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.
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.
|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|
|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|
|Zhao, Jun; Levy, Dan (2015) Modulation of intracranial meningeal nociceptor activity by cortical spreading depression: a reassessment. J Neurophysiol 113:2778-85|
|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|
|Zhao, Jun; Levy, Dan (2014) The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior. Pain 155:1392-400|
|Zhang, XiChun; Kainz, Vanessa; Zhao, Jun et al. (2013) Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol 73:741-50|
|Shen, Jianliang; Xu, Rong; Mai, Junhua et al. (2013) High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics. ACS Nano 7:9867-80|
|Sheng, Rong; Sun, Haiying; Liu, Liu et al. (2013) A potent bivalent Smac mimetic (SM-1200) achieving rapid, complete, and durable tumor regression in mice. J Med Chem 56:3969-79|
|Levy, Dan; Kainz, Vanessa; Burstein, Rami et al. (2012) Mast cell degranulation distinctly activates trigemino-cervical and lumbosacral pain pathways and elicits widespread tactile pain hypersensitivity. Brain Behav Immun 26:311-7|