Dissecting the Parabrachial Nucleus's Role in the Development and Maintenance of Neuropathic Pain

Project Summary Chronic pain conditions place significant burdens on patients, their families, and society by reducing quality of life and creating enormous financial consequences that total more than 630 billion USD annually for the United States of America alone. Neuropathic pain is a debilitating type of chronic pain that arises from a lesion or disease affecting the somatosensory system. Neuropathic pain affects 7-8% of the general population yet is poorly responsive to analgesic drugs, including opioids, thus, alternative therapeutics for treatment are desperately needed. However, the underlying mechanisms of the development and maintenance of neuropathic pain are poorly understood. It is hypothesized that neuropathic pain results from a loss of spinal cord dorsal horn inhibition and/or a gain in dorsal horn excitation that allows the propagation of low threshold innocuous inputs to be perceived as painful. Exactly how nerve injury disrupts this balance to generate a net pronociceptive tone, however, remains unclear. Specific Aim 1 describes promising preliminary data within our laboratory that implicates glutamatergic dorsal horn interneurons expressing the neuropeptide Y (NPY) Y1 receptor in both the development and maintenance of neuropathic pain. First, selective ablation of neuropeptide Y1 receptor- expressing interneurons (Y1-INs) with intrathecal NPY-saporin reduced the development of behavioral signs of neuropathic pain. Second, intrathecal pharmacology and intraspinal chemogenetic techniques indicate that Y1- INs are both necessary and sufficient for the behavioral manifestations of neuropathic pain. Lastly, both single cell RNA-sequencing and fluorescence in situ hybridization data indicate that Y1-INs segregate into three distinct dorsal horn interneuron subpopulations. Together, these observations form the premise for my central hypothesis that nerve injury increases the excitability of Y1-INs, and this makes one or more subpopulations of Y1-INs necessary for the behavioral symptoms of neuropathic pain. Specific Aim 2 will explore this hypothesis via intraspinal pharmacology, behavioral testing, in vivo wireless optogenetics, intersectional Cre-lox transgenics, and patch clamp electrophysiology. Together these methods will test which Y1-IN subpopulation(s) is/are necessary for the behavioral signs of neuropathic pain. Further, these methods will assess changes in pre- or postsynaptic excitatory and inhibitory activity to Y1-INs following nerve injury to uncover mechanistic changes in the circuit that might lead to the development of neuropathic pain. Specific Aim 3 details a plan to identify and pursue a neuroscience focused postdoctoral fellowship following the completion of the dissertation work described in Specific Aim 2. The overarching goals of this study are to increase our understanding of how nerve injury increases the excitability of Y1-IN subpopulations, and provide rationale for targeting spinal Y1-INs as a novel approach to treat neuropathic pain.