87: Astrocytic S1PR1 Role in S1PR1 Antagonist Mechanism in Comorbid Migraine/Temporomandibular Disorders

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic primary headache, , , Pharmacological interventions, Assessment and Measurement of Pain/Nociception, Behavioral studies, , , , , ,

Background and Aims: Migraine is one of the leading causes of disability, affecting 40 million people in the US alone[1, 2]. Overlapping pain conditions greatly exacerbate patients’ experience, exemplified by over 40 percent of Temporomandibular Disorder (TMD) patients who report migraine symptoms that elicit higher levels of pain and disability[3-8]. The mechanistic underpinnings of this connection remain unknown. We have previously shown that sphingosine-1-phosphate receptor subtype 1 (S1PR1) activation contributes to the development of chronic pain conditions[9-12]. Furthermore, our lab has identified astrocytes as the primary cellular substrate for S1PR1 activity[9, 11]. However, the role of astrocytic S1PR1 in TMD-migraine comorbidity is unknown.

Methods: Here, we confirmed the efficacy of the S1PR1 antagonist and specifically identified the role of astrocytic S1PR1 through a cell-type-specific knockout. We modeled chronic comorbid TMD and migraine in female C57BL/6 and male fl/fl; +/- GFAP-cre mice with an astrocyte-specific KO of S1PR1. This was done by injecting the right masseter muscle with complete Freund’s adjuvant (CFA) one week before a series of four, low-dose NTG injections, then measuring periorbital mechanical sensitivity with calibrated von Frey filaments on days 7-15.

Results: The development of behavioral hypersensitivity was similar in WT and astrocyte-specific S1PR1 KO mice. Ozanimod blocked the development of allodynia in the WT mice but not in the KO mice. The KO mice experienced profound pain throughout the entire course of treatment with Ozanimod.

Conclusions: This data, along with biochemical analysis, suggests that astrocytic S1PR1 and downstream signaling are essential to the mechanism of action of these S1PR1 antagonists and provide a framework for translatable therapy to treat migraines in patients with TMD. Funded by NIH (5R01NS138127-02).

References: 1. Cohen, F., et al., Prevalence and burden of migraine in the United States: A systematic review. Headache, 2024. 64(5): p. 516-532.
2. Yucel, A., et al., Estimating the economic burden of migraine on US employers. Am J Manag Care, 2020. 26(12): p. e403-e408.
3. Byun, S.H., et al., Increased Risk of Migraine in Patients with Temporomandibular Disorder: A Longitudinal Follow-Up Study Using a National Health Screening Cohort. Diagnostics (Basel), 2020. 10(9).
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8. Goncalves, D.A., et al., Temporomandibular symptoms, migraine, and chronic daily headaches in the population. Neurology, 2009. 73(8): p. 645-6.
9. Chen, Z., et al., Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain. Proc Natl Acad Sci U S A, 2019. 116(21): p. 10557-10562.
10. Doyle, T.M., et al., Activation of Sphingosine-1-Phosphate Receptor 1 in the Spinal Cord Produces Mechanohypersensitivity Through the Activation of Inflammasome and IL-1beta Pathway. J Pain, 2019. 20(8): p. 956-964.
11. Li, Y., et al., Contribution of S1pr1 -featured astrocyte subpopulation to cisplatin-induced neuropathic pain. bioRxiv, 2025.

Presenting Author: Spencer Jones
Submitting Author: Spencer Jones

Senior Author: Dr. Daniela Salvemini

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Karen Galen: Bsc. - Saint Louis University
• Marcela Romero-Reyes: DDS, PhD - University of Maryland-Baltimore
• Simon Akerman: PhD - University of Maryland-Baltimore
• Daniela Salvemini: PhD - Saint Louis University