Dissecting nociceptin opioid peptide function at the intersection of stress and reward circuitry

Abstract

Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid neuropeptide, and its G-protein coupled receptor NOPR are implicated in diverse behavioral states including the stress response, motivation, aversion, and reward-seeking. Stress-induced dysfunction in these behaviors is central to the development of both mood and substance use disorders, driving wide interest in NOPR as a therapeutic target. Despite promising evidence of NOPR's therapeutic potential, a critical gap remains in our understanding of how stress reshapes N/OFQ function within mesolimbic pathways that mediate motivated behavior. In particular, the discrete circuitry and specific mechanisms by which the N/OFQ-NOPR system influences and possibly links stress and reward responses remain largely unknown. Seeking to address this gap, my dissertation work investigates the expression, connectivity, and function of N/OFQ neurons within key mesolimbic reward circuitry during both stress and reward-related behaviors. Chapter 1 reviews N/OFQ's known roles in stress and motivation and introduces the mesolimbic pathway, a central reward circuit from the ventral tegmental area (VTA) to the striatum where we focused our investigations of N/OFQ's function. Chapter 2 identifies the spatial, molecular, and developmental expression of Pnoc, the N/OFQ precursor gene, across different striatal compartments. Chapter 3 presents NOPLight, a novel genetically encoded sensor we developed for real-time monitoring of N/OFQ release, and its use in detecting N/OFQ dynamics within the VTA during stress and reward. Chapter 4 characterizes VTA N/OFQ neuron activity in response to various stressors and identifies functional afferent connectivity to this population from the lateral hypothalamus. Finally, Chapter 5 discusses these findings in the context of existing literature surrounding N/OFQ's roles in stress and motivation, outlining future research directions. Overall, my research advances our understanding of N/OFQ's influence on stress and motivation by identifying N/OFQ circuitry that may integrate these two states, creating a foundation for further exploration of the N/OFQ-NOPR system's therapeutic potential and its role in the development and progression of reward-related disorders.