Activation of sphingosine-1-phosphate receptor 1 in the spinal cord produces mechano-hypersensitivity through the activation of inflammasome and IL-1β pathway

Dysregulation of sphingolipid metabolism in the dorsal horn of the spinal cord (DH-SC) has been linked to the development of nociceptive behaviors arising from chemotherapy,19,43 traumatic nerve injuries,10 cancer17 and opioids.28 The bioactive sphingolipid sphingosine-1-phosphate (S1P) is formed by phosphorylation of sphingosine by the two isoforms of sphingosine kinases (SphKs; SphK1 and SphK2),42 which are expressed throughout the central nervous system (CNS) including the spinal cord.5,50 S1P can act both as an intracellular mediator and an extracellular ligand to its five cognate G protein-coupled receptors, S1PR1-5, in an autocrine/paracrine manner to produce so-called “inside-out signaling”.

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