Sphingosine 1-Phosphate Mediates Hyperalgesia via a Neutrophil-Dependent Mechanism

Autor: Emanuela Esposito, Zhoumou Chen, Amanda Finley, Salvatore Cuzzocrea, Roger A. Sabbadini, Daniela Salvemini
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
Neutrophils
Sphingosine kinase
lcsh:Medicine
Pharmacology
Carrageenan
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Sphingosine
Drug Discovery
Molecular Cell Biology
Membrane Receptor Signaling
lcsh:Science
Receptor
Sensitization
0303 health sciences
Multidisciplinary
Animal Models
Receptors
Lysosphingolipid
medicine.anatomical_structure
Neurology
Neutrophil Infiltration
Hyperalgesia
Medicine
lipids (amino acids
peptides
and proteins)
medicine.symptom
Infiltration (medical)
Research Article
Signal Transduction
Agonist
medicine.drug_class
Immune Cells
Cognitive Neuroscience
Immunology
Pain
03 medical and health sciences
Model Organisms
Polysaccharides
medicine
Pain Management
Animals
Sphingosine-1-phosphate
Biology
Sphingosine-1-Phosphate Receptors
030304 developmental biology
Inflammation
lcsh:R
Immunity
medicine.disease
Rats
chemistry
Rat
lcsh:Q
Clinical Immunology
Lysophospholipids
030217 neurology & neurosurgery
Neuroscience
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 1, p e55255 (2013)
Popis: Novel classes of pain-relieving molecules are needed to fill the void between non-steroidal anti-inflammatory agents and narcotics. We have recently shown that intraplantar administration of sphingosine 1-phosphate (S1P) in rats causes peripheral sensitization and hyperalgesia through the S1P(1) receptor subtype (S1PR(1)): the mechanism(s) involved are largely unknown and were thus explored in the present study. Intraplantar injection of carrageenan in rats led to a time-dependent development of thermal hyperalgesia that was associated with pronounced edema and infiltration of neutrophils in paw tissues. Inhibition of 1) S1P formation with SK-I, a sphingosine kinase inhibitor, 2) S1P bioavailability with the S1P blocking antibody Sphingomab, LT1002 (but not its negative control, LT1017) or 3) S1P actions through S1PR(1) with the selective S1PR(1) antagonist, W146 (but not its inactive enantiomer, W140) blocked thermal hyperalgesia and infiltration of neutrophils. Taken together, these findings identify S1P as an important contributor to inflammatory pain acting through S1PR(1) to elicit hyperalgesia in a neutrophil-dependant manner. In addition and in further support, we demonstrate that the development of thermal hyperalgesia following intraplantar injection of S1P or SEW2871 (an S1PR(1) agonist) was also associated with neutrophilic infiltration in paw tissues as these events were attenuated by fucoidan, an inhibitor of neutrophilic infiltration. Importantly, FTY720, an FDA-approved S1P receptor modulator known to block S1P-S1PR(1) signaling, attenuated carrageenan-induced thermal hyperalgesia and associated neutrophil infiltration. Targeting the S1P/S1PR(1) axis opens a therapeutic strategy for the development of novel non-narcotic anti-hyperalgesic agents.
Databáze: OpenAIRE
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