Involvement of dopamine signaling in chronic pain-induced negative affective state and nicotine use comorbidity - Nicotine addiction among individuals with chronic pain is a serious public health concern with significant health- care expenses and lost productivity. Chronic pain-associated negative affective state, such as anxiety, is a risk factor for tobacco use. Greater chronic pain intensity increases sensitivity to anxiety, which is, in turn, associated with increased smoking and vaping. Therefore, I hypothesize there is a neurobiological mechanism in which chronic pain decreases mesolimbic dopaminergic signaling to causally induce a negative affective state, thereby increasing the risk of nicotine use. To investigate this causal mechanism in the comorbidity of chronic pain and nicotine use, I propose modeling this comorbidity in rats and the following aims: Aim 1: Evaluate ventral tegmental area – nucleus accumbens (VTA-NAc) dopamine (DA) signaling in a model of chronic pain to determine whether decreases in DA signaling underlie the chronic pain-induced negative affective state. Aim 2: Determine whether nicotine has increased reinforcing efficacy in chronic pain states compared to pain-naïve states. This proposal combines behavioral, pharmacological, neurochemical, and optogenetic approaches to reveal whether chronic pain-associated decreases in VTA-NAc DA signaling underlie chronic pain-induced negative affective states, and whether nicotine is more rewarding in chronic pain states compared to pain-naïve states due to decreased baseline DA signaling, thereby exacerbating nicotine’s effects on DA signaling. My overall career goal is to become an independent academic scientist, identifying neurobiological mechanisms underlying these phenomena to develop new interventions for patients with co-morbid pain and nicotine addiction. The proposed K01 trainings will increase my knowledge of neurobiology and circuitry of the mesolimbic reward pathway, allowing me to investigate its mediation in chronic pain-induced negative affect and nicotine addiction. My primary mentor Dr. Addy, an expert in neurobiology and neurochemistry of substance abuse, will provide training on mechanisms of drug reinforcement and in vivo voltammetry. My co-mentor Dr. DiLeone, an expert in neuronal circuits controlling reward-related behaviors, will provide training on neuromodulation and in vivo optogenetics. My co-mentor Dr. Porreca, an expert in pain-induced affective and motivational behaviors and reward circuits, will provide training and oversight on modeling and understanding brain reward circuitry in chronic pain and negative affect. My co-mentor Dr. Picciotto, the director of the Junior Faculty Mentoring Program for the Department of Psychiatry at Yale, will mentor my career enhancement trainings together with Dr. Addy. My consultant Dr. Ditre, an expert in human comorbidity of chronic pain and nicotine addiction, will provide insights in the discussions of human data. I will also receive extensive training by attending courses, seminars, conferences, and workshops. Through the proposed K01, I will effectively gain new technical skills and perspectives, ultimately facilitating a successful transition to become a principal investigator.
