title: The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1.
abstract: The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy- induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents.We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1β). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/ neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration- approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of FTY720 in chronic pain patients.
authors.forename: Kali
authors.initials: K
authors.lastname: Janes
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Little
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Collin
authors.initials: C
authors.lastname: Chen
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kamocki
authors.forename: Timothy
authors.initials: T
authors.lastname: Doyle
authors.forename: Ashley
authors.initials: A
authors.lastname: Snider
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Erhard
authors.initials: E
authors.lastname: Bieberich
authors.forename: Lina
authors.initials: L
authors.lastname: Obeid
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Grant
authors.initials: G
authors.lastname: Nicol
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology*; D063065:Organophosphonates / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D017239:Paclitaxel / Q000009:adverse effects* / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C532995:2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol; C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; D000813:Anilides; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D007166:Immunosuppressive Agents; D007189:Indans; D008246:Lysophospholipids; D063065:Organophosphonates; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; C503964:SEW2871; D000081025:Sphingosine-1-Phosphate Receptors; D013844:Thiazoles; D013876:Thiophenes; C060506:sphingosine 1-phosphate; C550169:ponesimod; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D017239:Paclitaxel