Targeting peroxynitrite production in a model of persistent temporomandibular disorder comorbid with migraine

BACKGROUND AND PURPOSE: The persistence of temporomandibular disorders (TMDs), particularly myogenous, in a person with migraine can lead to exacerbated clinical outcomes and limited response to treatment. The pro-nociceptive reactive nitroxidative species, peroxynitrite, is involved in migraine mechanisms, but little is known of its role in this comorbidity. Here, we validate a model of persistent TMD comorbid with migraine in rats and dissect the role of peroxynitrite in its underlying nociceptive mechanisms, and as a novel therapeutic target. EXPERIMENTAL APPROACH: A combination of masseteric muscle injection of CFA and delayed CGRP infusion were used to model persistent myogenic-TMD comorbid with migraine, respectively. Using electrophysiological and behavioural methods, we assessed migraine-like neuronal outcomes and periorbital withdrawal thresholds to validate this approach. We measured 3-nitrotyrosine expression, as a marker of nitroxidative species, including peroxynitrite, and used the peroxynitrite decomposition catalyst, FeTPPS, and to determine the role of peroxynitrite in these comorbid mechanisms. KEY RESULTS: Persistent myogenic-TMD exacerbated migraine-relevant neuronal outcomes in response to delayed CGRP, causing more prevalent and hypersensitive trigeminovascular neuronal responses to innocuous/noxious probing of dural and cutaneous-periorbital regions, demonstrating many of the signatures of 'latent sensitization'. We also observed increased expression of 3-nitrotyrosine along the trigeminal pain pathway in TMD, migraine and comorbid models and confirm that targeting peroxynitrite breakdown prevents the development of this nociceptive neuronal phenotype. CONCLUSION AND IMPLICATIONS: Our persistent comorbid myogenic-TMD/migraine model translates to the exacerbated clinical phenotype, validating it as an approach to study mechanisms. Production of peroxynitrite along the trigeminal pain pathway contributes to the mechanisms underlying this phenotype and is a potentially novel monotherapy or combination approach.