Prelimbic cortex contribution to ethanol seeking in chronic neuropathic pain

项目摘要 慢性疼痛和酒精使用障碍（AUD）是高度共病。患有慢性疼痛的人 比那些没有发展澳元的可能性。此外，慢性疼痛和高疼痛强度与 酒精使用复发的风险增加。尽管如此，关于神经生物学的临床前数据有限。 慢性疼痛背景下复发的潜在基质。患有慢性疼痛的人报告说， 减轻疼痛和伴随的心理压力，这可能会涉及不同的神经回路来调节 奖励寻求我们先前在慢性神经性疼痛的备用神经损伤模型中的数据表明， 乙醇有效地减少了异常性疼痛-慢性神经性疼痛的标志性症状-在男性和 雌性老鼠我们的初步数据进一步确定了促进疼痛诱导的乙醇寻求恢复， 慢性疼痛男性与其假损伤对应者的条件性位置偏好模型。 前边缘皮层（PL）-内侧前额叶皮层的一个亚区-是调节的共同底物 乙醇的寻求和痛苦。PL及其输出是恢复奖励寻求的关键调节器， 复发相关行为的模型。PL还介导慢性疼痛的情感和认知成分。 在啮齿类动物模型中的疼痛，并在慢性神经性疼痛患者中高度中断。这使得PL 在慢性疼痛条件下乙醇寻求和恢复的研究中有前途的目标。因此，在本发明中， 这项提案中的实验将测试慢性疼痛改变乙醇复发的总体假设， 相关的行为和相关的神经生物学底物，重点是PL及其皮质下 预测。为了检验慢性神经性疼痛改变PL活性的假设， 行为，目标1将联合收割机在体内电生理学与行为分析相结合，以研究PL活性， 成年人乙醇条件性位置偏爱获得、表达及痛诱发再恢复 雄性和雌性小鼠的神经损伤。此外，正如我们已经证明的，乙醇是抗异常性疼痛的， 在备用神经损伤模型中，乙醇对疼痛刺激周围的PL活性的影响将是 表征了目标2将检验离散PL预测调节乙醇恢复的假设 寻找我们将使用化学遗传学沉默PL投射到丘脑核核心或基底外侧 杏仁核，预期基底外侧杏仁核的投射对于疼痛诱导是必要的 在慢性疼痛的情况下，乙醇引发的恢复不是这样。总之，这些实验 将提供深入了解独特的神经行为利基介导乙醇寻求和复发相关的行为 在慢性疼痛的情况下。我们希望，完成这项建议将作为一个脚手架， 随后对乙醇寻求的神经生物学基础的研究。

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.