EFFECTS OF NEW s-TRIAZOLOBENZODIAZEPINE (D-40TA) AND OTHER CENTRAL MUSCLE RELAXANTS ON SPINAL AND SUPRASPINAL REFLEXES IN CATS

Abstract

Abstract-The inhibitory effect of benzodiazepine-type agents such as 8-chloro-6-phenyl-4H-s-triazolo [4, 3a] [1, 4] benzodiazepine (D-40TA), diazepam and nitrazepam on the spinal and supraspinal polysynaptic reflexes was compared with that of mephenesin, methocarbamol, chlorzoxazone and chlormezanone in cats. Benzodiazepines did not depress the spinal and supraspinal polysynaptic reflexes or reflex potentials in the spinal and the gallamine-immobilized cats. In these respects, chlormezanone resembled benzodiazepines.On the other hand, mephenesin, methocarbamol and chlorzoxazone blocked these reflexes in all kinds of preparations such as the anesthetized, the spinal, the decerebrate and the gallamine-immobilized preparations. D-40TA depressed gamma rigidity at the dose below that necessary to depress alpha rigidity. Moreover, it inhibited more profoundly the tonic stretch reflex than the phasic one. Spontaneous and evoked discharges of the muscle spindle in the decerebrate cat were significantly depressed by D-40TA, while those of spinal cat were unaffected. These results suggest that skeletal muscle relaxation by benzodiazepines including D-40TA is attributed to the primary depression of the brain stem reticular system and in turn the ascending inhibitory action via the gamma system on the spinal and supraspinal polysynaptic neurons. It should be stressed that the integrity of the connection between the brain stem and gamma system in the spinal cord and its related muscles is also required for eliciting the depression of supraspinal polysynaptic reflex by these agents. Mephenesin-type agents presumably inhibit directly the interneurons at the spinal and supraspinal levels. Later, the benzodiazepine agents have been found to possess tranquilizing and muscle relaxant properties. The depression of polysynaptic spinal reflexes by diazepam, one of these benzodiazepines, has been proposed to be due to the action principally on the brain stem reticular formation, on the basis of the finding that spinal polysynaptic depression in decerebrate cats is nullified by spinal transection (3).Our current study on the benzodiazepines led to the discovery of a new type of compound, 8-chloro-6-phenyl-4H-s-triazolo [4, 3a] [1, 4]-benzodiazepine (D-40TA) which was highly active in tranquilizing, sedative-hypnotic and muscle relaxant effects in experimental animals (4). In our neuropharmacological study on this agent, the depression of

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

“…were ineffective in postsynaptic inhibition, suggesting a selective action of diazepam on presynaptic inhibition in the spinal cord. This observation was later confirmed by all investigators and extended to other benzodiazepines as well as to other mammalian species (SCHLOSSER and ZAVATSKI, 1969;SCHLOSSER, 1971;STRATTEN and BARNES, 1971;CHANELET and LONCHAMPT, 1971;CHIBA and NAGAWA, 1973;MENETREY et aI., 1973;BLUMet aI., 1973;POLC et aI., 1974;POLC, unpublished observations;CHIN et aI., 1974;BANNA et aI., 1974;HAEFELyet aI., 1975b;MURAYAMA et aI., 1972;MURAYAMA and SUZUKI, 1975;SUZUKI and MURAYAMA, 1976;POLZIN and BARNES, 1976;NICOT et aI., 1976;NAFTCHI and LOWMAN, 1977;NAFTCHI et aI., 1979). It is clear that the spinal cord itself is the primary site of action for this effect of benzodiazepines on presynaptic inhibition, and some authors even believe that enhancement of presynaptic inhibition may be the only direct action ofbenzodiazepines on the spinal cord (STRAT-TEN and BARNES, 1971;CHIBA and NAGAWA, 1973).…”

“…These early findings were confirmed in many laboratories (SCHLOSSER and ZAVAT-SKI, 1969;SCHLOSSER, 1971;STRATTEN and BARNES, 1971;CHANELET and LONCHAMPT, 1971;PIXNER, 1966;NISTRI and CONSTANTI, 1978a, b;CHIBA and NAGAWA, 1973;MENETREY et al, 1973;BLUM et al, 1973;BANNA et al, 1974;MURAYAMA et al, 1972;SUZUKI and MURAYAMA, 1976;NAFTCHI and LOWMAN, 1977;NAFTCHI et aI., 1979;CHIN et aI., 1974;POLC et aI., 1974;NIcoTet aI., 1976;POLZIN and BARNES, 1976). Benzodiazepines seem to enhance presynaptic inhibition without significantly altering its time course, whereas barbiturates prolong presynaptic inhibition and have a moderate effect on the peak intensity of inhibition.…”