The Effect of Functional S1PR1 Antagonists on Central Trigeminovascular Neurons Using Migraine-Like Preclinical Approaches

Editor’s note: The research described below comes from a recipient of a 2023 MSC Travel Grant supporting travel to the 65th Annual Scientific Meeting of the American Headache Society. These grants reimburse travel expenses for those who have had their abstract for a presentation or poster accepted at a meeting.

By Ana Belen Salinas Abarca, PhD, postdoctoral researcher, University of Maryland, School of Dentistry, US

What is the research gap that your study addresses?

This project is about the potential of targeting S1PR1 with antagonists, to treat headache disorders. We are testing functional S1PR1 antagonists, such as fingolimod (FTY720) or ozanimod, which already have FDA approval for treating multiple sclerosis (MS), have a good safety profile, and have been shown to be effective at treating persistent pain states in preclinical models. These data will provide further support for S1PR1 as a novel target in migraine treatment and move our understanding of migraine pathobiology forward, describing a potentially novel molecular mechanism underlying migraine based on the mode of action of S1PR1 antagonists.

What is your research hypothesis?

Fingolimod or ozanimod treatment reduces the activity of dural-response neurons in the trigeminocervical complex in response to noxious and innocuous facial cutaneous and dural stimulation in the ophthalmic trigeminal division.

What methodology did you use to address your research hypothesis?

Using electrophysiological, molecular, and biochemical approaches in a stress-restraint/nitric oxide donor model of migraine, the project will dissect the role of the endogenous ligand, sphingosine-1-phosphate (S1P), and its signaling at S1PR1, in migraine-related mechanisms.

In vivo electrophysiological extracellular recording of dural-responsive neurons in the trigeminocervical complex (TCC) was carried out. We recorded ongoing neuronal activity of 2nd-order TCC neurons and measured neuronal responses to noxious and innocuous dural and cutaneous facial stimulation in the ophthalmic trigeminal division (V1). We measured responses to two functional S1PR1 antagonists, FTY720 (1 mg/kg, IV) and ozanimod (1 mg/kg, IV), or naratriptan (3 mg/kg, IV) as a positive control. Additional S1PR1 antagonist studies are being conducted in rats where TCC neurons are sensitized using a combination of stress and a migraine trigger.

What are the main results of your study?

Both fingolimod and ozanimod were able to inhibit intracranial dural-evoked Aδ and C fiber responses from 60 and 90 min, respectively, similar to the response of naratriptan (positive control). Only ozanimod significantly inhibited ongoing spontaneous neuronal firing from 60 min. Again, this is similar to the effects of naratriptan. Neither treatment affected innocuous (brush) or noxious (pinch) cutaneous facial stimulation in the ophthalmic division (V1).

What conclusions did you reach based on your results?

These are the first data to provide support for the participation of the S1P-S1PR1 signaling axis via direct modulation of migraine-like TCC neurons using functional S1PR1 antagonists, in a preclinical model. These data also provide preclinical evidence that S1PR1 antagonism, using ozanimod and FTY720, may represent a novel and promising approach for migraine management.

What are the limitations of your study?

Further validation is still necessary, using sensitized approaches, as is dissecting the locus and cellular substrate of action.

What is the relevance of your study to migraine?

The significance of these data is demonstrated by the fact that this drug class already has FDA approval and is used in the treatment of MS and is therefore considered a safe target. This means there is potential to expedite development to clinical trials to treat migraine.