title: Nitro-oleic acid desensitizes TRPA1 and TRPV1 agonist responses in adult rat DRG neurons.
abstract: Nitro-oleic acid (OA-NO2), an electrophilic fatty acid nitroalkene byproduct of redox reactions, activates transient receptor potential ion channels (TRPA1 and TRPV1) in primary sensory neurons. To test the possibility that signaling actions of OA-NO2 might modulate TRP channels, we examined: (1) interactions between OA-NO2 and other agonists for TRPA1 (allyl-isothiocyanate, AITC) and TRPV1 (capsaicin) in rat dissociated dorsal root ganglion cells using Ca(2+) imaging and patch clamp techniques and (2) interactions between these agents on sensory nerves in the rat hindpaw. Ca(2+) imaging revealed that brief application (15-30 s) of each of the three agonists induced homologous desensitization. Heterologous desensitization also occurred when one agonist was applied prior to another agonist. OA-NO2 was more effective in desensitizing the response to AITC than the response to capsaicin. Prolonged exposure to OA-NO2 (20 min) had a similar desensitizing effect on AITC or capsaicin. Homologous and heterologous desensitizations were also demonstrated with patch clamp recording. Deltamethrin, a phosphatase inhibitor, reduced the capsaicin or AITC induced desensitization of OA-NO2 but did not suppress the OA-NO2 induced desensitization of AITC or capsaicin, indicating that heterologous desensitization induced by either capsaicin or AITC occurs by a different mechanism than the desensitization produced by OA-NO2. Subcutaneous injection of OA-NO2 (2.5mM, 35 μl) into a rat hindpaw induced delayed and prolonged nociceptive behavior. Homologous desensitization occurred with AITC and capsaicin when applied at 15 minute intervals, but did not occur with OA-NO2 when applied at a 30 min interval. Pretreatment with OA-NO2 reduced AITC-evoked nociceptive behaviors but did not alter capsaicin responses. These results raise the possibility that OA-NO2 might be useful clinically to reduce neurogenic inflammation and certain types of painful sensations by desensitizing TRPA1 expressing nociceptive afferents.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, PR China. Electronic address: xiz50@pitt.edu.
authors.forename: Xiulin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Koronowski
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Woodcock
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: de Groat
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology*; D017879:Isothiocyanates / Q000494:pharmacology; D008041:Linoleic Acids / Q000494:pharmacology*; D035002:Lower Extremity / Q000294:innervation; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011722:Pyrethrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000819:agonists; D050916:TRPV Cation Channels / Q000819:agonists; D013997:Time Factors
chemical_list: C501855:10-nitro-9,12-octadecadienoic acid; D017879:Isothiocyanates; D008041:Linoleic Acids; D009570:Nitriles; D009574:Nitro Compounds; D011722:Pyrethrins; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; C017180:decamethrin; C041942:2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate; D002211:Capsaicin; D002118:Calcium
keywords: AITC; DRG; Desensitization; Nitro-oleic acid; Nociception; OA-NO(2); Primary sensory neuron; TRP channels; allyl-isothiocyanate; dorsal root ganglion; nitro-oleic acid