The Role of Mesoaccumbens Dopamine in Pain and Prescription Opioid Addiction

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This Veterans Affairs Career Development Award (CDA)-2 will provide support for academic career development through mentored research and professional skills development in preparation for transition to an academic research faculty position. Proposed activities will occur under the mentorship of Drs. Nicholas Gilpin, James Zadina, Scott Edwards, and Tiffany Wills and will foster hypothesis-driven research and independent investigation. Chronic pain affects >100 million American adults, costing the nation ~$635 billion every year in medical treatment costs and lost productivity. Due to the high prevalence of chronic pain among Veterans, treatment of chronic pain is a top priority of the Department of Veteran Affairs (VA), with prescription opioids a critical first-line treatment for chronic pain patients. However, Veterans treated chronically with opioids for their chronic pain may be vulnerable to developing opioid addiction and/or using illicit opioids to self-medicate pain symptoms. Chronic pain and opioid addiction each produce functional abnormalities in the nucleus accumbens (NAc), including dopamine (DA) deficits, which may be attributable to reduced cell firing of ventral tegmental area (VTA) DA neurons projecting to the NAc. The NAc mediates the acute rewarding effects of drugs of abuse via the mesoaccumbens pathway (VTA to NAc) and represents a functional terminus for ascending nociceptive pathways. However, there remains a gap in our knowledge regarding how chronic pain and limited/escalated opioid use interact to alter NAc neuronal excitability, drug intake, and pain sensitivity. The purpose of this project is to examine overlapping brain biochemical mechanisms of chronic pain and opioid dependence that may contribute to the worsening and potential interdependence of these two disorders. Our central hypothesis is that chronic pain induces mesolimbic dopaminergic signaling deficits that drive the development of prescription opioid (i.e., fentanyl) abuse, and fentanyl intake exaggerates pain-like outcomes in rats with chronic inflammatory pain. Here we propose that I) chronic inflammatory pain increases fentanyl intake, and that fentanyl intake exaggerates hyperalgesia in rats with chronic inflammatory pain, II) chronic inflammatory pain and fentanyl intake each increase the intrinsic excitability of NAc neurons and excitatory transmission onto NAc neurons, and III) VTA- NAc DA circuit activation and/or D2-like receptor agonist treatment each reduce hyperalgesia and escalated fentanyl intake in rats with chronic inflammatory pain. These hypotheses reflect the order of the aims in this CDA proposal. To investigate these hypotheses, we propose an innovative experimental strategy that compares the effects of chronic inflammatory pain states on the electrophysiological properties of NAc neurons and behavioral deficits (fentanyl intake/motivation, nociception) in animals given long access (LgA; 12 hrs) to fentanyl and short access (ShA; 1 hr) to fentanyl. Finally, we will use chemogenetics and targeted pharmacotherapies to test the effects of VTA-NAc DA circuit activation and D2-like receptor agonism on fentanyl intake/motivation and nociceptive measures in rats with chronic inflammatory pain. Conclusions resulting from these studies will have an important impact within both the pain management and addiction fields, as well as provide potential pharmacotherapeutic strategies for VA populations suffering from chronic pain and opioid addiction. In addition, an important feature of this CDA proposal is its provision of training in critical skills necessary for the applicant to attain her long-term goal of becoming an independent biomedical researcher and leader in the field of pain and opioid addiction research. Career development milestones and trajectories will guide her progression to an independent VA research career and include a transition to independence in terms of behavioral, surgical, electrophysiological, pharmacological, and chemogenetic techniques as well as a critical focus on professional skills development. In summary, this CDA award will greatly facilitate the applicant’s transition to an independent VA research position to continue future investigations into the biobehavioral mechanisms of chronic pain and opioid addiction.