Sphingosine lysolipids in the CNS: Endogenous cannabinoid antagonists or a parallel pain modulatory system?

Abstract

A significant number of patients experience chronic pain and the intractable side effects of currently prescribed pain medications. Recent evidence indicates important pain modulatory roles for two classes of G-protein-coupled receptors that are activated by endogenous lipid ligands, the endocannabinoid (eCB) and sphingosine-1-phosphate (S1P) receptors, which are widely expressed in both the immune and nervous systems. In the central nervous system (CNS), CB1 cannabinoid and S1P1 receptors are most abundantly expressed and exhibit overlapping anatomical distributions and similar signaling mechanisms. The eCB system has emerged as a potential target for treatment of chronic pain, but comparatively little is known about the roles of S1P in pain regulation. Both eCB and S1P systems modulate pain perception via the central and peripheral nervous systems. In most paradigms studied, the eCB system mainly inhibits pain perception. In contrast, S1P acting peripherally at S1P1 and S1P3 receptors can enhance sensitivity to various pain stimuli or elicit spontaneous pain. However, S1P acting at S1P1 receptors and possibly other targets in the CNS can attenuate sensitivity to various pain stimuli. Interestingly, other endogenous sphingolipid derivatives might play a role in central pain sensitization. Moreover, these sphingolipids can also act as CB1 cannabinoid receptor antagonists, but the physiological relevance of this interaction is unknown. Overall, both eCB and sphingolipid systems offer promising targets for the treatment of chronic pain. This review compares and contrasts the eCB and S1P systems with a focus on their roles in pain modulation, and considers possible points of interaction between these systems.

Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity

“…In mouse, thymic levels of the bioactive phospholipid S1P vary in parallel to that of P‐selectin , and S1P regulates lymphocyte trafficking as well as HSC mobilization similarly to CNR2 . CB‐ and S1P‐signaling interact at multiple levels: AEA increases S1P phosphorylation , and CNR1‐stimulation enhances ceramide biosynthesis, the substrate for S1P ; further, sphingosine can bind to CNR1 as an antagonist , suggesting potential feedback regulation. It will be interesting to determine if just as CNR2‐signaling modulates AGM HSCs through cross‐regulatory effects on PGE2; CHT and thymus colonization occurs via regulation of S1P or other lipid mediators.…”

Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with 13 C-encoded natural S1P as internal standard

“…Correlations of elevated lysoGb3 with pain have been earlier observed [46] and more recently experimental evidence has been presented directly implicating lysoGb3 in the damage of nociceptive neurons [47]. Of note, S1P acting peripherally at S1P1 and S1P3 receptors can enhance sensitivity to various pain stimuli or elicit spontaneous pain [48], S1P can also act as antagonists of CB1 cannabinoid receptors involved in pain suppression [48]. In addition, S1P has recently been reported to stimulate excitatory transmission in neurons [13].…”

The Sphingosine 1-Phosphate Signaling Pathway in Epilepsy: A Possible Role for the Immunomodulator Drug Fingolimod in Epilepsy Treatment

“…These effects appeared to be CB1 receptorindependent. Recently, regarding pain modulation, the same research group suggested probable points of interaction between the cannabinoids and endogenous sphingolipid systems [163].…”