The Responses of Rat Trigeminal Ganglion Neurons to Capsaicin and Two Nonpungent Vanilloid Receptor Agonists, Olvanil and Glyceryl Nonamide

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Abstract
Capsaicin, the pungent ingredient in hot pepper, activates and subsequently desensitizes a subset of polymodal nociceptors. Because its initial application to skin produces pain, nonpungent analogs such as olvanil and glyceryl nonivamide (GLNVA) were synthesized to enhance its clinical use. To explore how these nonpungent analogs differ from capsaicin, whole-cell patch-clamp recordings were performed on cultured rat trigeminal ganglion neurons.In neurons held at −60 mV, capsaicin, olvanil, and GLNVA were found to activate one or two kinetically distinct inward currents. Two inward currents were also activated when extracellular Ca2+was replaced with Ba2+and also when intracellular chloride was replaced by aspartate. The reversal potentials of the rapidly and slowly activating currents were 15.3 ± 6 and −4.0 ± 2.5 mV, respectively. These data provide strong evidence for subtypes of vanilloid receptors. One difference among these agonists is that, on average, the activation kinetics of the currents evoked by 1 μmolvanil and 30 μmGLNVA are considerably slower than those evoked by 1 μmcapsaicin. Measurements of the peak current,Ip, versus agonist concentration were fit to the Hill equation to yield values of the half maximal concentrations (K1/2), and the Hill coefficients (n). For capsaicin, olvanil, and GLNVA,K1/2= 0.68, 0.59, and 27.0 μm; andn= 1.38, 1.32, and 1.24, respectively.We propose that olvanil and GLNVA are nonpungent because they activate different subtypes of receptors and/or because of their activation kinetics (compared with capsaicin) are, on average, slower than the rate they inhibit action potentials from polymodal nociceptors.