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ORGANOCHLORINE INSECTICIDES AND GENERAL ANESTHETICS: A COMPARISON OF THEIR NEURAL EFFECTS FRANKS. LABELLA* Introduction The chlorinated hydrocarbon insecticides of the DDT (dichlorodiphenyltrichloroethane ) group or the cyclodienes (aldrin, dieldrin , chlordane, heptachlor) promote hyperstimulation of the insect nervous system which can progress to lethality. Fundamental and universal neuronal cellular processes may be affected by these agents, since toxicity induced in higher animals, including man, is characterized, similarly, by hyperexcitability. These insecticides appear to share a number of pharmacological properties with many general anesthetics. These similarities will be reviewed in support of the proposal that the relationship between neuroexcitant organochlorinated insecticides and their depressant analogues is similar to that between the convulsant analogs of general anesthetics and the (depressant) general anesthetics. Potencies ofNeural Actions Are Related to Lipid Solubility Nerve blocking and general anesthetic potencies of a large number of compounds of widely varying structures are highly correlated with lipid solubility of the drugs [I]. Since first described by Overton and Meyer 80 years ago, the "lipoid hypothesis of narcosis" has been repeatedly confirmed as one of the most striking correlations in pharmacology. Anesthetic potency and lipid solubility may vary 10,000-fold or more. The depth of general anesthesia is clearly related to the tissue (and presumably neuronal cell membrane) concentration of the anesthetic. Support by the Medical Research Council (MRC) of Canada and the Manitoba Heart Foundation. ?Career investigator of the MRC, professor, Department of Pharmacology and Therapeutics , Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W3.© 1981 by The University of Chicago. 003 1-5982/81/2403-0231$01.00 Perspectives in Biology and Medicine ¦ Spring 1981 447 The organochlorine insecticides are extremely lipophilic; DDT, the prototype of this class ofcompound, has an oil/water partition coefficient of about 106. Seeman [1] had shown a correlation between lipid solubility of various compounds and protection afforded to red blood cells by these agents against hemolysis. In accordance with that correlation, O'Brien and Hilton [2] showed that DDT and related compounds were more potent than the anesthetic drugs in protection against hemolysis. Perturbation ofLigand Binding in Brain Tissue We found, in accordance with observations on nerve block/anesthesia, that octanol was among the most potent agents, by several orders of magnitude, to perturb the in vitro binding to brain of several ligands [3]. The concentration ofoctanol to inhibit specific binding of3H-ouabain by 50 percent was about 1 mM. In unpublished work we found the IC50 for DDT on binding of 3H-naloxone to be about 0.1 mM and for a reportedly noninsecticidal metabolite, DDE, about 10 times greater. Thus, binding-site perturbation potency of the organochlorinated compounds, like that of anesthetics, appears to be correlated with lipophilicity. In other unpublished studies a distinction between the two classes of compounds was observed in the effect of sodium on binding perturbation. Neural Effects Are Dose Related and Reversible The reversibility and dose-related effects of nerve block (local anesthesia ) and general anesthesia are well-established pharmacological phenomena. Also, Dale, Gaines, and Hayes [4] showed convincingly that the degree of central excitation produced in rats was related to the brain concentration of DDT. Tremors developed at 50 ppm DDT in brain lipid, convulsions at 500 ppm, and death at 700 ppm. Reversibility of DDT neurotoxicity was evidenced in recovery of the animals as the brain levels in the chemical diminished. Furthermore, DDT-induced neurotoxicity in insects, can be relieved and induced alternately and repeatedly by raising and lowering the environmental temperature [5]. Neuropharmacological Effects Are the Summation ofExcitatory and Depressant Actions Detailed examination of central nervous system actions of any given general anesthetic agent exposes a complex pattern of excitatory and inhibitory effects on neuronal activity [6-8]. This pattern varies from one anesthetic to another. A major component of the actions of some anesthetic agents is depression of excitatory synapses, and, for other 448 Frank S. LaBeIIa ¦ Insecticides and General Anesthetics agents, facilitation of inhibitory synapses [6]. Concentrations of pentobarbital , ether, methoxyflurane, trichloreoethylene and the steroid, alphaxalone, that depressed synaptic transmission in the prepiriform cortex also depressed the sensitivity of neurons to glutamate; halothane also diminished synaptic transmission but had no effect on sensitivity to glutamate...


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