THE RESPONSES OF RAT TRIGEMINAL GANGLION NEURONS TO CAPSAICIN AND 2 NONPUNGENT VANILLOID RECEPTOR AGONISTS, OLVANIL AND GLYCERYL NONAMIDE

Capsaicin, the pungent ingredient in hot pepper, activates and subsequ ently desensitizes a subset of polymodal nociceptors. Because its init ial application to skin produces pain, nonpungent analogs such as olva nil and glyceryl nonivamide (GLNVA) were synthesized to enhance its cl inical use. To explore how these nonpungent analogs differ from capsai cin, whole-cell patch-clamp recordings were performed on cultured rat trigeminal ganglion neurons. In neurons held at -60 mV, capsaicin, olv anil, and GLNVA were found to activate one or two kinetically distinct inward currents. Two inward currents were also activated when extrace llular Ca2+ was replaced with Ba2+ and also when intracellular chlorid e was replaced by aspartate. The reversal potentials of the rapidly an d slowly activating currents were 15.3 +/- 6 and -4.0 +/- 2.5 mV, resp ectively. These data provide strong evidence for subtypes of vanilloid receptors. One difference among these agonists is that, on average, t he activation kinetics of the currents evoked by 1 mu M olvanil and 30 mu M GLNVA are considerably slower than those evoked by 1 mu M capsai cin. Measurements of the peak current, Ip, versus agonist concentratio n were fit to the Hill equation to yield values of the half maximal co ncentrations (K-1/2), and the Hill coefficients (n), For capsaicin, ol vanil, and GLNVA, K-1/2 = 0.68, 0.59, and 27.0 mu M; and n = 1.38, 1.3 2, and 1.24, respectively. We propose that olvanil and GLNVA are nonpu ngent because they activate different subtypes of receptors and/or bec ause of their activation kinetics (compared with capsaicin) are, on av erage, slower than the rate they inhibit action potentials from polymo dal nociceptors.