Why cooling is beneficial: non-linear temperature-dependency of stimulated iCGRP release from isolated rat skin.
The capsaicin receptor in nociceptive neurons is a target for the sensitizing actions of algogenic inflammatory mediators. Capsaicin and potential endogenous ligands are thought not to gate this heat-activated ion channel but to sensitize it so profoundly that even room temperature can open it. We investigated the temperature dependency of capsaicin-induced CGRP release from nociceptive nerve fibers in isolated rat skin over a range of ambient temperatures using different agonist concentrations (10(-7)-10(-5)M) and KCl (60 mM) for control. Ambient temperature (4-40 degrees C) showed no significant influence on the basal iCGRP outflow. The supramaximal capsaicin concentration of 10(-6)M as a stimulus evoked a response that was not significantly diminished by temperatures decreasing from 40 to 24 degrees C but lost 65% of its amplitude between 24 and 14 degrees C (Q(10) approximately 6.7). Such a collapse of the response occurred between 40 and 32 degrees C at lower capsaicin concentration (10(-7)M). The concentration-response curves showed a rightward shift upon cooling from 40 to 24 degrees C and a major loss of slope and maximum effect at 14 degrees C which formally describes a noncompetitive antagonism. KCl-induced iCGRP release showed a much more linear temperature dependency (Q(10) approximately 2.4 between 24 and 14 degrees C). Significant capsaicin responses even at 8 degrees C suggest a contribution of noxious-cold sensitive neurons known to coexpress CGRP and the capsaicin receptor. The heat-activated ion channels (TRPV1-4) are thought to play a significant role in inflammatory pain which is effectively relieved by cooling. The present results contribute to understanding this phenomenon.
Institut für Physiologie und Experimentelle Pathophysiologie, Universität Erlangen-Nürnberg, Universitätsstr.17, D-91054 Erlangen, Germany.
Tatjana I
TI
Kichko
Peter W
PW
Reeh
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012881:Skin Temperature / Q000187:drug effects / Q000502:physiology; D018709:Statistics, Nonparametric; D013697:Thermosensing / Q000502:physiology*
D011189:Potassium Chloride; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin