TY - JOUR T1 - Differential Tolerance to FTY720-induced Antinociception in Acute Thermal and Nerve Injury Mouse Pain Models: Role of S1P Receptor Adaptation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.248260 SP - jpet.118.248260 AU - Laura J. Sim-Selley AU - Jenny L. Wilkerson AU - James J. Burston AU - Kurt F. Hauser AU - Virginia McLane AU - Sandra P. Welch AU - Aron H. Lichtman AU - Dana E. Selley Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/06/26/jpet.118.248260.abstract N2 - The immunomodulatory pro-drug FTY720, which acts as an agonist for S1P receptors (S1PR) when phosphorylated, is proposed as a novel pain therapeutic. Here we assessed FTY720-mediated antinociception in the radiant heat tail-flick test and in the chronic constriction injury (CCI) model of neuropathic pain in mice. FTY720 produced antinociception and anti-allodynia, respectively, and these effects were dose-dependent and mimicked by the S1PR1 selective agonist CYM-5442. Repeated administration of FTY720 for one week produced tolerance to acute thermal antinociception, but not to anti-allodynia in the CCI model. S1PR-stimulated [35S]GTPγS autoradiography revealed apparent desensitization of G-protein activation by S1P or the S1PR1 agonist SEW2871 throughout the brain. Similar results were seen in spinal cord membranes, whereby the Emax value of S1PR-stimulated [35S]GTPγS binding was greatly reduced in repeated FTY720-treated mice. These results suggest that S1PR1 is a primary target of FTY720 in alleviating both acute thermal nociception and chronic neuropathic nociception. Furthermore, the finding that tolerance develops to antinociception in the tail-flick test but not in chronic neuropathic pain suggests a differential mechanism of FTY720 action between these models. The observation that repeated FTY720 administration led to desensitized S1PR1 signaling throughout the CNS suggests the possibility that S1PR1 activation drives the acute thermal antinociceptive effects, whereas S1PR1 desensitization mediates: 1) tolerance to thermal antinociceptive actions of FTY720; and 2) the persistent anti-allodynic effects of FTY720 in neuropathic pain by producing functional antagonism of pro-nociceptive S1PR1 signaling. ER -