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.

Modeling the effects of anesthesia on the electroencephalogram

Changes to the electroencephalogram (EEG) observed during general anesthesia are modeled with a physiological mean field theory of electrocortical activity. To this end a parametrization of the postsynaptic impulse response is introduced which takes into account pharmacological effects of anesthetic agents on neuronal ligand-gated ionic channels. Parameter sets for this improved theory are then identified which respect known anatomical constraints and predict mean firing rates and power spectra typically encountered in human subjects. Through parallelized simulations of the eight nonlinear, two-dimensional partial differential equations on a grid representing an entire human cortex, it is demonstrated that linear approximations are sufficient for the prediction of a range of quantitative EEG variables. More than 70 000 plausible parameter sets are finally selected and subjected to a simulated induction with the stereotypical inhaled general anesthetic isoflurane. Thereby 86 parameter sets are identified that exhibit a strong “biphasic” rise in total power, a feature often observed in experiments. A sensitivity study suggests that this “biphasic” behavior is distinguishable even at low agent concentrations. Finally, our results are briefly compared with previous work by other groups and an outlook on future fits to experimental data is provided.