Dissociation between the anti-allodynic effects of fingolimod (FTY720) and desensitization of S1P 1 receptor-mediated G-protein activation in a mouse model of sciatic nerve injury.

Autor: Pondelick AM; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Moncayo LV; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Donvito G; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., McLane VD; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Gillespie JC; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Hauser KF; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Spiegel S; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Lichtman AH; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Sim-Selley LJ; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Selley DE; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Electronic address: Dana.Selley@vcuhealth.org.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Dec 15; Vol. 261, pp. 110165. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1016/j.neuropharm.2024.110165
Abstrakt: Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism.
Competing Interests: Declaration of competing interest None.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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