Preclinical studies to dissect the neural mechanism for the comorbidity of migraine and temporomandibular disorders (TMD): the role of CGRP.

BACKGROUND AND PURPOSE: Temporomandibular disorders (TMD) and migraine can be co-morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine-like symptoms. However, the underlying putative mechanisms involved are not known. Our objective was to dissect these neural mechanisms, and the role of calcitonin gene-related peptide (CGRP) as a key modulator, in this co-morbidity. METHODS: We combined experimental approaches, using CGRP, known to trigger a migraine-like response in patients, with masseteric muscle injection of complete Freund's adjuvant (CFA), to model myofascial TMD-like inflammation. Using validated electrophysiological methods, assessing each approach independently, or in combination, we examined their effects on the response properties of migraine-like dural-trigeminocervical neurons. KEY RESULTS: Independently, in ~2/3 of animals each approach caused delayed migraine-like activation and sensitisation of dural-trigeminocervical neurons. The response to masseteric-CFA was attenuated by a selective CGRP receptor antagonist. The combination approach caused a migraine-like neuronal response in all animals tested, with somatosensory-evoked cranial hypersensitivity significantly exacerbated. CONCLUSIONS AND IMPLICATIONS: The data demonstrate a neuronal phenotype that translates to the exacerbated clinical co-morbid phenotype; supporting this combination approach as a relevant platform to study putative mechanisms. It provides a pathophysiological rationale for this exacerbated phenotype, strongly implicating CGRP in the mechanisms involved. Therefore, the data provide support for targeting the CGRP pathway as a novel monotherapy approach for this co-morbid condition. This has key implications into our understanding of this co-morbid condition, as well as potentially addressing the major unmet need for novel and effective therapeutic approaches.