Adolescent Intermittent Ethanol-Induced Changes in Pain-Related Plasticity Associated with Pain Sensitivity in Adulthood

青少年间歇性乙醇引起的与成年期疼痛敏感性相关的疼痛相关可塑性变化

• 批准号: 10537245
• 负责人: James Daniel Obray
• 金额: $ 7.21万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2023-08-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537245
• 关键词: Absence of pain sensation; Acute Pain; Adolescence; Adolescent; Adult; Alcohol consumption; Amygdaloid structure; Anxiety; Area; Behavior; Behavior assessment; Brain; Brain region; Communication Research; Development; Disinhibition; Dopamine; Electrophysiology (science); Ethanol; Evaluation; Health; Heavy Drinking; Hyperalgesia; In Situ; Individual; Inflammatory; Instruction; Interneurons; Label; Life; Long-Term Effects; Measures; Medial; Mediating; Modeling; Neurons; Nociception; Nociceptive Stimulus; Output; Pain; Parvalbumins; Play; Predisposition; Prefrontal Cortex; Process; Quality of life; Rattus; Research Technics; Risk Factors; Rodent; Rodent Model; Role; Safety; Signal Transduction; Slice; Stimulus; Structure; Synapses; Techniques; Testing; Training; Ventral Tegmental Area; adolescent alcohol abuse; adolescent alcohol effect; adolescent alcohol exposure; adolescent alcohol misuse; alcohol misuse; allodynia; cell type; chronic pain; critical period; developmental plasticity; experimental study; global health; hippocampal pyramidal neuron; improved; inflammatory pain; information processing; insight; mature animal; midbrain central gray substance; neural circuit; neuromechanism; neurotransmission; novel; optogenetics; pain processing; pain sensitivity; patch clamp; pre-clinical; receptor function; response; sex; stressor; therapy design; underage drinking

PROJECT SUMMARY Adolescent alcohol abuse is a significant risk factor for alcohol misuse in adulthood. Of particular concern are the potential long-term effects on the ability of an individual to appropriately process and respond to pain. Emerging evidence indicates that adolescent alcohol abuse enhances pain sensitivity and anxiety in adulthood, and increased pain sensitivity and heightened anxiety may enhance the potential for alcohol misuse later in life. Recently, a role for a circuit involving the basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and ventrolateral periaqueductal gray (vlPAG) in pain processing has been described. Within this circuit, enhanced activity of BLA inputs to the mPFC results in inactivation of mPFC outputs to the vlPAG whereas inhibition of these inputs results in analgesia. Activity within this circuit is further modulated by dopamine inputs to the mPFC, which originate in the ventral tegmental area (VTA), leading to a reduction in BLA-driven feedforward inhibition of vlPAG projecting mPFC neurons. Adolescence is a critical period for development. Environmental insults occurring during adolescence, such as those caused by repeated episodes of binge-like alcohol consumption, may disrupt normal development of this circuitry resulting in persistent changes in pain processing. Interestingly, we have previously demonstrated that adolescent intermittent ethanol (AIE) disrupts dopamine 1 (D1) receptor function and reduces fast-spiking interneuron excitability in the mPFC of adult animals, highlighting the susceptibility of the mPFC to AIE-induced changes. The overarching hypothesis of this proposal is that hyperalgesia in adult rats subjected to AIE-exposure is associated with selective strengthening of BLA synapses onto parvalbumin positive fast-spiking interneurons (PVINs) in the prelimbic cortex (PrL). It is further hypothesized that decreased dopamine modulation of PVINs following AIE will contribute reduced activation of PrL PVINs in response to an inflammatory pain challenge. The proposed studies will use a combination of projection and cell-type specific labelling, optogenetics, and patch-clamp slice electrophysiology to assess the effects of AIE-induced changes on pain-related plasticity in BLA-PrL-vlPAG circuitry as well as AIE-induced alterations in dopamine modulation of mPFC FSINs following a pain challenge. These experiments will provide novel insight into how alcohol consumption during adolescence contributes to increased pain sensitivity and anxiety in adulthood. These insights could prove valuable in informing the development of new treatments designed to target neurocircuitry involved in aberrant pain processing in adults who consumed alcohol during adolescence.

项目摘要 青少年酒精滥用是成年期酒精滥用的一个重要风险因素。特别令人关切的是 对个体适当处理和应对疼痛的能力的潜在长期影响。 新的证据表明，青少年酗酒会增加成年后的疼痛敏感性和焦虑， 疼痛敏感性增加和焦虑加剧可能会增加以后滥用酒精的可能性 生活最近，涉及基底外侧杏仁核（BLA），内侧前额叶皮层（mPFC）， 和腹外侧导水管周围灰质（vlPAG）在疼痛处理中的作用。在这个电路中， BLA输入到mPFC的活性增强导致mPFC输出到vlPAG的失活， 抑制这些输入会导致镇痛。这个回路中的活动进一步受到多巴胺输入的调节 起源于腹侧被盖区（VTA）的mPFC，导致BLA驱动的 vlPAG投射mPFC神经元的前馈抑制。青春期是发展的关键时期。 在青春期发生的环境伤害，如反复发作的暴饮暴食引起的伤害 酒精的消耗，可能会破坏这种电路的正常发展，导致疼痛的持续变化， 处理.有趣的是，我们以前已经证明，青少年间歇性乙醇（AIE）破坏了 多巴胺1（D1）受体功能，并降低成人mPFC中的快速尖峰中间神经元兴奋性 动物，突出的mPFC AIE诱导的变化的敏感性。最重要的假设是 这一建议是，成年大鼠的痛觉过敏受到AIE暴露与选择性 边缘前区小清蛋白阳性快速尖峰中间神经元（PVIN）上BLA突触的加强 皮质（PrL）。进一步假设，AIE后PVIN的多巴胺调节降低将导致 有助于减少响应炎性疼痛挑战的PrL PVIN的活化。拟议 研究将使用投射和细胞类型特异性标记、光遗传学和膜片钳切片的组合。 电生理学以评估AIE诱导的变化对BLA-PrL-vlPAG中疼痛相关可塑性的影响 回路以及AIE诱导的mPFC FSIN的多巴胺调制在疼痛挑战后的改变。 这些实验将提供新的见解，了解青春期饮酒如何有助于 成年后疼痛敏感性和焦虑增加。这些见解可以证明是有价值的， 开发新的治疗方法，旨在靶向参与成人异常疼痛处理的神经回路 在青春期饮酒的人