title: 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.
authors.forename: Dong Dong
authors.initials: DD
authors.lastname: Zhang
authors.forename: Bona
authors.initials: B
authors.lastname: Linke
authors.forename: Jing
authors.initials: J
authors.lastname: Suo
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Zivkovic
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schreiber
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.forename: Marina
authors.initials: M
authors.lastname: Henke
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017403:In Situ Hybridization; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D010755:Organophosphates / Q000494:pharmacology* / Q000627:therapeutic use; D063065:Organophosphonates / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D014947:Wounds and Injuries / Q000150:complications*; D000099157:Sphingosine Kinase
chemical_list: D000700:Analgesics; D000813:Anilides; D008246:Lysophospholipids; D010755:Organophosphates; D063065:Organophosphonates; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; C525008:FTY 720P; C060506:sphingosine 1-phosphate; C000603447:sphingosine kinase 2, mouse; D000099157:Sphingosine Kinase