General anesthetics activate a nociceptive ion channel to enhance pain and inflammation.
General anesthetics (GAs) have transformed surgery through their actions to depress the central nervous system and blunt the perception of surgical insults. Counterintuitively, many of these agents activate peripheral nociceptive neurons. However, the underlying mechanisms and significance of these effects have not been explored. Here, we show that clinical concentrations of noxious i.v. and inhalation GAs excite sensory neurons by selectively activating TRPA1, a key ion channel in the pain pathway. Further, these GAs induce pain-related responses in mice that are abolished in TRPA1-null animals. Significantly, TRPA1-dependent neurogenic inflammation is greater in mice anesthetized with pungent compared with nonpungent anesthetics. Thus, our results show that TRPA1 is essential for sensing noxious GAs. The pronociceptive effects of GAs combined with surgical tissue damage could lead to a paradoxical increase in postoperative pain and inflammation.
Departments of Pharmacology and Physiology and Biophysics, Georgetown University, 3900 Reservoir Road, NW, Washington, DC 20007, USA.
José A
JA
Matta
Paul M
PM
Cornett
Rosa L
RL
Miyares
Ken
K
Abe
Niaz
N
Sahibzada
Gerard P
GP
Ahern
D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D017487:Ankyrins; D015220:Calcium Channels / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D007530:Isoflurane / Q000494:pharmacology*; D051379:Mice; D010146:Pain / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
D018681:Anesthetics, General; D017487:Ankyrins; D015220:Calcium Channels; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat; C498947:Trpm8 protein, rat; C493922:Trpv1 protein, rat; D007530:Isoflurane