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Inhibition of chemotherapy‐induced neuropathic pain with S1P receptor modulators
Author(s) -
Salvemini Daniela,
Janes Kali,
Doyle Timothy,
Bryant Leesa,
Stockstill Katherine,
Chen Zhoumou,
Cuzzocrea Salvatore,
Kamocki Krzysztof,
Snider Ashley,
Obeid Lina,
Petrache Irina
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.887.12
Subject(s) - neuropathic pain , medicine , s1pr1 , pharmacology , sphingosine 1 phosphate receptor , neuroinflammation , sphingosine , sphingosine 1 phosphate , receptor , inflammation , vegf receptors , vascular endothelial growth factor a , vascular endothelial growth factor
Chemotherapy‐induced peripheral neuropathy (CIPN), accompanied by chronic neuropathic pain, is the major dose‐limiting toxicity of numerous antitumor agents. We now show that paclitaxel‐induced neuropathic pain is associated with increased sphingosine 1‐phosphate (S1P) formation in spinal cord acting through S1P1 receptor‐mediated NF‐κB and MAPKs activation and proinflammatory cytokine release. Inhibition of spinal cord S1P‐to‐S1PR1 signaling with the S1PR1 antagonist, W146, or FTY720, a FDA‐approved functional S1PR1 antagonist for treating multiple sclerosis, attenuated neuroinflammation and neuropathic pain. The effects of FTY720 occurred at non‐immunosuppressive doses without interfering with antitumor actions and extend to oxaliplatin and bortezomib‐induced neuropathic pain. Our findings identify the key role of the S1P‐to‐ S1PR1 pathway in CIPN and provide a first mechanistic insight into the S1P‐mediated biochemical pathways; establishing a pharmacological basis for S1PR modulators as chemotherapeutic adjuncts to block CIPN. Supported by Saint Louis University President Research Funds, Saint Louis University Cancer Center, Lymphoma and Leukemia Society Translational Research Grant.