The role of neuro-immune interactions in PACAP induced migraine

Migraine headache is the most common neurological disorder and comes with great socioeconomic burden. Much is still not known about the mediators and receptor subtypes involved in this debilitating disease, but studies (preclinical and clinical) have shown that neurogenic inflammation as a result of neuropeptide release may be involved. Animal studies have shown crosstalk between mast cells and meningeal nociceptors is crucial to the initiation and maintenance of migraine. The mast cell specific GPCR MrgprB2, and its human homologue MRGPRX2, is known to contribute to neurogenic inflammation in animal models of pain. Previous research showed that activating MrgprB2 causes mast cells to release a broad range of pro-inflammatory cytokines, contributing to pain pathophysiology. Our lab’s preliminary data reveals MrgprB2 receptors are expressed in the resident tissue mast cells within the dura, in close proximity to meningeal afferents. We used a non-invasive dural stimulation migraine model to demonstrate that activation of MrgprB2 by its agonist Compound 48/80 produced facial mechanical hypersensitivity and grimace expressions indicative of migraine-like pain behavior. The endogenous neuropeptide Pituitary adenylate cyclase-activating peptide-38 (PACAP-38) has been found to increase in the acute phase of migraine. We found PACAP-38 prompts MrgprB2-dependent mast cell degranulation in vitro, indicating that PACAP-38 may act on MrgprB2 during migraine. This compelling preliminary data supports testing our central hypothesis that MrgprB2/MRGPRX2-expressing mast cells play an important role in the migraine pain pathway, interacting with meningeal afferents and the endogenous peptide PACAP-38. The current application examines what role MrgprB2, and its human homologue MRGPRX2, may play in triggering a migraine like pain phenotype, how the endogenous neuropeptide PACAP-38 may interact with the immune system to induce migraine pain pathology via MrgprB2/MRGPRX2 activation, and whether MrgprB2/MRGPRX2+ mast cells cause migraine like pain through direct activation of meningeal sensory neurons. Using state-of the art approaches, the following specific aims will test our hypothesis: Aim 1. Characterize the contribution of mast cells and their receptor MrgprB2/MRGPRX2 in mouse models of migraine like pain. Aim 2. Examine MrgprB2/X2 interaction with known migraine-inducing endogenous peptide PACAP-38. Aim 3. Examine the interaction between MrgprB2+/MRGPRX2+ mast cells and meningeal sensory neurons in vivo. The proposed research is significant because it will examine the contribution of these mast cell receptors to the mechanisms underlying migraine pain, expanding our understanding on MrgprB2 and MRGPRX2 and their role in linking neural and immune systems to migraine-induced pain pathology. Importantly, MrgprB2/X2 may provide a new target to potentially treat migraine.