Microglia and Sphingosine-1-Phosphate Receptor 1 in the Spinal Cord Regulate Neuropathic Pain in Multiple Sclerosis
Abstract (summary)
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by inflammation, demyelination, and neurodegeneration. In addition to motor and cognitive impairments, neuropathic pain is a prevalent but often underrecognized symptom of MS, affecting up to 90% of patients. Current MS treatments primarily target adaptive immune responses to reduce relapse rates and slow disease progression but fail to adequately address MS-associated neuropathic pain (MSNP). Existing analgesics provide limited relief, underscoring the need for novel, mechanism-based pain therapies. This dissertation investigates the role of spinal microglia and sphingosine-1-phosphate receptor 1 (S1PR1) signaling in MSNP, identifying microglial S1PR1 as a critical modulator of pain hypersensitivity and a promising therapeutic target.
Using a non-pertussis toxin EAE (EAE-nPTX) model, this work demonstrates that spinal microglia drive mechanical hypersensitivity in MSNP. Pharmacologic depletion and chemogenetic inhibition of spinal microglia significantly attenuate pain behaviors, while whole-CNS or brain-specific microglial inhibition fails to produce similar effects. This dissertation further identifies S1PR1 signaling in spinal microglia as a key regulator of MSNP. Activation of S1PR1 using pharmacologic agonists significantly reduces pain hypersensitivity, whereas blocking S1PR1 prevents pain relief. EAE induces S1PR1 desensitization in the spinal cord, yet targeted S1PR1 activation effectively reverses hypersensitivity.
These findings establish that spinal microglia play a central role in MSNP maintenance and that S1PR1 activation modulates their pain-related function. The results support S1PR1-targeted interventions as a potential approach for pain relief in MS and highlight the importance of spinal neuroimmune interactions in shaping pain sensitivity. This work provides a mechanistic foundation for understanding MSNP and identifies microglial S1PR1 as a critical node in its regulation and indicates that the S1PR1 pathway is an exciting therapeutic target.
Indexing (details)
Cellular biology;
Genetics;
Immunology
0379: Cellular biology
0982: Immunology
0369: Genetics
