Mast cell receptor linked to alcohol withdrawal-associated headaches

In a recent study published in Neuron, researchers investigate the role of the mast-cell-specific receptor Mas-related G-protein-coupled receptor B2 (MrgprB2) in alcohol-withdrawal-induced headaches and its potential as a therapeutic target.

Study: Mast-cell-specific receptor mediates alcohol-withdrawal-associated headache in male mice. Image Credit: Syda Productions /


Alcohol addiction affects 283 million people globally. Crises such as terrorism, economic hardships, and the coronavirus disease 2019 (COVID-19) pandemic heighten alcohol intake and risky behaviors.

Rehabilitation is essential; however, withdrawal headaches often limit recovery by driving many back to drinking. This exacerbates the addiction cycle and degrades life quality.

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 and are linked to the MrgprB2 receptor, are implicated in withdrawal headaches. Considering alcohol's effect on mast cells, understanding the role of MrgprB2 is crucial.

Further research is needed, considering rising alcohol abuse and insufficient withdrawal symptom treatments.

About the study 

The present study utilized various methods to examine specific peptide and drug interactions in mice. Corticotropin-releasing factor (CRF) peptide, R-7050, Phenyl-N-tert-butylnitrone (PBN), SB366791, and astressin were obtained and either prepared in synthetic interstitial fluid or 5% dimethyl sulfoxide (DMSO) for administration.

Behavioral tests, such as the von Frey test assessing the mice's sensitivity to touch and open field test observing their movements in an unfamiliar environment, were conducted with blinded observations.

For more invasive procedures, the mice underwent dorsal root ganglion (DRG) and trigeminal ganglion (TG) exposure surgeries. In vivo imaging tracked DRG and TG Pirt-GCaMP3 calcium (Ca2+) levels in real-time post-surgery.

Ca2+ imaging in human embryonic kidney 293 cells (HEK293) and mast cells offered insights into cellular responses to stimuli. Blood vessel and immunofluorescence imaging in the dura mater provided additional insights into the physiological reactions.

Additional techniques involved analyzing dura mater reactions to injected compounds and assessing CRF responses in specific cells. Western blotting and enzyme-linked immunosorbent assay (ELISA) were also utilized to quantify and analyze protein expression and interactions.

Study findings 

Mice 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.

The researchers also assessed the effects of ethanol withdrawal on TG neurons using in vivo imaging. To this end, a significant increase in the number of activated TG neurons was observed in alcohol-withdrawal mice as compared to controls.

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 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 TG 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 allodynia. Alcohol withdrawal-induced headaches were also linked to TNF-α and transient receptor potential channel V1 (TRPV1).

Taken together, these findings suggest that mast cell activation through MrgprB2 plays a significant role in the headaches and pain behaviors that result from alcohol withdrawal.

Journal reference:
  • Son, H., Zhang, Y., Shannonhouse, J., et al. (2023). Mast-cell-specific receptor mediates alcohol-withdrawal-associated headache in male mice. Neurondoi:10.1016/j.neuron.2023.09.039 
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    


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