The results of studies in mice by scientists at the University of Texas Health Science Center at San Antonio suggest that a receptor found on immune system mast cells may represent a potential target for treating alcohol withdrawal-associated headaches among individuals undergoing rehabilitation from alcohol addiction. The research team, headed by neuroscience researcher Yu Shin Kim, PhD, identified a role for the mast-cell-specific receptor MrgprB2 in the development of alcohol-withdrawal-induced headache, in a mouse model. Their studies showed that alcohol withdrawal in alcohol-acclimated mice induced headache behaviors and a number of symptoms equivalent to those observed in humans. Those alcohol withdrawal-related behaviors were absent in mice lacking MrgprB2.
Kim and colleagues reported on their findings in Neuron, in a paper titled, “Mast-cell-specific receptor mediates alcohol withdrawal-associated headache in male mice.”
About 283 million people worldwide suffer from alcohol use (AUD), a debilitating health challenge for which limited therapeutic options are available. The cost to society is estimated at greater than $2 trillion annually. “People try to rehabilitate, but it is very challenging,” said Kim, who is associate professor of oral and maxillofacial surgery in the Health Science Center’s School of Dentistry. “Headache is one of the severe withdrawal symptoms that pushes the rehabilitating patient back to alcohol because people know that, after drinking, alcohol will actually reduce the headache. It becomes a vicious cycle. This is how they develop alcohol dependence.” The authors added, “Despite a major unmet medical need for treating alcohol-withdrawal-induced headache, there is no appropriate therapeutic option available. To develop better therapeutics, it will be necessary to obtain a clearer understanding of alcohol-withdrawal-induced headache pain mechanisms.”
The team carried out studies in mice that preferentially consume ethanol. Their experiments in wild-type (WT) mice and knockout (KO) animals lacking MrgprB2, found that withdrawal from ethanol in WT mice, but not in MrgprB2 KO mice, resulted in headache behaviors, which suggested that “mast-cell-specific MrgprB2 mediates alcohol-withdrawal-induced headache,” they wrote. Subsequent work in the mouse models also showed that the mast cell receptor is required for mast cell degranulation triggered by alcohol withdrawal, “suggesting that mast cell activation via MrgprB2 results in development of alcohol-withdrawal-induced headache and pain behaviors.”
Continuing their research the team wanted to find what activates MrgprB2 after alcohol withdrawal. “Our findings indicate that degranulation of mast cells via MrgprB2 sensitizes TG neurons to evoke alcohol-withdrawal-induced periorbital mechanical hypersensitivity and pain behaviors, but it remains unclear how alcohol withdrawal mediates activation of MrgprB2 leading to degranulation of mast cells,” the team noted. They discovered that a stress hormone called corticotropin-releasing factor (CRF) activates mast cells in the dura, which is the thin, transparent membrane under the skull. Dura matter includes peripheral nerve fibers and peripheral blood vessels.
“After alcohol withdrawal, the CRF stress hormone is released from the hypothalamus, a brain region that controls many functions,” Kim said. “The CRF travels through peripheral blood vessels to dura matter, where it is released from the vessels and binds to MrgprB2. This signals the mast cells to degranulate, or open, and secrete chemical messengers that induce functions including blood vessel dilation (widening). This also activates peripheral nerve fibers extending from trigeminal ganglia neurons, which are sensory neurons. That is how these neurons are sensitized and a person has alcohol-withdrawal headache.”
It is this process that sends the pain signals. Researchers knew that peripheral neural fibers must be related to vessel dilation that occurs with alcohol withdrawal. The new results have demonstrated that CRF binds to the mast cell receptor MrgprB2, Kim said. The authors further commented, “These results indicate that CRF, which is likely released from dural blood vessels, induces mast cell degranulation via MrgprB2 activation, and regulates development of alcohol-withdrawal-induced headache and pain behaviors by sensitization of TG nerve in dura mater.”
“MrgprB2 is a very specific receptor for mast cells,” Kim added. “Only mast cells have these receptors.” This research may benefit further studies of various substance use disorder mechanisms including withdrawal, he said. It may be possible to develop a small-molecule drug therapy to inhibit the CRF and MrgprB2 interaction, resulting in fewer pain signals during alcohol withdrawal. The authors concluded, “Here, we show that blockade of mast-cell-specific MrgprB2 attenuates alcohol-withdrawal-induced headache behaviors. These results identify MrgprB2 as a possible new therapeutic target for treating alcohol-withdrawal-induced headache and alcohol dependence.”