Literature Review

Mast Cells Release Migraine-Inducing PACAP

This finding may explain the observed association between allergy and migraine.


Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

Angela J. Okragly

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

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