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

项目总结 青少年酗酒是成年后酗酒的一个重要风险因素。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。 新出现的证据表明，青少年酗酒会增强成年后的疼痛敏感性和焦虑感， 而疼痛敏感度的增加和焦虑的加剧可能会增加以后酗酒的可能性 生活。最近，一个涉及杏仁基底外侧核(BLA)、内侧前额叶皮质(MPFC)、 以及腹外侧导水管周围灰质(VlPAG)在疼痛处理中的作用。在这条赛道内， 到mPFC的BLA输入的增强的活性导致到vlPAG的mPFC输出的失活 抑制这些输入会导致止痛。这个回路中的活动进一步受到多巴胺输入的调节 到mPFC，它起源于腹侧被盖区(VTA)，导致血乳酸驱动的 前馈抑制vlPAG投射mPFC神经元。青春期是发育的关键时期。 青春期发生的环境侮辱，例如因反复暴饮暴食而造成的侮辱 饮酒，可能会扰乱这一回路的正常发展，导致疼痛的持续变化 正在处理。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(D_1)受体在成人mPFC中的作用及降低快峰型中间神经元兴奋性 动物实验，突出了mPFC对AIE诱导的改变的敏感性。最重要的假设是 这一建议认为，AIE暴露下的成年大鼠的痛觉过敏与选择性 BLA突触对小白蛋白阳性快脉冲中间神经元的强化作用 大脑皮层(PRL)。进一步假设，AIE后PVIN的多巴胺调制减少将 有助于减少PRL PVIN的激活，以应对炎性疼痛挑战。建议数 研究将使用投影和细胞类型特异性标记、光遗传学和膜片钳切片相结合的方法 电生理学评估AIE对BLA-PRL-vlPAG痛相关可塑性的影响 在疼痛挑战后，AIE诱导的mPFC FSIN的多巴胺调制的改变。 这些实验将提供关于青春期饮酒如何影响健康的新见解 成年后疼痛敏感度和焦虑感增加。这些见解可能被证明是有价值的，可以为 开发针对参与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。

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.