Effect of ADP on cumulative TRPV1 desensitization to capsaicin in rat DRG neurons.

Transient receptor potential vanilloid 1 (TRPV1) channels play a key role in nociception and undergo Ca2+-dependent desensitization, which is closely linked to cellular metabolic state. In nociceptive dorsal root ganglion (DRG) neurons, TRPV1 channels are coexpressed with metabotropic purinergic receptors P2Y1, P2Y2, P2Y4, and P2Y6, among which ATP is an agonist for P2Y1. In this study, we examined the effect of ADP on reversal of TRPV1 desensitization in rat DRG neurons (P8-10; 1-2 days in vitro) using Fura-2 AM Ca2+ imaging. Elevation of intracellular Ca2+ with 50 mM KCl resulted in a significant reduction in capsaicin action (18.4 ± 4.0% of control), which is associated with rapid Ca2+-dependent inactivation of TRPV1 channels. This effect was reversible, with recovery observed within 10-15 min. Repeated application of capsaicin (100 nM, 10 s; 3-5 trials at 2-5 min intervals) resulted in a progressive reduction in capsaicin-induced Ca2+ transients, consistent with cumulative TRPV1 desensitization. Application of adenosine-5'-diphosphate (ADP; 0.1 mM, 60 s) 10 min after repeated capsaicin stimulation was associated with a partial restoration of the subsequent capsaicin-induced Ca2+ response. These data indicate that postponed purinergic signaling may counteract cumulative TRPV1 desensitization in DRG sensory neurons.