Modulation of I _A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons

Abstract

Liu, L., and S. A. Simon. Modulation of I A currents by capsaicin in rat trigeminal ganglion neurons. J Neurophysiol 89: 1387-1401, 2003; 10.1152/jn.00210.2002. 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 M capsaicin. In capsaicin-insensitive (CIS) rat TG neurons, or smalldiameter mouse VR1Ϫ/Ϫ neurons, 1 M 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 M) 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 M N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide HCl (a calcium-calmodulin kinase inhibitor). In the presence of 0.5 M KT5823, an inhibitor of protein kinase G (PKG) pathways, 1 M 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.

Regulation of the Benzamil-Insensitive Salt Taste Receptor by Intracellular Ca2+, Protein Kinase C, and Calcineurin

“…In addition, all rinse and stimulating solutions were supplemented with 0.01 M CaCl 2 (Table 2) . RTX-chorda tympani dose-response profiles were obtained before and after topical lingual application of KN-93, a specific blocker of CaMK II (Liu and Simon 2003) or specific inhibitors of PP2B (cyclosporin A or FK-506) (Klee et al 1998;Pearce et al 2008). As a control for KN-93, we used the kinaseinactive analog KN-92 (Table 2).…”

Nicotine Inhibits Voltage-Dependent Sodium Channels and Sensitizes Vanilloid Receptors

“…All animal protocols were approved by the Duke University Institutional Animal Care and Use Committee. The methods for culturing TG neurons from adult Sprague-Dawley rats have been described previously (Liu and Simon 2003). Trigeminal ganglia were dissected and collected in modified Hank's balanced salt solution (mHBSS).…”

Voltage-Gated Ion Channels in Nociceptors: Modulation by cGMP

“…Throughout the experiments we used 0.1 and 1 mM CPT-cGMP because at these concentrations, this membrane-permeable cGMP analogue has been shown to decrease I A currents (Liu and Simon 2003) and affect voltage-gated sodium currents (Renganathan et al 2002).…”

“…I A currents were obtained from the total outward current using TEACl to block I K ; I K was obtained from the total outward current using 4-aminopyridine (4-AP) to block I A currents (Liu and Simon 2003). The I A and I K current-voltage relation was determined using a voltage step protocol in which the cells were depolarized for 250 ms from a holding potential of -80 to test potentials varying between -70 and ϩ60 mV in 10-mV increments.…”

“…Capsaicin-sensitive neurons are a common type of nociceptor that contains tetrodotoxinresistant (TTX-R) sodium channels (Kim et al 1999;Liu et al 2001), which contribute to the rising phase of the action potential and are important in the pathological states relating to hyperalgesia and allodynia (Kim et al 1999;Liu et al 2001). Capsaicin-sensitive neurons also possess transient (I A ) and delayed (I K ) potassium channels, which regulate action potential activity (Liu and Simon 2003). Consequently, we examined the extent to which CPT-cGMP altered each of these three types of ion channels.…”