RT Journal Article
SR Electronic
T1 Nitro-Oleic Acid Inhibits Firing and Activates TRPV1- and TRPA1-Mediated Inward Currents in Dorsal Root Ganglion Neurons from Adult Male Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 883
OP 895
DO 10.1124/jpet.109.163154
VO 333
IS 3
A1 A. Sculptoreanu
A1 F. A. Kullmann
A1 D. E. Artim
A1 F. A. Bazley
A1 F. Schopfer
A1 S. Woodcock
A1 B. A. Freeman
A1 W. C. de Groat
YR 2010
UL http://jpet.aspetjournals.org/content/333/3/883.abstract
AB Nitro-oleic acid (OA-NO2), an electrophilic fatty acid by-product of nitric oxide and nitrite reactions, is present in normal and inflamed mammalian tissues at up to micromolar concentrations and exhibits anti-inflammatory signaling actions. The effects of OA-NO2 on cultured dorsal root ganglion (DRG) neurons were examined using fura-2 Ca2+ imaging and patch clamping. OA-NO2 (3.5–35 μM) elicited Ca2+ transients in 20 to 40% of DRG neurons, the majority (60–80%) of which also responded to allyl isothiocyanate (AITC; 1–50 μM), a TRPA1 agonist, and to capsaicin (CAPS; 0.5 μM), a TRPV1 agonist. The OA-NO2-evoked Ca2+ transients were reduced by the TRPA1 antagonist 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl) acetamide (HC-030031; 5–50 μM) and the TRPV1 antagonist capsazepine (10 μM). Patch-clamp recording revealed that OA-NO2 depolarized and induced inward currents in 62% of neurons. The effects of OA-NO2 were elicited by concentrations ≥5 nM and were blocked by 10 mM dithiothreitol. Concentrations of OA-NO2 ≥5 nM reduced action potential (AP) overshoot, increased AP duration, inhibited firing induced by depolarizing current pulses, and inhibited Na+ currents. The effects of OA-NO2 were not prevented or reversed by the NO-scavenger carboxy-2-phenyl-4,4,5,5-tetramethylimidazolineoxyl-1-oxyl-3-oxide. A large percentage (46–57%) of OA-NO2-responsive neurons also responded to CAPS (0.5 μM) or AITC (0.5 μM). OA-NO2 currents were reduced by TRPV1 (diarylpiperazine; 5 μM) or TRPA1 (HC-030031; 5 μM) antagonists. These data reveal that endogenous OA-NO2 generated at sites of inflammation may initially activate transient receptor potential channels on nociceptive afferent nerves, contributing to the initiation of afferent nerve activity, and later suppresses afferent firing. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics