Molecular Triggers of Migraine Pain: Discovering Their Site(s) and Mechanism(s) of Action
Mapping migraine triggers from molecules to pain signals
A series of complementary animal experiments will clarify where and how molecular migraine triggers act, forming an integrated picture of migraine neurobiology. Central to this work is the hemi-skull model, which provides direct access to the trigeminal nerve and meninges.
Chemical stimulation evokes the release of molecular migraine triggers (e.g., CGRP, PACAP) and helps identify new signaling molecules. Using proteomics, metabolomics, RNAscope, and immunohistochemistry, we map the release, composition, and synthesis of neuropeptides and neurotransmitters in migraine relevant intracranial structures, creating a detailed molecular atlas that informs subsequent functional studies.
Parallel experiments will measure electrical activity in pain sensing nerve cells of the meninges and brain before and after applying migraine triggers, offering real time insight into how and where migraine related pain signals arise. To link neuronal activity with observable outcomes, we will also assess headache related behaviors—such as grimace scores—in freely moving mice.
Together, these electrophysiological and behavioral approaches provide new understanding of migraine mechanisms and directly connect cellular responses with pain relevant behaviors.
Sub-projects exploring migraine mechanisms
Molecular mapping of migraine triggers
Investigating Molecular Dynamics of Migraine Pathogenesis in a Rodent Model.
Objective:
To characterize the release patterns, molecular content, and synthesis of neuropeptides and neurotransmitters within migraine-relevant intracranial structures using a rodent model.
Potential Significance:
This research will advance understanding of neurobiological and genetic mechanisms driving migraine attacks. Identifying key neuropeptides and neurotransmitters will clarify which molecules act as migraine triggers and where they take effect. The comparison of FHM mutants with wild type mice offers insights relevant to differences between individuals with migraine with aura and healthy controls.
Neuronal and behavioral pain responses
Discovering the Effects of Molecular Migraine Triggers and Therapeutic Agents on Neuronal Activity and Behavioral Pain Responses in Rodents.
Objective:
To characterize the effects of molecular migraine triggers and their pharmacological antagonists/blockers on the activation of dura-sensitive TG and TNC neurons, and to assess the corresponding behavioral pain responses in rodents.
Potential Significance:
Our results will offer groundbreaking insights into the molecular and cellular mechanisms that underpin migraine attack initiation and termination. Mapping the specific pathways involved in the activation and inhibition of pain responses is expected to catalyze the development of novel targeted mechanism-based therapies for migraine.