Ozanimod, a functional sphingosine-1-phosphate receptor 1 antagonist, restores brainstem descending pain pathways in murine models of neuropathic pain

Activation of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) in the spinal cord contributes to neuropathic pain; however, its role at supraspinal sites remains unexplored. Ozanimod is a new FDA-approved S1PR1 antagonist for multiple sclerosis. Here, we show that systemic ozanimod administration reverses behavioral hypersensitivities in male rodents induced by chronic sciatic nerve constriction and chemotherapy (oxaliplatin and paclitaxel). Moreover, bilateral ozanimod injection in the rostral ventral medulla (RVM) reversed behavioral hypersensitivities in a time-dependent manner, evincing a role for S1PR1 in the descending pain modulatory system. RNA-Seq analysis of the RVM revealed that traumatic nerve injury downregulated type I interferons (IFN-I) signaling. Intra-RVM ozanimod administration normalized IFN-I-associated gene expression levels, suggesting that S1PR1 activation mediated IFN-I signaling downregulation that, in turn, may regulate RVM descending pain pathways. In the RVM, engagement of noradrenergic and serotonergic inhibitory circuits suppressed spinal nociception. Intrathecal injection of an α2 antagonist (yohimbine) or a serotonin antagonist (methysergide) prevented the antinociceptive effects of ozanimod in both models of neuropathic pain implicating these descending inhibitory projections in S1PR1 antagonism. In contrast to the disease state, intra-RVM injection of the S1PR1 agonist SEW2871 to uninjured animals did not cause behavioral hypersensitivities, underscoring a state-dependent role of S1PR1 in nociception. Our results establish a role for S1PR1 in descending facilitation and suggest that this function may inhibit IFN-I signaling pathways. Our findings support repurposing FDA-approved functional S1PR1 antagonists as nonopioid treatments for neuropathic pain.