Pungent general anesthetics activate transient receptor potential-A1 to produce hyperalgesia and neurogenic bronchoconstriction.
BACKGROUND
Volatile anesthetics such as isoflurane and halothane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anesthesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of peripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways.


METHODS
To test the hypothesis that irritant inhaled anesthetics activate the excitatory ion-channel transient receptor potential (TRP)-A1 and thereby contribute to hyperalgesia and irritant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our functional experiments, we used models of isolated guinea pig bronchi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice.


RESULTS
Irritant inhaled anesthetics activate TRPA1 expressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonirritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction.


CONCLUSIONS
General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting.
Eilers
Helge
H
Department of Anesthesia, University of California, San Francisco, California 94143-0427, USA. eilersh@anesthesia.ucsf.edu
Cattaruzza
Fiore
F
Nassini
Romina
R
Materazzi
Serena
S
Andre
Eunice
E
Chu
Catherine
C
Cottrell
Graeme S
GS
Schumacher
Mark
M
Geppetti
Pierangelo
P
Bunnett
Nigel W
NW
D018681:Anesthetics, General / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism / Q000502:physiology*
D018681:Anesthetics, General; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse