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

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $620,278

## Abstract

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 in...

## Key facts

- **NIH application ID:** 10937249
- **Project number:** 1R01NS138127-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Simon Akerman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $620,278
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937249

## Citation

> US National Institutes of Health, RePORTER application 10937249, Molecular basis for functional S1PR1 antagonists in the treatment of comorbid migraine and temporomandibular disorders (1R01NS138127-01). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10937249. Licensed CC0.

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