Respiratory and cardiovascular depressant effects of nabilone, N-methyllevonantradol and delta 9-tetrahydrocannabinol in anesthetized cats

Abstract

Drug effects were examined in cats anesthetized with a mixture of pentobarbital and barbital injected i.p. Respiratory observations were analyzed according to effects produced on 1) chemoregulatory responsiveness determined by changes in tidal volume resulting from CO2 inhalation or measured during isocapnic stabilization, and on 2) mechanoreflex control of respiratory frequency through the vagus nerves. Blood pressure and heart rate were recorded concomitantly. Cardiovascular effects were manifested as dose-related hypotension and bradycardia that were generally response-limited by contrast with the respiratory depressant effects which progressed ultimately to failure. Relative potency of the three agents to produce an elevation of 4% in resting alveolar CO2 fraction was 100 times for N-methyllevonantradol and 10 times for nabilone by comparison with delta 9-tetrahydrocannabinol. Marked slowing of respiratory frequency occurred in vagotomized as well as in nerve-intact cats. Apneustic respiration was not observed in any case. It is concluded that the effects of the cannabinoids resulted from 1) an upward shift in CO2 setpoint of the central chemorespiratory "detector"; 2) decreased gain of the CO2-tidal volume "controller"; 3) depression of the respiratory "oscillator" in the lower medulla; 4) depression of the vasomotor center; and 5) a central vagotonic action in addition to a direct cardiodecelerator action on the heart.