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)高度并存。患有慢性疼痛的人增加了 患AUD的可能性比那些没有的人高。此外，慢性疼痛和高疼痛强度与 再次酗酒的风险增加。尽管如此，有关神经生物学的临床前数据有限。 在慢性疼痛的背景下，复发的潜在基础。慢性疼痛患者报告使用酒精 缓解疼痛和随之而来的心理社会压力，这可能需要不同的神经回路来调节 寻求回报。我们先前在慢性神经病理性疼痛的备用神经损伤模型中的数据显示 酒精有效地减少了男性和女性的超常疼痛--慢性神经性疼痛的一个显著症状-- 雌性老鼠。我们的初步数据进一步证实了促进乙醇寻求的疼痛诱导的恢复。 慢性疼痛男性患者的条件性位置偏爱模型与假损伤的男性患者相比。 前额叶皮质(PL)--内侧前额叶皮质的一个亚区--是调节的共同底物 酒精的寻求和痛苦。公共利益及其产出是恢复奖赏寻求的关键调节因素 与复发相关的行为模式。此外，PL还在慢性期的情感成分和认知成分中起中介作用 在啮齿动物模型中的疼痛，并在慢性神经病理性疼痛的患者中高度中断。这使得PL成为一个 在慢性疼痛条件下酒精寻求和恢复的研究中有希望的靶点。因此， 这项提议中的实验将检验最重要的假设，即慢性疼痛改变酒精复发-- 相关的行为和相关的神经生物学基础，重点是PL及其皮质下 投射。验证慢性神经病理性疼痛在复发相关期间改变PL活性的假设 行为，目标1将结合体内电生理学和行为分析来研究PL在 成人乙醇条件性位置偏爱和疼痛恢复的获得和表达 雄性和雌性小鼠有备用的神经损伤。此外，正如我们已经证明的那样，乙醇具有抗过敏性 在备用神经损伤模型中，乙醇对疼痛刺激周围PL活性的影响将是 特色化的。目标2将检验离散PL投射调节乙醇恢复的假设 寻找。我们将使用化学遗传学来抑制向伏隔核核心或基底外侧核的PL投射 杏仁核，期望向杏仁基底外侧核投射是引起疼痛所必需的 在慢性疼痛的情况下，恢复，但不是乙醇启动的恢复。总而言之，这些实验 将提供对调节酒精寻求和复发相关行为的独特神经行为利基的洞察 在慢性疼痛的情况下。我们期望这项提议的完成将成为 随后对寻求酒精的神经生物学底物进行了研究。

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.