Acetate Causes Alcohol Hangover Headache in Rats

Background: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache. Methods: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats. Results: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate increased nociceptive behaviors suggesting that acetate, not acetaldehyde, accumulation results in hangover-like hypersensitivity in our model. Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity. Discussion: Our study shows that acetate contributes to hangover headache. These findings provide insight into the mechanism of hangover headache and the mechanism of headache induction

Caffeine blocks ethanol induced hypersensitivity.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g004" target="_blank">Figure 4</a> shows the effect of caffeine (i.p.) on periorbital pressure thresholds 3 hours after ethanol (gavage) administration. The black bar depicts ethanol alone. The grey bar shows time course following the combination of ethanol and caffeine.</p

Acetate causes ethanol induced hypersensitivity.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g003" target="_blank">Figure 3a</a> displays changes in threshold for sensitized rats that received 20 (black) and 60 (grey) mg/kg acetate i.p. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g003" target="_blank">Figure 3b</a> shows changes in threshold for infusion naive rats that received 20 (black) and 60 (grey) mg/kg acetate.</p

Inhibition of alcohol metabolism by alcohol dehydrogenase or acetaldehyde metabolism by aldehyde dehydrogenase cause analgesia and prevents nociceptive behaviors.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g002" target="_blank">Figure 2a</a> illustrates changes in threshold over 6 hours in IS infused rats that received ethanol combined with 4-Methyl Pyrazole (4MP blue line). Thresholds are also shown for ethanol alone (black line) from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g001" target="_blank">Figure 1a</a> as a comparison. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g002" target="_blank">Figure 2b</a> displays change in threshold relative to baseline at 0–2 hours following ethanol +4MP and 4–6 hours following ethanol +4MP. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g002" target="_blank">Figure 2c</a> illustrates changes in threshold over time in IS infused rats that received ethanol combined with disulfiram (red line). Thresholds for ethanol alone (black line) are included from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g001" target="_blank">Figure 1a</a> as a comparison. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g002" target="_blank">Figure 2d</a> displays change in threshold relative to baseline at 0–2 hours following ethanol + disulfiram and 4–6 hours following ethanol + disulfiram.</p

Motor activity during ethanol and control treatment.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-t001" target="_blank">Table 1</a> shows the difference in locomotor activity between control and ethanol gavage in ten minute epochs. Positive numbers represent higher activity rates in the control condition. Negative numbers represent higher activity rates in the ethanol condition. T-test results are included.</p

Ketorolac blocks ethanol induced hypersensitivity.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g005" target="_blank">Figure 5a</a> demonstrates the effect of ethanol on periorbital pressure thresholds when given an injection of saline or ketorolac. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015963#pone-0015963-g005" target="_blank">Figure 5b</a> shows the minimum thresholds between 4 and 6 hours post ethanol in rats that were given ethanol + saline or ethanol + ketorolac.</p