Nitro-oleic acid inhibits firing and activates TRPV1- and TRPA1-mediated inward currents in dorsal root ganglion neurons from adult male rats.

Abstract

Nitro-oleic acid (OA-NO(2)), 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-NO(2) on cultured dorsal root ganglion (DRG) neurons were examined using fura-2 Ca(2+) imaging and patch clamping. OA-NO(2) (3.5-35 microM) elicited Ca(2+) transients in 20 to 40% of DRG neurons, the majority (60-80%) of which also responded to allyl isothiocyanate (AITC; 1-50 microM), a TRPA1 agonist, and to capsaicin (CAPS; 0.5 microM), a TRPV1 agonist. The OA-NO(2)-evoked Ca(2+) 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 microM) and the TRPV1 antagonist capsazepine (10 microM). Patch-clamp recording revealed that OA-NO(2) depolarized and induced inward currents in 62% of neurons. The effects of OA-NO(2) were elicited by concentrations >or=5 nM and were blocked by 10 mM dithiothreitol. Concentrations of OA-NO(2) >or=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-NO(2) 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-NO(2)-responsive neurons also responded to CAPS (0.5 microM) or AITC (0.5 microM). OA-NO(2) currents were reduced by TRPV1 (diarylpiperazine; 5 microM) or TRPA1 (HC-030031; 5 microM) antagonists. These data reveal that endogenous OA-NO(2) 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.

• Authors: A Sculptoreanu, F A Kullmann, D E Artim, F A Bazley, F Schopfer, S Woodcock, B A Freeman, W C de Groat
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 333 Issue 3 Pg. 883-95 (Jun 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20304940 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 10-nitro-oleic acid
• Ankyrins
• Anti-Inflammatory Agents
• Calcium Channels
• Oleic Acids
• Sodium Channel Agonists
• Sodium Channels
• TRPA1 Cation Channel
• TRPC Cation Channels
• TRPV Cation Channels
• Trpa1 protein, rat
• Trpv1 protein, rat
• Nitric Oxide

Topics

• Action Potentials (drug effects)
• Animals
• Ankyrins
• Anti-Inflammatory Agents (pharmacology)
• Calcium Channels (drug effects, metabolism)
• Calcium Signaling (drug effects)
• Cell Separation
• Electrophysiology
• Ganglia, Spinal (cytology, drug effects)
• Image Processing, Computer-Assisted
• Male
• Membrane Potentials (drug effects)
• Neurons, Afferent (drug effects)
• Nitric Oxide (physiology)
• Nociceptors (drug effects)
• Oleic Acids (pharmacology)
• Patch-Clamp Techniques
• Rats
• Sodium Channel Agonists
• Sodium Channels (drug effects)
• TRPA1 Cation Channel
• TRPC Cation Channels
• TRPV Cation Channels (agonists, metabolism)