Prelimbic cortex contribution to ethanol seeking in chronic neuropathic pain

前边缘皮质对慢性神经病理性疼痛中乙醇寻找的贡献

• 批准号: 10811100
• 负责人: JACQUELINE M BARKER
• 金额: $ 21.78万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-26 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10811100
• 关键词: Acute Pain; Adult; Affective; Alcohol consumption; Alcohols; Amygdaloid structure; Animals; Automobile Driving; Behavior; Behavioral; Chronic; Cognitive; Complex; Data; Development; Distress; Dose; Electrophysiology (science); Ethanol; Exhibits; Extinction; Female; Genetic; Glutamates; Heterogeneity; High Prevalence; Impairment; Implant; Individual; Investigation; Link; Maintenance; Medial; Mediating; Modeling; Mus; Negative Reinforcements; Neurobiology; Nucleus Accumbens; Output; Pain; Pain intensity; Patients; Persons; Positive Reinforcements; Prefrontal Cortex; Psychosocial Stress; Regulation; Relapse; Reporting; Research; Rewards; Risk; Rodent Model; Role; Surgical Injuries; Testing; Therapeutic; Training; Treatment Efficacy; Woman; Work; alcohol effect; alcohol exposure; alcohol relapse; alcohol reward; alcohol seeking behavior; alcohol use disorder; allodynia; chronic neuropathic pain; chronic pain; chronic painful condition; comorbidity; conditioned place preference; conditioning; expectation; experience; experimental study; in vivo; inflammatory pain; injured; insight; male; men; multi-electrode arrays; nerve injury; neural; neural circuit; neurobehavioral; pain processing; pain reduction; persistent symptom; pre-clinical; psychosocial; reduced alcohol use; relapse risk; scaffold; spared nerve; targeted treatment

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.

项目摘要 慢性疼痛和饮酒障碍（AUD）高度合并。慢性疼痛的人增加了 发展AUD的可能性比没有的声音。此外，慢性疼痛和高疼痛强度与 升高饮酒的风险升高。尽管如此，关于神经生物学的临床前数据有限 在慢性疼痛的背景下，底物继电器的底物。患有慢性疼痛报告的人用酒精 减轻疼痛和参与的社会心理压力，这可能会引起不同的神经循环以调节 寻求奖励。我们先前在慢性神经性疼痛的神经损伤模型中的数据证明了 男性和 雌鼠。我们的初步数据进一步确定了准备好的疼痛引起的恢复乙醇的恢复 与假受伤的男性相比，患有慢性疼痛的男性中有条件的地方偏好模型。 前轴皮层（PL） - 中位前额叶皮层的子区域 - 是调节中的常见底物 寻求乙醇和痛苦。 PL及其输出是恢复奖励寻求奖励的关键调节者 与继电器相关行为的模型。 PL还介导了慢性的情感和认知成分 啮齿动物模型的疼痛，并在患有慢性神经性疼痛的患者中受到高度破坏。这使PL A 在慢性疼痛条件下寻求和恢复乙醇的投资的有希望的目标。那， 该提案中的实验将检验以下总体假设，即慢性疼痛会改变乙醇缓解 - 相关的行为和相关的神经生物学底物，重点是PL及其皮层 预测。测试以下假设：慢性神经性疼痛在中继相关期间改变PL活性 行为，AIM 1将结合体内电生理学与行为分析，以研究PL活性 乙醇条件的位置偏好和疼痛引起的成人的恢复原状的获取和表达 雄性和雌性小鼠患有幸免的神经损伤。此外，正如我们已经证明乙醇是抗卵的那样 在避免的神经损伤模型中，乙醇对围绕疼痛刺激的PL活性的影响将是 特征。 AIM 2将检验以下假设，即离散PL项目调节乙醇的恢复原状 寻求。我们将使用化学遗传学来使PL项目沉默到伏隔核或副核心。 杏仁核，期望向副杏仁核项目进行项目，这对于疼痛引起的疼痛是必不可少的 在慢性疼痛的背景下，恢复原状但不是乙醇剂的恢复原状。在一起，这些实验 将提供有关介导乙醇和继电器相关行为的独特神经行为的洞察力的见解 在慢性疼痛的情况下。我们预计该提案的完成将成为 随后对寻求乙醇的神经生物学底物进行研究。