Effect of Alcohol Withdrawal on Pain Sensitization

 描述（由申请人提供）：过度饮酒通常先于慢性疼痛的发展。据报道，在一些酗酒者中，在相对较短的过量饮酒后会出现神经病的主观症状。在酗酒的动物模型中，过度饮酒会增加酒精戒断期间的疼痛敏感性，这种痛觉过敏在三周内转变为疼痛的皮肤和肌肉神经病变。重要的是，疼痛敏感性的这些变化是由应激激素的释放介导的，应激激素反过来又改变了伤害感受器中的蛋白激酶C β（PKCe）信号。因为这些发现对于理解酒精滥用和疼痛状况之间的关联的潜在机制具有潜在意义，所以人类研究有必要确定酒精戒断诱导的痛觉过敏的现象和机制的普遍性。到目前为止，还没有人类研究研究酒精戒断对疼痛敏感性的影响[在酗酒的早期阶段]。这样的研究可以确定酒精是否在不可逆的慢性神经性疼痛发生之前就能使疼痛通路敏感。因此，这项研究将探讨酗酒对疼痛敏感性的影响， 年轻的成年人来确定，首先，与对照组相比，狂饮者的基础疼痛敏感性是否增强（即，中度饮酒者和戒酒者），并在戒酒期间进一步加剧。第二，这项研究将检验这种痛觉过敏是否与肾上腺素和皮质醇的循环水平升高有关。负面情绪在酒精戒断引起的痛觉过敏中的作用也将被探讨，因为它与人类增强的生理应激反应和疼痛敏感性有关。实验1是在先前的动物研究之后建模的，并且将检查狂饮是否改变外周疼痛敏感性（即，热痛阈值、机械性痛觉过敏和压迫性疼痛）。实验2将使用神经性疼痛的实验室模型，局部辣椒素试验，以诱导原发性和继发性痛觉过敏，这反映了中枢疼痛敏化。假设在实验前48小时内饮酒的酗酒者与那些没有饮酒的人和对照组相比，表现出增强的外周和中枢疼痛敏感性。此外，肾上腺素和皮质醇的循环水平预期介导酒精戒断诱导的痛觉过敏。最后，预期负面影响与增强的酒精戒断性痛觉过敏有关。这项研究的结果将确定是否酒精戒断引起的痛觉过敏和神经病变的机制，在动物模型中观察到的酗酒翻译为人类酗酒者，并可能建议减少压力作为一个新的治疗目标，以预防和治疗酒精神经病变。使用这个实验模型，未来的研究可以调查与酒精镇痛，酒精戒断引起的痛觉过敏，周围神经病变的敏感性增强相关的遗传机制的贡献。

 DESCRIPTION (provided by applicant): Excessive alcohol consumption often precedes the development of chronic pain. Subjective symptoms of neuropathy are reported to emerge after relatively short periods of excessive drinking in some binge drinkers. In animal models of binge drinking, excessive alcohol consumption increases pain sensitivity during alcohol withdrawal, and this hyperalgesia transitions to painful cutaneous and muscle neuropathy within three weeks. Importantly, these changes in pain sensitivity are mediated by the release of stress hormones, which in turn alter protein kinase C epsilon (PKCe) signaling in nociceptors. Because these findings have potential implications for understanding the mechanisms underlying the association between alcohol abuse and pain conditions, human studies are warranted to determine the generality of the phenomenon and mechanisms of alcohol withdrawal- induced hyperalgesia. To date no human research has examined the effects of alcohol withdrawal on pain sensitivity [in early stages of binge drinking.] Such a study could determine whether alcohol sensitizes pain pathways well before the development of irreversible chronic neuropathic pain. Thus, the proposed study will investigate the effects of binge drinking on sensitization of pain in young adults to determine, first, whether binge drinkers' basal pain sensitivity is enhanced in comparison to the controls (i.e., moderate alcohol users and abstainers), and further intensified during alcohol withdrawal. Second, the proposed study examines whether this hyperalgesia is associated with elevated circulating levels of epinephrine and cortisol. The role of negative affect in alcohol withdrawal-induced hyperalgesia will also be explored because it is linked to enhanced physiological stress responses and pain sensitivity in humans. Experiment 1 is modeled after prior animal studies and will examine whether binge drinking alters peripheral pain sensitization (i.e., heat pain thresholds, mechanical hyperalgesia, and pressure pain). Experiment 2 will use a laboratory model of neuropathic pain, the topical capsaicin test, to induce primary and secondary hyperalgesia, which reflects central pain sensitization. Binge drinkers who have consumed alcohol within 48 hours prior to the experiment are hypothesized to show enhanced peripheral and central pain sensitization compared to those who have not, and to the controls. In addition, circulating levels of epinephrine and cortisol are expected to mediate alcohol withdrawal-induced hyperalgesia. Finally, negative affect is expected to be associated with enhanced alcohol withdrawal hyperalgesia. The results of this study will determine whether the mechanisms underlying alcohol withdrawal-induced hyperalgesia and neuropathy observed in animal models of binge drinking translate to human binge drinkers, and may suggest stress reduction as a new therapeutic target to prevent and treat alcohol neuropathy. Using this experimental model, future studies could investigate the contribution of genetic mechanisms associated with enhanced sensitivity to alcohol analgesia, alcohol withdrawal-induced hyperalgesia, and peripheral neuropathy.