Why cooling is beneficial: non-linear temperature-dependency of stimulated iCGRP release from isolated rat skin

Abstract

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 °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 °C but lost 65% of its amplitude between 24 and 14 °C (Q 10∼6.7). Such a collapse of the response occurred between 40 and 32 °C at lower capsaicin concentration (10 −7 M). The concentration-response curves showed a rightward shift upon cooling from 40 to 24 °C and a major loss of slope and maximum effect at 14 °C which formally describes a noncompetitive antagonism. KCl-induced iCGRP release showed a much more linear temperature dependency (Q 10∼2.4 between 24 and 14 °C). Significant capsaicin responses even at 8 °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.