The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain

Abstract

Introduction: Neuropathic pain disorders are diverse, and the currently available therapies are ineffective in the majority of cases. Therefore, there is a major need for gaining novel mechanistic insights and developing new treatment strategies for neuropathic pain. Areas covered: We performed an in-depth literature search on the molecular mechanisms and systemic importance of the ceramide-to-S1P rheostat regulating neuron function and neuroimmune interactions in the development of neuropathic pain. Expert opinion: The S1P receptor modulator FTY720 (fingolimod, Gilenya®), LPA receptor antagonists and several mechanistically related compounds in clinical development raise great expectations for treating neuropathic pain disorders. Research on S1P receptors, S1P receptor modulators or SPHK inhibitors with distinct selectivity, pharmacokinetics and safety must provide more mechanistic insight into whether they may qualify as useful treatment options for neuropathic pain disorders. The functional relevance of genetic variations within the ceramide-to-S1P rheostat should be explored for an enhanced understanding of neuropathic pain pathogenesis. The ceramide-to-S1P rheostat is emerging as a critically important regulator hub of neuroimmune interactions along the pain pathway, and improved mechanistic insight is required to develop more precise and effective drug treatment options for patients suffering from neuropathic pain disorders.

Emerging Roles of Ceramide in Cardiovascular Diseases

“…It comprises a fatty chain connected by sphingosine bases and amides, with lengths ranging from C14:0 to C26:0 [ 12 ]. The central role of ceramide in the sphingolipid pathway is mainly attributed to its involvement in synthesizing complex structural sphingolipids (sphingomyelin and ganglioside) and as the precursor of the survival molecule and immunomodulator, S1P [ 13 ].…”

Combination of paeoniflorin and liquiritin alleviates neuropathic pain by lipid metabolism and calcium signaling coordination

“…Integration of multiple omics technologies has emerged as an approach to provide a comprehensive view of health and disease and may provide a better understanding of pharmacotherapy ( Karczewski and Snyder, 2018 ). The lipids (i.e., sphingolipids, ceramides, and lysophosphatidic acids) are critical for the initiation of NP ( Patti et al, 2012 ; Langeslag and Kress, 2020 ), which called for the application of lipidomics, a branch of metabolomics that focuses on lipids and analyzes lipid metabolism network changes under different physiological conditions ( Yang and Han, 2016 ). Transcriptomics is mainly performed to identify the gene expression profile which could provide an insight into the alteration of biological processes at the gene level.…”

Lipidomic Profiling Identifies Serum Lipids Associated with Persistent Multisite Musculoskeletal Pain

“…LPC can also be hydrolyzed by autotaxin (ATX), a secreted exoenzyme with lysophospholipase D activity, to generate LPA, a compound that has been reported to be profoundly involved in the initiation and maintenance of chronic pain [ 17 , 39 ]. LPA mediates the activation of ion channels such as TRPV1 in DRG neurons to induce central sensitization [ 40 ]. Through the activation of G protein-coupled receptors, LPA also mediates the demyelination of central neurons, which is associated with the development of chronic pain [ 41 , 42 ].…”