Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons

Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to p roduce pain and inflammation. However, repeated exposures of capsaicin will cause desensitization to nociceptive stimuli. In cultured trigeminal gangl ion (TG) neurons, we investigated mechanisms underlying capsaicin-mediated inhibition of action potentials (APs) and modulation of voltage-gated sodiu m channels (VGSCs). Capsaicin (1 muM) inhibited APs and VGSCs only in capsa icin-sensitive neurons. Repeated applications of capsaicin produced depolar izing potentials but failed to evoke APs. The capsaicin-induced inhibition of VGSCs was prevented by preexposing the capsaicin receptor antagonist, ca psazepine (CPZ). The magnitude of the capsaicin-induced inhibition of VGSCs was dose dependent, having a K-1/2 = 0.45 muM. The magnitude of the inhibi tion of VGSCs was proportional to the capsaicin induced current (for -I-CAP < 0.2 nA). Capsaicin inhibited activation of VGSCs without changing the vo ltage dependence of activation or markedly changing channel inactivation an d use-dependent block. To explore the changes leading to this inhibition, i t was found that capsaicin increased cAMP with a K-1/2 = 0.18 <mu>M. At 1 m uM capsaicin, this cAMP generation was inhibited 64% by 10 muM CPZ, suggest ing that activation of capsaicin receptors increased cAMP. The addition of 100 muM CPT-cAMP increased the capsaicin-activated currents but inhibited t he VGSCs in both capsaicin-sensitive and -insensitive neurons. In summary, the inhibitory effects of capsaicin on VGSCs and the generation of APs are mediated by activation of capsaicin receptors. The capsaicin-induced activa tion of second messengers, such as cAMP, play a part in this modulation. Th ese data distinguish two pathways by which neuronal sensitivity can be dimi nished by capsaicin: by modulation of the capsaicin receptor sensitivity, s ince the block of VGSCs is proportional to the magnitude of the capsaicin-e voked currents, and by modulation of VGSCs through second messengers elevat ed by capsaicin receptor activation. These mechanisms are likely to be impo rtant in understanding the analgesic effects of capsaicin.