerable progress has been made in the development of novel NaV1.7 blockers for the treatment of pain, much work is needed to improve their specificity and efficacy. Similarly, while existing NaV blockers can provide symptomatic relief in patients, their utility is limited due to non-specificity and significant CNS side effects. Gabapentinoids, the current first line treatment for chronic pain, inhibit trafficking of presynaptic voltage-gated calcium channel to the plasma membrane or disrupt Rab11-dependent recycling, thus reducing calcium currents and transmitter release. By analogy to gabapentinoids' mode of action for the treatment of pain, and recent focus on trafficking proteins as therapeutic targets in CNS disorder, targeting trafficking machinery of Nav1.7 might represent a novel approach to pain treatment. However, little is known about molecules and mechanisms that control sodium channel trafficking and surface distribution along the length of sensory axons—a target of opportunity that we explore in this proposal. In this proposal, we aim to elucidate molecular mechanisms that control trafficking of NaV1.7 and their distribution in the axonal plasma membrane of sensory neurons, in an effort to identify potential new targets for the treatment of chronic pain. Specifically, we will build upon a powerful new platform that we developed, that enables real-time imaging of single sodium channels within living sensory neurons at a distance from the soma with unprecedented spatial- and temporal-resolution. Knowledge gleaned from these studies will provide unprecedented clarity about mechanisms that regulate sub- cellular distribution of sodium channels in sensory neurons, particularly along the length of axons, in normal and disease states. These studies, in turn, will enable discovery of new targets for treatment of chronic pain. Our ultimate goal is to develop safer and more effective treatments without addictive potential and other serious side effects.

Chronic pain is common among Veterans with poly-trauma, traumatic nerve injury, and traumatic limb amputation. While opioids are currently used for chronic pain, they are not very effective and carry serious side effects including the risk of addiction and abuse. We, and others, have discovered that peripheral voltage- gated sodium channels (NaVs) play a central role in human pain disorders, which has led to the pursuit of inhibitors of these channels as treatments that would avert central side effects. Although NaV channel blockers exist, they are of limited utility due to non-specificity and significant CNS effects. The goal of this project is to identify new targets toward the development of more effective treatments for chronic pain through the study of trafficking and polarized distribution of NaV channels within sensory neurons. The outcomes are expected to facilitate development of safer, more effective, and non-addictive treatments for chronic pain.