Complex modulation of the cold receptor TRPM8 by volatile anaesthetics and its role in complications of general anaesthesia.
The 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.
Inserm U1003, Equipe labellisée par la Ligue Nationale Contre le Cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics; Université des Sciences et Technologies de Lille (USTL), Villeneuve d'Ascq, France.
Fabien
F
Vanden Abeele
Artem
A
Kondratskyi
Charlotte
C
Dubois
George
G
Shapovalov
Dimitra
D
Gkika
Jérôme
J
Busserolles
Yaroslav
Y
Shuba
Roman
R
Skryma
Natalia
N
Prevarskaya
D000768:Anesthesia, General / Q000009:adverse effects*; D018685:Anesthetics, Inhalation / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050053:TRPM Cation Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D018685:Anesthetics, Inhalation; D011994:Recombinant Proteins; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human
Anaesthetic; DRG; Dorsal root ganglion neuron; Hypothermia; TRPM8 cold receptor; Trpm8-knockout mice; Volatile general anaesthetics