Modulation of IA currents by capsaicin in rat trigerninal ganglion neurons

When capsaicin, the pungent compound in hot pepper, is applied to epithelia it produces pain, allodynia, and hyperalgesia. We investigated, using whole cell path clamp, whether some of these responses induced by capsaicin could be a consequence of capsaicin blocking I-A currents, a reduction in which, such as occurs in injury, increases neuronal excitability. In capsaicin-sensitive (CS) rat trigeminal ganglion (TG) neurons, capsaicin inhibited I-A currents in a dose-dependent manner. I-A currents were reduced 49% by 1 muM capsaicin. In capsaicin-insensitive (CIS) rat TG neurons, or small-diameter mouse VR1 -/- neurons, 1 muM capsaicin inhibited I-A currents 9 and 3%, respectively. These data suggest that in CS neurons the vast majority of the capsaicin-induced inhibition of I-A currents occurs as a consequence of the activation of vanilloid receptors. Capsaicin (1 muM) did not alter the I-A conductance-voltage relationship but shifted the inactivation-voltage curve about 15 mV to hyperpolarizing voltages, thereby increasing the number of inactivated I-A channels at the resting potential. I-A currents were relatively unaffected by 1 mM CTP-cAMP or 500 nM phorbol-12, 13-dibuterate (a protein kinase C agonist) but were inhibited by 20-30% with either 1 mM CTP-cGMP or 25 muM N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide HCl (a calcium-calmodulin kinase inhibitor). In the presence of 0.5 muM KT5823, an inhibitor of protein kinase G (PKG) pathways, 1 muM capsaicin inhibited I-A by only 26%. In summary, in CS neurons, capsaicin decreases I-A currents through the activation of vanilloid receptors. That activation, partially through the activation of cGMP-PKG and calmodulin-dependent pathways should result in increased excitability of capsaicin-sensitive nociceptors.