Modulation ofIACurrents by Capsaicin in Rat Trigeminal Ganglion Neurons

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Abstract
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 IAcurrents, a reduction in which, such as occurs in injury, increases neuronal excitability. In capsaicin-sensitive (CS) rat trigeminal ganglion (TG) neurons, capsaicin inhibited IAcurrents in a dose-dependent manner. IAcurrents were reduced 49% by 1 μM capsaicin. In capsaicin-insensitive (CIS) rat TG neurons, or small-diameter mouse VR1−/− neurons, 1 μM capsaicin inhibited IAcurrents 9 and 3%, respectively. These data suggest that in CS neurons the vast majority of the capsaicin-induced inhibition of IAcurrents occurs as a consequence of the activation of vanilloid receptors. Capsaicin (1 μM) did not alter the IAconductance-voltage relationship but shifted the inactivation-voltage curve about 15 mV to hyperpolarizing voltages, thereby increasing the number of inactivated IAchannels at the resting potential. IAcurrents 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 μM N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide HCl (a calcium-calmodulin kinase inhibitor). In the presence of 0.5 μM KT5823, an inhibitor of protein kinase G (PKG) pathways, 1 μM capsaicin inhibited IAby only 26%. In summary, in CS neurons, capsaicin decreases IAcurrents 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.