Complex modulation of the cold receptor TRPM8 by volatile anaesthetics and its role in complications of general anaesthesia

Abstract

SummaryThe mechanisms by which volatile general anaesthetics (VAs) produce a depression of central nervous system are beginning to be better understood, but little is known about a number of side effects. Here, we show that the cold receptor transient receptor potential melastatin 8 (TRPM8) undergoes a complex modulation by clinical concentrations of VAs in dorsal root ganglion neurons and HEK-293 cells heterologously expressing TRPM8. VAs produced a transient enhancement of TRPM8 through a depolarizing shift of its activation towards physiological membrane potentials, followed by a sustained TRPM8 inhibition. The stimulatory action of VAs engaged molecular determinants distinct from those used by the TRPM8 agonist. Transient TRPM8 activation by VAs could explain side effects such as inhibition of respiratory drive, shivering and the cooling sensation during the beginning of anaesthesia, whereas the second phase of VA action, that associated with sustained TRPM8 inhibition, might be responsible for hypothermia. Consistent with this, both hypothermia and the inhibition of respiratory drive induced by VAs are partially abolished in Trpm8-knockout animals. Thus, we propose TRPM8 as a new clinical target for diminishing common and serious complications of general anaesthesia.

The Pore Loop Domain of TRPV1 Is Required for Its Activation by the Volatile Anesthetics Chloroform and Isoflurane

“…However, the cold-activated channel TRPM8 was activated by chloroform (9.4 mM), in line with previous reports that TRPM8 activity is modulated by VGAs (Fig. 4D) (McKemy et al, 2002;Peier et al, 2002;Vanden Abeele et al, 2013). Furthermore, TRPM8 was activated in a dose-dependent manner by chloroform with an EC 50 of 7.95 mM (Supplemental Fig.…”

TRPV1 variants impair intracellular Ca2+ signaling and may confer susceptibility to malignant hyperthermia

“…24–27 However, how this channel is activated by diverse physical and chemical stimuli remains largely unknown. Recently, we demonstrated that anesthetic produces a depolarizing shift in the voltage dependence of the TRPM8 channel activation, 28 which might underlie its agonistic action mechanism. Our results suggest that TRPV1 shares a similar behavior, because VA exposure also produces a depolarizing shift in the voltage dependence of TRPV1.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Conversely, TRPM8 antagonists might provide symptomatic relief by reducing mucus secretion. Of note, TRPM8 appears to mediate the respiratory depressive action of some volatile anesthetics (Vanden Abeele et al, 2013) and TRPM7 seems to be involved in the proliferation of human lung fibroblasts in response to TGFb 1 .…”