Role for peroxynitrite in sphingosine-1-phosphate-induced hyperalgesia in rats.
Sphingosine-1-phosphate (S1P) is an important mediator of inflammation recently shown in in vitro studies to increase the excitability of small-diameter sensory neurons, at least in part, via activation of the S1P(1) receptor subtype. Activation of S1PR(1) has been reported to increase the formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide (O(2)(·-)) and nitric oxide synthase (NOS)-derived nitric oxide (NO). This process favors the formation of peroxynitrite (ONOO(-) [PN]), a potent mediator of hyperalgesia associated with peripheral and central sensitization. The aims of our study were to determine whether S1P causes peripheral sensitization and thermal hyperalgesia via S1PR(1) activation and PN formation. Intraplantar injection of S1P in rats led to a time-dependent development of thermal hyperalgesia that was blocked by the S1PR(1) antagonist W146, but not its inactive enantiomer W140. The hyperalgesic effects of S1P were mimicked by intraplantar injection of the well-characterized S1PR(1) agonist SEW2871. The development of S1P-induced hyperalgesia was blocked by apocynin, a NADPH oxidase inhibitor; N(G)-nitro-l-arginine methyl ester, a nonselective NOS inhibitor; and by the potent PN decomposition catalysts (FeTM-4-PyP(5+) and MnTE-2-PyP(5+)). Our findings provide mechanistic insight into the signaling pathways engaged by S1P in the development of hyperalgesia and highlight the contribution of the S1P(1) receptor-to-PN signaling in this process. Sphingosine-1-phosphate (S1P)-induced hyperalgesia is mediated by S1P1 receptor activation and mitigated by inhibition or decomposition of peroxynitrite, providing a target pathway for novel pain management strategies.
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA.
Tim
T
Doyle
Amanda
A
Finley
Zhoumou
Z
Chen
Daniela
D
Salvemini
D000098:Acetophenones / Q000627:therapeutic use; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D008246:Lysophospholipids / Q000009:adverse effects*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D063065:Organophosphonates / Q000627:therapeutic use; D010069:Oxadiazoles / Q000009:adverse effects; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000009:adverse effects / Q000031:analogs & derivatives*; D013876:Thiophenes / Q000009:adverse effects; D013997:Time Factors
C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; C492721:5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato-iron(III); D000098:Acetophenones; D000813:Anilides; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D008665:Metalloporphyrins; D063065:Organophosphonates; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D030421:Peroxynitrous Acid; C060506:sphingosine 1-phosphate; C056165:acetovanillone; D013110:Sphingosine; D019331:NG-Nitroarginine Methyl Ester
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