Molecular basis for functional S1PR1 antagonists in the treatment of comorbid migraine and temporomandibular disorders

Project Summary/Abstract Overlapping pain conditions greatly exacerbate patients’ pain experience. This includes comorbid migraine and temporomandibular disorders (TMDs), which is associated with a reciprocal increase in their prevalence/severity, increased risk of chronification, negatively impacting therapeutic outcomes. This underscores this comorbidity

as a significant public health concern. However, little is known of its underlying pathobiology, highlighted by a dearth of validated animal models and a lack of evidence-based treatment approaches. Investigations into the underlying molecular mechanisms involved are therefore imperative, with the aim of identifying critically needed

novel treatments that are effective, safe, and with potential for rapid clinical translation. Our recent studies highlight the important role of sphingosine-1-phosphate (S1P) signaling at S1P receptor 1 (S1PR1) in spinal neuropathic pain models. Further, at the molecular level we also demonstrate that S1PR1 activation engages

neuroinflammatory processes downstream of NLRP3/IL-1β activation. Despite this, the effects of targeting S1PR1 in trigeminal pain disorders, such as comorbid migraine/TMD, and S1PR1 downstream mechanisms, is unknown. Our preliminary studies demonstrate S1PR1 is highly expressed along the trigeminal pain pathway,

ideally positioned to modulate neuronal mechanisms related to migraine/TMD. Further, through the development of a novel preclinical approach to study this chronic comorbidity, we reveal that blocking S1PR1, or S1P production, prevents and inhibits noxious behavioral and neuronal responses in this novel model. Importantly,

the migraine preventive, topiramate, was ineffective in this comorbid model, translating to reduced efficacy in comorbid patients. Furthermore, inhibition of the NLRP3 pathway also attenuates noxious responses using this approach. Together, these data directly link molecular S1P-S1PR1 signaling and downstream NLRP3

mechanisms in the chronic comorbidity of migraine/TMD. Therefore, we hypothesize that S1P-S1PR1 signaling along the dural-trigeminal pain pathway drives noxious migraine/TMD-like responses in preclinical models of comorbid migraine/TMD, through a downstream NLRP3-IL-1β inflammatory cascade. Therefore, S1PR1

represents a novel therapeutic target. We will use a multidisciplinary approach, across independent laboratories with extensive experience in in vivo studies, using behavioral and molecular pharmacology, electrophysiology, genetics, biochemistry, immunohistochemistry, and mass spectrometry. In Aim 1 we will establish S1PR1 as a

novel monotherapy target in comorbid migraine/TMD treatment. Aim 2 will determine the role of NLRP3/IL-1β- driven inflammation downstream of S1PR1 activation in the development of this chronic comorbidity. Validation of a therapeutic target will have a huge impact on the treatment of chronic comorbid migraine/TMD patients.

Our proposed studies will provide foundational insights into S1PR1/NLRP3 signaling in the development of this chronic co-morbidity, validating S1PR1 as a target, with functional S1PR1 antagonists a unique monotherapy approach for intervention, with the advantage that they are already FDA-approved for other indications.