Modulation of IA currents by capsaicin in rat trigeminal ganglion neurons.
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 microM capsaicin. In capsaicin-insensitive (CIS) rat TG neurons, or small-diameter mouse VR1-/- neurons, 1 microM 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 microM) 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 microM N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide HCl (a calcium-calmodulin kinase inhibitor). In the presence of 0.5 microM KT5823, an inhibitor of protein kinase G (PKG) pathways, 1 microM 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.
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Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA. lieju@neuro.duke.edu
Simon
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D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D002227:Carbazoles; D002273:Carcinogens / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003570:Cytidine Triphosphate / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000235:genetics* / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000166:cytology / Q000502:physiology*; D000096926:Benzenesulfonamides
D000470:Alkaloids; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002147:Calmodulin; D002211:Capsaicin; D002227:Carbazoles; D002273:Carcinogens; D000242:Cyclic AMP; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D003570:Cytidine Triphosphate; D004791:Enzyme Inhibitors; D007211:Indoles; D015240:Phorbol 12,13-Dibutyrate; D011188:Potassium; D024642:Potassium Channels, Voltage-Gated; D011955:Receptors, Drug; D013449:Sulfonamides; C073601:KT 5823; C072105:KN 93; D000096926:Benzenesulfonamides