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Hangovers and headache: a tale of receptors, mast(er) cells and “painful” neurochemical agreements

Alcohol addiction affects 283 million people globally. Crises such as terrorism, economic hardships and the coronavirus pandemic heighten alcohol intake and risky behaviors. Rehabilitation is pivotal; however, withdrawal headaches often limit recovery by driving many back to drinking. This exacerbates the addiction cycle and degrades life quality. Further research is needed, considering rising alcohol abuse and insufficient withdrawal symptom treatments. Despite the urgency, effective treatments for withdrawal headaches are scarce. These headaches likely originate from the activation of trigeminal ganglia neurons and dura mater inflammation. Mast cells in the dura mater, which release proinflammatory cytokines are implicated in withdrawal headaches. Considering alcohol’s effect on mast cells, a research team investigated the role of MrgprB2 receptor in mice.

The animals exhibited a notable preference for ethanol. Over three weeks, mouse intake of ethanol gradually increased, thus suggesting that they developed ethanol dependence. However, this intake did not affect their food consumption or body weight. Interestingly, the absence of a specific receptor, MrgprB2, did not deter the mice from developing this ethanol preference. When wild-type mice were withdrawn from ethanol after consuming it for three or eight weeks, they exhibited hypersensitivity in the periorbital area for up to four days. Additionally, 24 hours after alcohol withdrawal, their pain scores significantly increased. Reduced exploratory behaviors after alcohol withdrawal were also observed, which aligned with the avoidance of physical activity typically observed in migraine sufferers.

However, these behaviors induced by alcohol withdrawal were absent in MrgprB2-deficient mice. Thus, mast-cell-specific MrgprB2 likely plays a role in mediating behaviors linked to alcohol-withdrawal-induced headaches.Ethanol consumption also had a modulating effect on mast cell activities, including increasing degranulation. In the dura mater of mice that consumed ethanol, there was an increase in both degranulated and total mast cells; however, this increase was negated in the absence of MrgprB2. The activation of mast cells through MrgprB2 was instrumental in the development of headaches and pain behaviors induced by alcohol withdrawal. The researchers also investigated whether peptide corticotropin releasing factor (CRF) played a role in MrgprB2 activation and subsequent mast cell degranulation.

To this end, higher CRF levels were observed in the plasma and dura mater of alcohol-withdrawal mice. CRF was also found to induce degranulation in mouse mast cells, an effect that was absent in MrgprB2-deficient mice. Alcohol withdrawal in mice also led to the sensitization of trigeminal ganglia nerves by various stimuli, thus suggesting that MrgprB2 is involved in this sensitization. Mice that were subjected to three to eight weeks of voluntary ethanol consumption exhibited hypersensitivity in the hind paw following alcohol withdrawal, an observation consistent with previous studies. However, the lack of MrgprB2 did not prevent this hypersensitivity. Inhibiting the tumor necrosis factor-alpha (TNF-α) receptor blocked alcohol-withdrawal-induced mechanical skin pain sensation.

Alcohol withdrawal-induced headaches were also linked to TNF-α and transient receptor potential channel V1 (TRPV1). This cellular channel is also sensitive to capsaicin, the chili pepper spicing compound, which modulates pain, confirming that there is a complex inter-play of receptors and ion channels triggered by alcohol consumption that involves the pain neural network, especially after alcohol withdrawal.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Son H, Zhang Y et al. Neuron 2023 Oct 26; in press.

Mackus M et a. J Clin Med. 2023 Mar 7; 12(6):2090.

Eriksson CJP et al. Alcohol Alcohol. 2020; 55(6):705.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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