Nitro-oleic acid desensitizes TRPA1 and TRPV1 agonist responses in adult rat DRG neurons

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 Ca²⁺ imaging and patch clamp techniques and (2) interactions between these agents on sensory nerves in the rat hindpaw. Ca²⁺ imaging revealed that brief application (15-30s) 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 (20min) 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, 35μl) into a rat hindpaw induced delayed and prolonged nociceptive behavior. Homologous desensitization occurred with AITC and capsaicin when applied at 15minute intervals, but did not occur with OA-NO₂ when applied at a 30min 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.