In Response: We thank Dr. Morgan for his interest and comments. As he points out, our use of polyhalogenated nonanesthetic alkanes [1] to test for a possible mechanism of anesthesia assumes a common (unitary) mechanism of inhaled anesthetic action. He believes, as does Dr. Eckenhoff [2], that there is more than one site of anesthetic action. As stated in our previous response [3], we agree that there are at least two sites for inhaled anesthetic action: the spinal cord likely modulates movement in response to noxious stimuli during general anesthesia, and the brain is the probable site of anesthetic action for amnesia and unconsciousness. However, different anatomic sites for different anesthetic end-points do not preclude a common mechanism of inhaled action when a single anesthetic end-point is evaluated (e.g., minimum alveolar anesthetic concentration). We have also noted [3] that the testing of a multiple-site theory of anesthesia is overwhelming since the combinations of possible sites of anesthetic action and anesthetic molecules approaches an astronomical value. Dr. Morgan, although believing in multiple sites of action, seems to accept the possibility of a limited number of sites (e.g., two or three). We suggest that even with a limited number of possible sites, the nonanesthetics [1] will be useful tools in defining the molecular and microscopic sites and mechanisms of anesthetic action. For example, if an investigator has a model in which only two sites are thought to be important in the production of the anesthetic end-point, then the nonanesthetics should not produce the same in vitro effects as anesthetics at both of these sites. The title of Dr. Morgan's letter presumably derives from his speculation that the absence of an anesthetic effect by a nonanesthetic might arise from an antagonism of excitatory and inhibitory effects of the compound and result in "behavioral effects [that] tend to cancel out, leaving the agent relatively impotent." However, we note that although several nonanesthetics had convulsant properties [1], some nonanesthetics (e.g., perfluoropropane) have little or no excitatory activity [4]. In addition, for the nonanesthetic convulsant compounds, the consistent finding of no appreciable change in the minimum alveolar anesthetic concentration of agents given concurrently (e.g., desflurane) would seem remarkably fortuitous. That is, it is difficult to imagine a precise balancing of excitatory and inhibitory effects by the diverse compounds that are nonanesthetics. (The nonanesthetics are not limited to alkanes--we have also found alcohols and ethers that are nonanesthetics [unpublished work]). Finally, some volatile compounds that cause convulsions (e.g., flurothyl) have anesthetic properties. Thus, it seems unlikely that the absence of anesthetic properties for these compounds is simply explained by an excitatory effect that "cancels out" an anesthetic effect. We conclude that 1 + 0 = 1. Donald D. Koblin, PhD, MD Edmond I Eger II, MD Department of Anesthesia University of California San Francisco, CA 94143-0464, and Anesthesiology Service (129) Veteran's Administration Hospital San Francisco, CA 94121 Michael J. Halsey, DPhil Nuffield Department of Anaesthetics University of Oxford Oxford, England
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