1. Whole cell patch-clamp records from cultured rat trigeminal ganglion cells having soma diameters ranging from 20 to 50 microM revealed that capsaicin activated two inward currents and an outward current. At -60 mV, the inward currents could be distinguished by their different peak times, which were 4.2 +/- 3.1 and 41.4 +/- 16.4 (SD) s. 2. Cells with the smallest soma diameters had the largest current densities. 3. The more rapidly activating current had a linear current-voltage relation and a reversal potential near 0 mV. 4. The more slowly activating current is not a Ca(2+)-activated Cl- current. 5. The peak of the rapid current (Ip)-capsaicin concentration (C) relationship was characterized by Ip/Ipmax = [1 + (C/Kd)n]-1, where n = 1.2 and the dissociation constant (Kd) = 0.68 microM. 6. The rapidly activating current was heterogeneous in regards to both its rate of activation and extent of desensitization. In cells bathed in buffer containing calcium and held at -60 mV, most of the capsaicin-activated currents desensitized. Removal of extracellular Ca2+ could reduce, eliminate, or have no effect on desensitization. 7. At positive holding potentials the currents very slowly desensitized, even in the presence of Ca2+. 8. Repeated 30-s applications of 1 microM capsaicin separated by 0.5, 2.5, and 5.5 min all induced tachyphylaxis. Tachyphylaxis decreased exponentially until the current remained approximately constant. Decreasing the time between capsaicin applications increased the extent of tachyphylaxis, whereas elimination of extracellular Ca2+ markedly reduced tachyphylaxis.
Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to produce pain and inflammation. However, repeated exposures of capsaicin will cause desensitization to nociceptive stimuli. In cultured trigeminal ganglion (TG) neurons, we investigated mechanisms underlying capsaicin-mediated inhibition of action potentials (APs) and modulation of voltage-gated sodium channels (VGSCs). Capsaicin (1 microM) inhibited APs and VGSCs only in capsaicin-sensitive neurons. Repeated applications of capsaicin produced depolarizing potentials but failed to evoke APs. The capsaicin-induced inhibition of VGSCs was prevented by preexposing the capsaicin receptor antagonist, capsazepine (CPZ). The magnitude of the capsaicin-induced inhibition of VGSCs was dose dependent, having a K(1/2) = 0.45 microM. The magnitude of the inhibition of VGSCs was proportional to the capsaicin induced current (for -I(CAP) < 0.2 nA). Capsaicin inhibited activation of VGSCs without changing the voltage dependence of activation or markedly changing channel inactivation and use-dependent block. To explore the changes leading to this inhibition, it was found that capsaicin increased cAMP with a K(1/2) = 0.18 microM. At 1 microM capsaicin, this cAMP generation was inhibited 64% by10 microM CPZ, suggesting that activation of capsaicin receptors increased cAMP. The addition of 100 microM CPT-cAMP increased the capsaicin-activated currents but inhibited the 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 activation of second messengers, such as cAMP, play a part in this modulation. These data distinguish two pathways by which neuronal sensitivity can be diminished by capsaicin: by modulation of the capsaicin receptor sensitivity, since the block of VGSCs is proportional to the magnitude of the capsaicin-evoked currents, and by modulation of VGSCs through second messengers elevated by capsaicin receptor activation. These mechanisms are likely to be important in understanding the analgesic effects of capsaicin.
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