Adenosine and Migraine
Abstract
Delayed ethanol-induced headache (DEIH), aka the hangover headache, occurs in migraineurs and non-migraineurs alike. Migraineurs, however, experience this headache with much less alcohol, suggesting that physiological differences in these patients contribute to DEIH susceptibility. The pathophysiology behind migraine is poorly understood. Identifying the mechanisms behind the susceptibility of migraineurs to ethanol’s effect on trigeminal pain may reveal relevant physiology behind migraine. Although acetate was identified as the critical metabolic product of ethanol that induces trigeminal pain, the mechanism behind this effect are unknown. To examine this, we utilized two rat models of trigeminal sensitivity that have migraine-like features: inflammatory stimulation model (IS rats) and spontaneous trigeminal allodynia model (STA rats). To characterize the mechanisms behind acetate-induced trigeminal sensitivity in DEIH, behavioral analysis and brainstem measurement of neurotransmitters with microdialysis and HPLC was performed while pharmacologically manipulating acetate transport and adenosine signaling. To identify physiological changes in these animals that may contribute to acetate/ethanol sensitivity, behavioral analysis, measurement of blood-brain barrier permeability in multiple brain regions, immunohistochemical analysis of glial activation in the brainstem, and respirometry of brainstem sections were used. Acetate treatment induced trigeminal sensitivity in both models but not in naive animals. Adensine A2A receptor activation was necessary for this acetate-induced trigeminal sensitivity. Brainstem perfusion of acetate dose-dependently increased extracellular adenosine and glutamate concentrations that were significantly greater than in naive animals. Antagonizing adenosine A2A receptor activation prevented the increase in glutamate and the induction of trigeminal sensitivity. Blood-brain barrier permeability was increased in the brainstem but not in other areas involved in trigeminal pain. A decreased spare respiratory capacity was found in brainstem sections of IS rats. These data present numerous physiological changes that may modulate acetate utilization or the formation of adenosine production, contributing to the enhanced presence of extracellular adenosine during acetate perfusion in these models. This increased adenosine concentration during acetate perfusion is likely responsible for the increased susceptibility of IS and STA rats to DEIH. These studies suggest that adenosine is a key mediator of ethanol’s effect on trigeminal pain and that modulation of it may serve as a future therapeutic option in headache.
Subject Area
Neurosciences
Recommended Citation
Fried, Nathan Thomas, "Adenosine and Migraine" (2015). ProQuest ETD Collection - Thomas Jefferson University. AAI3732018.
https://jdc.jefferson.edu/dissertations/AAI3732018
