Effects of TRPV1 receptor antagonists on stimulated iCGRP release from isolated skin of rats and TRPV1 mutant mice.
Capsaicin antagonists including ruthenium red, capsazepine and iodo-resiniferatoxin (I-RTX) have recently been shown to inhibit the activation by noxious heat of the capsaicin receptor (TRPV1) expressed in non-neuronal host cells, and natively, in cultured dorsal root ganglion cells. Noxious heat has been shown to release immunoreactive calcitonin gene-related peptide (iCGRP) from the isolated rat skin. In this model, ruthenium red, I-RTX as well as capsazepine 10 microM caused no alteration in iCGRP release at 32 degrees C by themselves whereas capsazepine 100 microM doubled it reversibly. In wild-type mice 100 microM capsazepine also stimulated iCGRP release while it was without effect in TRPV1 knockout littermates. In the rat skin, both ruthenium red and capsazepine (10/100 microM) reduced and abolished, respectively, capsaicin-induced iCGRP release while I-RTX (1/10 microM) was ineffective. Only ruthenium red 100 microM showed an unspecific effect inhibiting iCGRP release induced by KCl. Ruthenium red and capsazepine (10/100 microM) caused no significant alteration of iCGRP release induced by heat stimulation at 47 degrees C. Employing 45 degrees C stimulation intensity, capsazepine and I-RTX (in the higher concentrations) showed a significant facilitatory effect on the heat response suggesting a partial agonistic action of the compounds. It is concluded that noxious heat-induced iCGRP release in the isolated rat skin occurs through a mechanism that is not inhibited by TRPV1 antagonism reflecting a different pharmacological profile of noxious heat transduction in terminals of sensory neurons compared to that in cultured cell bodies and TRPV1-transfected host cells.
Pethö
Gábor
G
Institute of Physiology and Experimental Pathophysiology, University Erlangen/Nürnberg, Universitaetsstr. 17, D-91054 Erlangen, Germany.
Izydorczyk
Iwona
I
Reeh
Peter W
PW
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006358:Hot Temperature / Q000009:adverse effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000294:innervation* / Q000503:physiopathology
D004224:Diterpenes; D011955:Receptors, Drug; C468130:iodoresiniferatoxin; D012430:Ruthenium Red; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin