Mechanisms of Alcohol Hangover Headache

描述(由申请人提供)：急性过量饮用酒精饮料，在延迟一段时间后，会导致被称为“宿醉”的醉酒后时期，其中包括阵发性头痛以及许多其他令人不快的身体症状。宿醉有许多社会经济后果，包括降低生产率和增加事故风险。宿醉头痛倾向与未来发展为酒精使用障碍的风险增加有关。宿醉头痛如何在酒精使用障碍和其他与酒精相关的问题的病因学中发挥作用仍是一个悬而未决的问题，主要是因为调节宿醉症状的因素和神经机制，包括头痛，人们知之甚少。这种知识的缺乏可以部分归因于临床研究的匮乏，以及几乎完全缺乏对该现象背后的生理和神经生理过程的基础研究。我们以前已经建立了一个独特的动物模型来研究脑膜伤害性感受器的活动和机械敏感性，脑膜伤害性感受器是与头痛的发生最直接相关的外周神经元群体。我们现在建议使用这个动物模型来首次研究在调节宿醉头痛的因素中发挥作用的因素，宿醉头痛是宿醉状态最常见的症状之一。利用麻醉大鼠脑膜伤害性感受器的活体单个单位记录，我们建议从研究酒精相关物质的身份以及可能导致宿醉头痛的神经过程开始这一系列的研究。具体目标1将研究急性乙醇给药对脑膜伤害性感受器活动和机械敏感性的时程和剂量相关影响。具体目标2将确定乙醇的第一代谢物乙醛在给药醉酒剂量后介导脑膜伤害性感受器激活和敏化中的相对贡献。具体目标3将研究酒精饮料或其代谢物甲酸盐和甲酸中发现的主要有毒同系物之一甲醇是否会增加脑膜伤害性感受器的活性和机械敏感性，并进一步确定甲醇是否可以增强或延长与急性乙醇中毒相关的脑膜伤害性感受器的激活和敏化。这些实验是研究主要宿醉症状头痛背后的神经生物学机制的第一个方法学步骤。来自这个探索性项目的数据将开始填补我们关于可能导致宿醉头痛的因素和过程的知识空白，并提供急需的数据，以产生关于头痛和潜在的其他宿醉症状的来源的进一步可验证的假说。这些数据将在未来的研究中发挥重要作用，这些研究将解决对宿醉的敏感程度如何与酗酒倾向的差异以及潜在的其他与宿醉相关的健康问题有关的问题。

DESCRIPTION (provided by applicant): Acute excessive consumption of alcoholic beverages leads, after a delay, to a post-intoxication period known as the "hangover", which consists of throbbing headache as well as numerous other unpleasant physical symptoms. Hangover has many socioeconomic consequences, including reduced productivity and increased accident risk. Hangover headache proneness has been associated with increased risk for future development of alcohol use disorders. How hangover headache plays a role in the etiology of alcohol use disorders as well as other alcohol-related problems remains an open question, largely because the factors and neuronal mechanisms that mediate the hangover symptoms, including the headache are poorly understood. This lack of knowledge can be attributed, in part to the paucity of clinical studies and the almost complete lack of basic research on the physiological and neurophysiological processes underlying the phenomenon. We have previously established a unique animal model for studying the activity and mechanosensitivity of meningeal nociceptors, the peripheral neuronal population that has been most directly implicated in the genesis of headache. We now propose to use this animal model to investigate for the first time the factors that play a role in mediating the hangover headache, one of the most common symptoms of the hangover state. Using in vivo single unit recordings of meningeal nociceptors in anesthetized rats, we propose to start this line of investigation by addressing the identity of the alcohol-related substances as well as the neural processes that might potentially contribute to the hangover headache. Specific aim 1 will examine time-course and dose- related effects of acute ethanol administration on the activity and mechanosensitivity of meningeal nociceptors. Specific Aim 2 will determine the relative contribution of ethanol's first metabolite acetaldehyde in mediating meningeal nociceptor activation and sensitization following administration of intoxicating doses of ethanol. Specific Aim 3 will examine whether methanol, one of the major toxic congeners found in alcoholic beverages or its metabolites formate and formic acid increase the activity and mechanosensitivity of meningeal nociceptors and further determine whether methanol can enhance or prolong the activation and sensitization of meningeal nociceptors associated with acute ethanol intoxication. These experiments are the first methodological step in the study of the neurobiological mechanisms underlying a major hangover symptom, the headache. Data from this exploratory project will begin to fill the gaps in our knowledge regarding the factors and processes the may contribute to the hangover headache and provide much needed data to generate further testable hypotheses on the origin of the headache and potentially other hangover symptoms. Data will be instrumental in future studies that address the question of how the degree of sensitivity to hangover is related to differences in the propensity of developing alcoholism and potentially other hangover- related health problems.