Effect of Alcohol Withdrawal on Pain Sensitization

 描述(申请人提供)：过量饮酒通常是慢性疼痛发展的先兆。据报道，一些酗酒者在相对较短的时间内过度饮酒后，神经病的主观症状就会出现。在狂饮的动物模型中，过量饮酒会增加戒酒期间的疼痛敏感性，这种痛觉过敏在三周内会转化为痛性皮肤和肌肉神经病变。重要的是，这些疼痛敏感性的变化是由应激激素的释放介导的，而应激激素反过来又改变了伤害性感受器中的蛋白激酶C epsilon(PKCE)信号。由于这些发现对了解酒精滥用和疼痛状况之间潜在的联系机制具有潜在的意义，因此有必要进行人体研究，以确定酒精戒断引起的痛敏现象和机制的普遍性。到目前为止，还没有人体研究检验戒酒[在酗酒的早期阶段]对疼痛敏感的影响。这样的研究可以确定酒精是否在不可逆转的慢性神经病理性疼痛发生之前就使疼痛通路变得敏感。因此，这项拟议的研究将调查酗酒对疼痛敏感化的影响 首先，确定与对照组(即中度饮酒者和戒酒者)相比，酗酒者的基础疼痛敏感性是否增强，并在戒酒期间进一步增强。其次，这项拟议的研究检查了这种痛觉过敏是否与循环中肾上腺素和皮质醇水平升高有关。还将探讨负性情绪在酒精戒断引起的痛敏中的作用，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是以先前的动物研究为基础，研究酗酒是否会改变外周痛觉敏化(即热痛阈值、机械性痛敏和压痛感)。实验2将使用神经病理性疼痛的实验室模型，局部辣椒素测试，以诱导原发和继发性痛敏，这反映了中枢性疼痛敏化。在实验前48小时内饮酒的酗酒者被假设比没有饮酒的人和对照组表现出更强的外周和中枢疼痛敏感化。此外，肾上腺素和皮质醇的循环水平被认为是酒精戒断引起的痛敏的中介。最后，负面影响可能与酒精戒断痛觉过敏增强有关。这项研究的结果将确定在酗酒动物模型中观察到的酒精戒断引起的痛觉过敏和神经病变的机制是否适用于人类酗酒者，并可能建议将减压作为预防和治疗酒精神经病的新的治疗靶点。利用这个实验模型，未来的研究可以探索与酒精止痛、酒精戒断诱导的痛敏和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.