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Sphingosine 1‐phosphate receptor 1 mediates morphine‐induced antinociceptive tolerance and hyperalgesia
Author(s) -
Doyle Timothy M.,
Bryant Leesa,
Cuzzocrea Salvatore,
Salvemini Daniela
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.887.2
Subject(s) - s1pr1 , hyperalgesia , pharmacology , methyllycaconitine , agonist , antagonist , nociception , medicine , chemistry , receptor , nicotinic agonist , nicotinic acetylcholine receptor , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors
The clinical utility of morphine is hampered by the development of antinociceptive tolerance and hyperalgesia. We have reported these conditions arise in part from ceramide‐sphingosine‐1‐phosphate (S1P)‐dependant proinflammatory processes in tolerant rats, but the signaling pathways are not clear. We now show in rats chronically treated with morphine that the S1P signaling is dependent on the activation of the S1P receptor 1 (S1PR1). Systemic FTY720, a functional antagonist of S1PR1 that inhibits S1P signaling through S1PR1 internalization and degradation, attenuated NF‐κB and MAPK activation, TNFα and IL1β release in spinal cord, and completely prevented the development of tolerance and hyperalgesia in a dose‐dependent manner. The role of S1PR1 signaling was further supported by the attenuation of tolerance and hyperalgesia with intrathecal administration of selective S1PR1 antagonist, W146, but not its inactive enantiomer, W140, and by the induction of hyperalgesia in normal rats by intrathecal SEW2870, a selective S1PR1 agonist. Collectively, our findings identify a role of the S1P‐to‐S1PR1 pathway in morphine tolerance and hyperalgesia and, since FTY720 is FDA‐approved for the treatment of multiple sclerosis, may provide a fast‐track to clinical application of S1PR modulators as adjuncts to opiates. Supported by NIH/NIDA [R01 DA024074] and APS Future Leaders in Pain Research Grant.