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.

项目概要 青少年酗酒是成年后滥用酒精的一个重要危险因素。特别值得关注的是 对个人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，青少年酗酒会增强成年后的疼痛敏感性和焦虑感， 疼痛敏感性的增加和焦虑的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）、内侧前额皮质（mPFC）的回路的作用， 中脑导水管周围灰质腹外侧区（vlPAG）在疼痛处理中的作用已被描述。在这个电路中， BLA 对 mPFC 输入的活动增强会导致 mPFC 对 vlPAG 的输出失活，而 抑制这些输入会导致镇痛。该电路内的活动进一步受到多巴胺输入的调节 mPFC 起源于腹侧被盖区 (VTA)，导致 BLA 驱动的减少 vlPAG 投射 mPFC 神经元的前馈抑制。青春期是发育的关键时期。 青春期发生的环境侵害，例如因反复暴饮暴食而造成的侵害 饮酒可能会破坏该回路的正常发育，导致疼痛持续变化 加工。有趣的是，我们之前已经证明青少年间歇性乙醇（AIE）会破坏 多巴胺 1 (D1) 受体功能并降低成人 mPFC 中快速尖峰中间神经元的兴奋性 动物，强调了 mPFC 对 AIE 引起的变化的敏感性。总体假设是 该提议认为，暴露于 AIE 的成年大鼠的痛觉过敏与选择性 增强前边缘小白蛋白阳性快速尖峰中间神经元 (PVIN) 上的 BLA 突触 皮质（PrL）。进一步假设 AIE 后 PVIN 的多巴胺调节减少将 有助于减少 PrL PVIN 的激活以应对炎性疼痛挑战。拟议的 研究将结合使用投影和细胞类型特异性标记、光遗传学和膜片钳切片 电生理学评估 AIE 诱导的变化对 BLA-PrL-vlPAG 疼痛相关可塑性的影响 疼痛挑战后，AIE 引起的 mPFC FSIN 多巴胺调节发生变化。 这些实验将为青春期饮酒如何促进健康提供新的见解。 成年后疼痛敏感性和焦虑感增加。这些见解对于为人们提供信息可能很有价值 开发旨在针对成人异常疼痛处理的神经回路的新疗法 在青春期饮​​酒的人。