Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors

Abstract

FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720. Accordingly, intrathecal administration of S1P1 receptor agonists was not sufficient to evoke an antinociceptive effect. Taken together, the data show that, in contrast to its effects on chemotherapy-induced neuropathy, FTY720 reduces trauma-induced neuropathic pain by simultaneous activation of spinal S1P1 and S1P3 receptor subtypes.

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

“…Next, we tested the effects of S1PR inhibition on neutrophil accumulation after LPS challenge. For this purpose, 4h-LPS-inflamed mice were administered FTY720-an antagonist of all sphingosine 1-phosphate receptors widely used to treat multiple sclerosis [35][36][37][38]. To further confirm the importance of specific S1PR on inflammatory response, we employed JTE013, a potent selective antagonist of S1PR2 [26][27][28]39].…”

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

“…These findings suggest that inhibiting S1PR1 with an antagonist would be beneficial to treating neuropathic pain. However, studies in models of traumatic nerve injury have attributed the analgesic effects of the S1PR modulator, FTY720 (Fingolimod) (13), to S1PR1 agonism (14) or combined S1PR1/S1P3 agonism (15). Several hypotheses have been offered for these apparently opposing mechanisms of action for S1PR1, including differences in the neuropathic pain etiology (chemical toxicity versus traumatic injury) (15).…”

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

“…In contrast, S1PR1 or S1PR3 antagonists reversed FTY720 antiallodynia in the mouse spared nerve injury model of neuropathic pain (Zhang et al, 2015). However, it should be noted that a single, low dose of FTY720 (0.01 mg/kg) only partially reversed allodynia in this model, whereas higher and lower doses were ineffective.…”

“…Sphingosine-1-phosphate (S1P) is a novel pain modulatory system proposed to mediate both antinociception and pronociceptive effects depending on site of action and nociceptive test (Welch et al, 2012;Salvemini et al, 2013;Selley et al, 2013). 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), an immunomodulatory prodrug Food and Drug Administration approved to treat multiple sclerosis (Chun and Brinkmann, 2011), produces antiallodynic/ antihyperalgesic effects in models of inflammatory and neuropathic pain (Coste et al, 2008;Janes et al, 2014;Zhang et al, 2015). FTY720 is rapidly phosphorylated in vivo to FTY720-phosphate (FTY720-P), which is an agonist of all S1P receptors (S1PR), except S1PR2 (Brinkmann et al, 2002).…”