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.

Public Health Relevance

Increased hangover frequency and susceptibility are associated with increased risk for future development of alcohol use disorders as well as other alcohol related health problems. How the degree of sensitivity to hangover is related to differences in the propensity of developing alcoholism is unknown, in part because of the poor understanding of the mechanisms underlying the hangover state. This project will begin to explore, using an animal model, the mechanisms underlying the hangover headache, one of the most common and disabling symptoms of the hangover.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Liu, Qi-Ying
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Li, Yi; Wang, Li-Hui; Zhang, Hao-Tian et al. (2018) Disulfiram combined with copper inhibits metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma through the NF-?B and TGF-? pathways. J Cell Mol Med 22:439-451
Zheng, Hong-Li; Wang, Li-Hui; Sun, Bao-Shan et al. (2017) Oligomer procyanidins (F2) repress HIF-1? expression in human U87 glioma cells by inhibiting the EGFR/ AKT/mTOR and MAPK/ERK1/2 signaling pathways in vitro and in vivo. Oncotarget 8:85252-85262
Aguilar, Angelo; Lu, Jianfeng; Liu, Liu et al. (2017) Discovery of 4-((3'R,4'S,5'R)-6?-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2?-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3?-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minut J Med Chem 60:2819-2839
Liu, Xinwei; Wang, Lihui; Cui, Wei et al. (2016) Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells. Oncotarget 7:58516-58530
Wang, L; Li, H; Ren, Y et al. (2016) Targeting HDAC with a novel inhibitor effectively reverses paclitaxel resistance in non-small cell lung cancer via multiple mechanisms. Cell Death Dis 7:e2063
Wang, Li-Hui; Jiang, Xiao-Rui; Chen, Guo-Liang et al. (2016) Anti-tumor activity of SL4 against breast cancer cells: induction of G2/M arrest through modulation of the MAPK-dependent p21 signaling pathway. Sci Rep 6:36486
Benromano, T; Defrin, R; Ahn, A H et al. (2015) Mild closed head injury promotes a selective trigeminal hypernociception: implications for the acute emergence of post-traumatic headache. Eur J Pain 19:621-8
Li, Jin-Ming; Zhang, Wei; Su, Hua et al. (2015) Reversal of multidrug resistance in MCF-7/Adr cells by codelivery of doxorubicin and BCL2 siRNA using a folic acid-conjugated polyethylenimine hydroxypropyl-?-cyclodextrin nanocarrier. Int J Nanomedicine 10:3147-62
Zhao, Jun; Levy, Dan (2015) Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: a reassessment. J Neurophysiol 113:2778-85
Zhao, Jun; Levy, Dan (2014) The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior. Pain 155:1392-400

Showing the most recent 10 out of 20 publications