Differential Tolerance to FTY720-Induced Antinociception in Acute Thermal and Nerve Injury Mouse Pain Models: Role of Sphingosine-1-Phosphate Receptor Adaptation

Abstract

The immunomodulatory prodrug 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), which acts as an agonist for sphingosine-1-phosphate (S1P) receptors (S1PR) when phosphorylated, is proposed as a novel pain therapeutic. In this study, 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 antiallodynia, respectively, and these effects were dose-dependent and mimicked by the S1PR1-selective agonist CYM-5442. Repeated administration of FTY720 for 1 week produced tolerance to acute thermal antinociception, but not to antiallodynia in the CCI model. S1PR-stimulated [S]GTPS autoradiography revealed apparent desensitization of G protein activation by S1P or the S1PR1 agonist 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (SEW-2871) throughout the brain. Similar results were seen in spinal cord membranes, whereby the E value of S1PR-stimulated [S]GTPS 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 central nervous system suggests the possibility that S1PR1 activation drives the acute thermal antinociceptive effects, whereas S1PR1 desensitization mediates the following: 1) tolerance to thermal antinociceptive actions of FTY720 and 2) the persistent antiallodynic effects of FTY720 in neuropathic pain by producing functional antagonism of pronociceptive S1PR1 signaling.

Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain

“…chemotherapy-induced neuropathic pain (9). A recent study has hinted at the possibility of functional S1PR1 antagonism in the antiallodynic effects of FTY720 following traumatic nerve injury (16), but selective S1PR1 antagonists and the cell substrate of this S1PR1 activity were not investigated.…”

Sphingosine 1-phosphate receptor modulation attenuate mechanical allodynia in mouse model of chronic complex regional pain syndrome by suppressing pathogenic astrocyte activation

“…It is G-protein-coupled receptor (S1PR1, S1PR2, S1PR3, and S1PR5) and synthetic enzymes (sphingosine kinases 1 and 2) are expressed throughout the CNS 27–29. In the neuropathic pain model, S1P has been reported to originate from the dorsal horn of the spinal cord, and it plays a role in central sensitization by selectively activating the S1PR1 and S1PR3 in astrocytes 12 29–31. Moreover, the genetic and pharmacological inhibition of S1PR1 and S1PR3 with multiple antagonists was reported to attenuate and even reverse neuropathic pain in a rodent model 29.…”

“…FTY720 ((2-amino-2-)2-[4-octylphenyl]ethyl)−1,3-propanediol), a Food and Drug Administration (FDA)-approved immunomodulatory S1P receptor ligand for multiple sclerosis, has antihyperalgesic and antiallodynic effects on models of inflammatory and neuropathic pain 12–14. Despite the therapeutic potency of FTY720, to the best of our knowledge, there has been no study regarding the effects of FTY720 on CRPS rodent models.…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…In fact, SphK1/SphK2-double knockout mice [30] and S1P1R knockout mice show impaired neurogenesis (decreased proliferation and increased apoptosis) and embryonic death. Modifications of S1P metabolism, S1PR expression profile, and S1P-mediated signaling have been described in neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease for recent reviews see [29,31,32] and neuropathic pain [33][34][35][36][37]. Some S1P analogues have been approved for the treatment of multiple sclerosis or have passed phase III trial [31,38], while the effects of other enzyme activators and inhibitors and S1PR agonists/antagonists are being tested in animal models of neurodegenerative diseases.…”