Prelimbic cortex contribution to ethanol seeking in chronic neuropathic pain

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Project Summary Chronic pain and alcohol use disorders (AUD) are highly comorbid. People with chronic pain have an increased likelihood to develop AUD than those without. Further, chronic pain and high pain intensity are associated with elevated risk for relapse to alcohol use. Despite this, there is limited preclinical data on the neurobiological substrates underlying relapse in the context of chronic pain. People with chronic pain report using alcohol to alleviate pain and the accompanying psychosocial stress, which likely engages distinct neurocircuits to regulate reward seeking. Our previous data in the spared nerve injury model of chronic neuropathic pain demonstrate that ethanol effectively reduced allodynia – a hallmark symptom of chronic neuropathic pain – in both male and female mice. Our preliminary data further identified facilitated pain-induced reinstatement of ethanol seeking in a conditioned place preference model in males with chronic pain as compared to their sham injured counterparts. The prelimbic cortex (PL) – a subregion of the medial prefrontal cortex – is a common substrate in the regulation of ethanol seeking and pain. The PL and its outputs are key regulators of reinstatement of reward seeking, a model of relapse-related behavior. The PL also mediates both affective and cognitive components of chronic pain in rodent models and is highly disrupted in patients with chronic neuropathic pain. This makes the PL a promising target in investigation of ethanol seeking and reinstatement under conditions of chronic pain. Thus, experiments in this proposal will test the overarching hypothesis that chronic pain alters ethanol relapse- related behaviors and associated neurobiological substrates, with a focus on the PL and its subcortical projections. To test the hypothesis that chronic neuropathic pain alters PL activity during relapse-related behavior, Aim 1 will combine in vivo electrophysiology with behavioral analyses to investigate PL activity during the acquisition and expression of ethanol conditioned place preference and pain-induced reinstatement in adult male and female mice with a spared nerve injury. Further, as we have demonstrated that ethanol is antiallodynic in the spared nerve injury model, the effect of ethanol on PL activity surrounding painful stimulation will be characterized. Aim 2 will test the hypothesis that discrete PL projections regulate reinstatement of ethanol seeking. We will use chemogenetics to silence PL projections to the nucleus accumbens core or basolateral amygdala, with the expectation that projections to the basolateral amygdala are necessary for pain induced reinstatement but not ethanol-primed reinstatement in the context of chronic pain. Together, these experiments will provide insight into the unique neurobehavioral niche mediating ethanol seeking and relapse-related behavior under conditions of chronic pain. We expect that completion of this proposal will serve as a scaffold for subsequent research into the neurobiological substrates of ethanol seeking.