The role of calcium in capsaicin-induced desensitization in rat cultured dorsal root ganglion neurons.
The effects of capsaicin cytosolic Ca2+ concentration ([Ca2+]i) were measured in individual dorsal root ganglion neurons of the rat in culture. Capsaicin produced a rapid concentration-dependent (EC50 value of 72 nM) increase in [Ca2+]i which was entirely dependent on Ca2+ entry. Exposure of the neurons to a high concentration of capsaicin resulted in desensitization, but only in the presence of external Ca2+. Raising [Ca2+]i with a depolarizing concentration of potassium or the Ca2+ ionophore ionomycin did not reduce the response to a subsequent application of capsaicin. Capsaicin did not induce desensitization in Ca(2+)-free medium even if [Ca2+]i was simultaneously raised with a combination of ionomycin plus carbonyl cyanide m-chlorophenyl-hydrazone. Okadaic acid, a known inhibitor of protein phosphatases 1 and 2A, caused a transient dose-dependent (EC50 value, 100nM) rise in [Ca2+]i, but had no effect on either the responsiveness to capsaicin or capsaicin induced desensitization. The capsaicin antagonist capsazepine blocked the increase in [Ca2+]i evoked by capsaicin and prevented desensitization. These results suggest that desensitization requires the presence of extracellular Ca2+, cannot be mimicked by raising the concentration of [Ca2+]i and may involve Ca2+ entry through activated capsaicin-operated ion channels.
Cholewinski
A
A
Sandoz Institute for Medical Research, London, U.K.
Burgess
G M
GM
Bevan
S
S
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002478:Cells, Cultured; D004361:Drug Tolerance; D004988:Ethers, Cyclic / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D007295:Inositol Phosphates / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D019319:Okadaic Acid; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D004988:Ethers, Cyclic; D007295:Inositol Phosphates; D007473:Ion Channels; D019319:Okadaic Acid; D015759:Ionomycin; D011189:Potassium Chloride; C071423:capsazepine; D002211:Capsaicin; D001920:Bradykinin; D002118:Calcium