Demyelination-Related Pain: Role of Lysophosphatidic Acid in Satellite Glial Cell-Neuron Crosstalk

Background Demyelination diseases are characterized by injury to large (A-type) myelinated nerve fibers, and by secondary damage to small (C-type) sensory fibers, which leads to chronic pain symptoms, such as allodynia. The mechanisms underlying the interactions between the two fiber types are not clear. This study aims to investigate the role of lysophosphatidic acid (LPA) signaling in satellite glial cells (SGCs) within the dorsal root ganglia (DRG) in demyelination-induced chronic pain. Methods A demyelination model was established by injecting cobra venom into the tibial nerve of 8–10-week-old Sprague-Dawley rats to selectively damage A-fiber myelin. Myelin morphology was observed via transmission electron microscopy (TEM) at 1, 3, 7, and 14 days post-injection. Pain behaviors (mechanical hypersensitivity, thermal hyperalgesia, and spontaneous pain) were assessed to evaluate progression. In vivo electrophysiology was performed to analyze sensory conduction and excitability changes in A- and C-type neurons. Immunofluorescence staining assessed SGC activation, LPA1R expression, and connexin 43 (Cx43) dynamics in the L4 DRG over time. Pharmacological interventions targeting LPA1R and SGC activation were applied to evaluate their effects on pain behaviors, cytokine release, and neuronal excitability using RT-PCR, ELISA, and spinal electrophysiology. Results Cobra venom induced a selective A-fiber demyelination and persistent pain in rats. It also upregulated the expression of LPA1 receptors (LPA1R) on SGCs that surround large DRG neurons, which normally mediate non-noxious input, and increased gap junction-mediated coupling via Cx43, leading to the activation of SGCs surrounding small nociceptive neurons. The activated SGCs released inflammatory mediators that increased nociceptive neuron excitability, driving chronic pain. In support of these results, pharmacological inhibition of LPA1R-mediated SGCs activation reversed this process. Conclusions Our findings demonstrate that following myelin injury, the increased secretion of LPA acts on LPA1R on SGCs surrounding large neurons, leading to their activation. This activation results in enhanced coupling between SGCs via gap junctions, which subsequently activates SGCs around small nociceptive neurons. The activated SGCs release inflammatory cytokines that increase the excitability of nociceptive small neurons and drive chronic pain.