Letter to the Editor: In Response
We thank Drs. Gillman and Lichtigfeld for their interest in our report . The first report on the effects of nitrous oxide (N2 O) on the dopaminergic system was Hynes and Berkowitz  in 1983, which was followed by Dorris and Troung . These studies did not deal with psychotropic actions but with locomotor activity enhanced by N2 O. In February 1994, we first found an activation of dopaminergic cells by measuring dopamine metabolites and related it to the psychotropic and emetic actions of N2 O . Further, we observed a short-term attenuation (acute tolerance) of the central nervous system actions of N2 O, and the determination of its mechanism was one of our primary purposes. Unfortunately, Hynes and Berkowitz  and Dorris and Troung  observed the drug effects only for 60 min and did not confirm whether the drug action attenuated after that. The activation of dopaminergic cells in our study decreased in 2-4 h in parallel with the electroencephalographic slowing, activation of the brainstem reticular cells, suppression of the somatosensory evoked response, suppression of drug-and electrical stimulation-induced convulsions, and recovery of consciousness during anesthesia in humans and/or laboratory animals. The analgesia was the only drug action that did not attenuate. Our hypothesis was this time supported by an abstract by Lichtigfeld and Gillman in May 1994 . The above letter is an extrapolated assumption from the findings in locomotor and dopaminergic cell activities . The basis of extrapolation from the locomotor system to the psychological functions has not been provided. With regard to the opioid receptor-N2 O interaction, Berkowitz et al., in 1976 and 1977, first demonstrated the opioid-like action of N2 O [5,6]. Since then, numerous reports have appeared, and the generally agreed view, at present, is that the N2 O analgesia is never fully antagonized by opioid antagonists and that it involves other unidentified actions . Gillman and Lichtigfeld postulate an activation of the mu- and kappa-opioid receptor subtypes as the basis for the absence of addiction to N2 O. This postulate is based on the hypothesis by Spanagel et al.  that mu-subtype activation enhances dopaminergic cell activity and kappa-subtype activation suppresses it. We regret, however, that we cannot understand how such differential actions of N2 O explain the absence of addiction to N2 O and the attenuation of dopaminergic cell activation observed by us during constant inhalation. Further, no evidence has ever been provided to indicate that the N2 O-induced dopaminergic activation is induced through its opioid-like action. The mu-, kappa-, and delta-subtypes of rat opioid receptor have already been cloned in our laboratory [9-11], and the direct interaction of N2 O with these receptor subtypes will be clarified soon. Gillman and Lichtigfeld oppose our statement that N2 O was abused in social settings. It is a historical fact that N2 O was inhaled as a joy, and we simply described it as abuse but not addiction.
Kenjiro Mori, MD, FRCA
Takehiko Adachi, MD
Masahiro Murakawa, MD
Shin-ichi Nakao, MD
Koh Shingu, MD
Norimasa Seo, MD
Department of Anesthesia, Kyoto University Hospital, Kyoto 606, Japan
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