Adenosine modulates extracellular glutamate levels via adenosine A2A receptors in the delayed-ethanol induced headache

Identifying the mechanism behind delayed ethanol-induced headache (DEIH), otherwise known as the hangover headache, may provide insight into the mechanisms behind common headache triggers. Acetate was previously shown to be the key ethanol metabolite behind DEIH in the recurrent inflammatory stimulation (IS) rat model of headache. The reversal of trigeminal sensitivity following ethanol exposure with caffeine previously suggested a role of adenosine in DEIH. To characterize this, behavioral analysis and measurement of brainstem adenosine and glutamate with microdialysis and HPLC was performed while pharmacologically manipulating adenosine signaling in the IS and Spontaneous Trigeminal Allodynia (STA) rat models of headache. Blocking adenosine A2A receptor activation with istradefylline or acetate transport into astrocytes with the monocarboxylate transporter competitive inhibitor, alpha-cyano-4-hydroxycinnamate (4-CIN), prevented acetate-induced trigeminal sensitivity. Blocking adenosine A1, A2B, and A3 receptor signaling did not prevent trigeminal sensitivity. Compared to control rats, IS rats had greater increases in extracellular adenosine and glutamate within the trigeminal nucleus caudalis (TNC) of the brainstem during local acetate perfusion. Blocking transport of acetate into astrocytes with 4-CIN prevented the increase in adenosine and glutamate. Blocking A2A receptor activation prevented the increase in extracellular glutamate, but not adenosine in the TNC. These data are the first to demonstrate the physiological consequence of acetate on adenosinergic systems within trigeminal pain by suggesting that acetate-induced trigeminal sensitivity in DEIH is mediated by adenosine A2A receptor activation which modulates extracellular glutamate levels in the TNC.Significance StatementIt is unknown how several common headache triggers induce headache pain. Since migraineurs are more sensitive to these triggers, studying the mechanisms behind their effects may reveal unique migraine pathophysiology. In this study, we explored the common headache trigger, ethanol, which migraineurs are particularly sensitive to. When ethanol is ingested, its quickly metabolized to acetaldehyde and subsequently into acetate. We find that acetate increases brainstem adenosine and causes trigeminal sensitivity, which is exacerbated in the rat headache model. Blocking either acetate uptake or adenosine signaling prevents trigeminal sensitivity and brainstem glutamatergic signaling, suggesting that adenosine is involved in the hangover headache and that differences in acetate metabolism may account for the increased sensitivity to ethanol in migraineurs.

Hangover Headache and Prostaglandins: Prophylactic Treatment with Tolfenamic Acid

Tolfenamic acid (TA), a potent inhibitor of prostaglandin (PG) biosynthesis and action, was tested prophylactically against hangover symptoms in 30 healthy volunteers in a double–blind cross-over study. One capsule of TA (200 mg) or placebo was taken before starting to drink alcohol and another before going to bed. The hangover symptoms were evaluated in the morning. TA was found significantly better than placebo in the subjective evaluation of drug efficacy ( p<0.001) and in reducing the reported hangover symptoms in general (p < 0.01). In the TA group, significantly lower symptom scores were obtained for headache (p<0.01), and for nausea, vomiting, irritation, tremor, thirst and dryness of mouth (all p < 0.05). In a separate study with eight participants, plasma levels of PGs were followed during ingestion of alcohol with or without TA. The plasma concentrations of PGE2 and TXB2 (a metabolite of thromboxane A2) were lower in the TA group during alcohol ingestion, while PGF2a and 6-keto-PGF1a (a metabolite of prostacyclin) were unaffected. TXB2 correlated with blood alcohol levels in a U-shaped manner.