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The Journal of Neurophysiology Vol. 85 No. 2 February 2001, pp. 745-758
Copyright ©2001 by the American Physiological Society
Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina 27710
Liu, L.,
M. Oortgiesen,
L. Li, and
S. A. Simon.
Capsaicin Inhibits Activation of Voltage-Gated Sodium
Currents in Capsaicin-Sensitive Trigeminal Ganglion Neurons. J. Neurophysiol. 85: 745-758, 2001. 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 µM) 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
K1/2 = 0.45 µM. The magnitude of the
inhibition of VGSCs was proportional to the capsaicin induced current
(for -ICAP < 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
K1/2 = 0.18 µM. At 1 µM capsaicin, this cAMP generation was inhibited 64% by10 µM CPZ, suggesting that
activation of capsaicin receptors increased cAMP. The addition of 100 µM 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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