Behavioral-Pharmacological Studies on the Antagonistic Effect of Physostigmine on Ketamine Anesthesia

Antagonistic effects of physostigmine on ketamine-induced anesthesia and analgesia were studied in male Sprague-Dawley rats using behavioral tests. Rats were divided into six groups. Immediately after loss of the righting reflex following an intraperitoneal injection of ketamine, 75mg/kg, each group of rats was given an intraperitoneal injection of either physostigmine of 0.05, 0.1, 0.2, 0.4, 0.6mg/kg or saline as the control, respectively. Physostigmine 0.1mg/kg caused the greatest antagonistic effect on ketamine anesthesia as indicated by the sleeping time, duration of ataxia and Rota-rod performance. The antagonistic effects of physostigmine were decreased with the increased doses of physostigmine, of more than 0.1mg/kg. On the other hand, physostigmine did not antagonize ketamine analgesia as indicated by the tail-flick latency. Moreover, physostigmine, of more than 0.2mg/kg, prolonged the tail-flick latency. The effects of physostigmine itself on motor function and analgesia were examined using the Rota-rod and tail-flick tests. Physostigmine, of more than 0.2mg/kg, brought about a decline in the Rota-rod performance while it prolonged the tail-flick latency. It is presumed that the higher doses of physostigmine did not cause the antagonistic effect on ketamine anesthesia because of the enhancement in motor-suppressive action and that ketamine-induced analgesia was increased by physostigmine. In order to investigate the antagonistic effect of repeatedly administered physostigmine, the same procedure was once again performed 8 to 10 days after the first experiment. There was no difference in the antagonistic effects of physostigmine on ketamine anesthesia between the first and second experiment, while the tail-flick latency in physostigmine-treated rats was shorter in the second experiment than in the first. Repeated injections of physostigmine alone every 8 to 10 days caused a gradual decrease in the analgesic effect, while the result of the fourth injection was significantly different from that of the first one at the dose of 0.6mg/kg of physostigmine. The motor-suppressive action of physostigmine, 0.6mg/kg, remained unchanged until the fourth injection, when the action declined significantly. It seemes that the sensitivity to physostigmine decreases by the repeated administration. In another group of rats, it was confirmed that central cholinergic agents, oxotremorine, 0.05mg/kg, and 4-aminopyridine, 3mg/kg, also antagonized ketamine anesthesia. Furthermore, the antagonistic action of the central cholinergic agents including physostigmine was suppressed by the central anticholinergic agent, l-hyoscyamine, 0.5mg/kg, pretreated subcutaneously. These results suggest that the antagonistic effect of physostigmine on ketamine anesthesia is due to its central cholinergic action