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Opioid Effects of Psychotropic Analgesic Nitrous Oxide on the Dopaminergic System

Gillman, M. A. BDS, DSc; Lichtigfeld, F. J. MBBch, BSc, FF(Psych)

Letter to the Editor

South African Brain Research Institute, Waverley 2090, Johannesburg, South Africa.

To the Editor:

The work by Murakawa et al. [1] gives further support for the actions of nitrous oxide on influencing dopamine (DA) activity [2]. Opioids can also influence mesolimbic DA, with mu-receptor activation and kappa attenuation of DA release in the nucleus accumbens (NA) [3]. Compelling evidence has accumulated that psychotropic analgesic nitrous oxide (PAN) is the first gaseous member of the opioid family [4,5]. These facts have been used to propose that PAN is able to modulate the mesolimbic DA system through its agonistic activity at mu and kappa receptors [6]. Murakawa et al. [1] give some further evidence for these two opposing opioid effects of PAN on DA. In both the hippocampus and cerebellum, their data show a more rapid swing from stimulation to attenuation of DA release in less than 2 h after exposure, while in the midbrain this biphasic effect is only seen after 4 h [1]. Unfortunately, they did not specifically measure DA levels in the DA, which is the site believed to be directly involved in addictive processes [3]. It would seem that PAN has the unique property among opioids to modulate DA levels in the NA in opposite directions by activating both mu and kappa receptors [6]. It would seem that PAN has similar actions in other brain areas [1]. This bidirectional modulation would explain the insignificant addictive potential of PAN despite the fact that medical professionals may misuse it mainly during their student years [4]. Based on evidence presented elsewhere [4], we take issue with Murakawa et al. [1] when they state that the gas "has been abused in social settings." Although these authors [1] suggest that nausea and vomiting, as well as the psychotropic effects of the gas, are mediated by DA, a more comprehensive explanation is that PAN acts through both its opioid and dopaminergic effects.

M. A. Gillman, BDS, DSc

F. J. Lichtigfeld, MBBch, BSc, FF(Psych)

South African Brain Research Institute, Waverley 2090, Johannesburg, South Africa

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1. Murakawa M, Adachi T, Nakao S-i, et al. Activation of the cortical and medullary dopaminergic systems by nitrous oxide in rats: a possible neurochemical basis for psychotropic effects and postanesthetic nausea and vomiting. Anesth Analg 1994;78:376-81.
2. Dorris RL, Troung VI. Locomotor effects of nitrous oxide in mice: requirement of newly-synthesized and main intraneural storage pools of dopamine. J Pharm Pharmacol 1993;45:315-6.
3. Spanagel R, Herz A, Shippenberg TS. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 1992;89:2046-50.
4. Gillman MA. Nitrous oxide abuse in perspective. Clin Neuropharmacol 1992;15:297-306.
5. Gillman MA, Lichtigfeld FJ. Pharmacology of psychotropic analgesic nitrous oxide as a multipotent opioid agonist. Int J Neurosci 1994;76:5-12.
6. Lichtigfeld FJ, Gillman MA. Role of dopamine mesolimbic system in opioid action of psychotropic analgesic nitrous oxide (PAN) in alcohol and drug withdrawal [abstract]. Neuropsychopharmacology 1994;10 Suppl 2:72S.
© 1995 International Anesthesia Research Society