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Cyclobenzaprine reduced segmental evoked monosynaptic potentials to a much greater degree in decerebrate as compared with spinal cats. Post-tetanic potentiated responses were also reduced, but to a lesser degree so that the PTP ratio tended to exhibit a dose-related increase, especially in decerebrate preparations. Tonic vibration reflex responses were evaluated in decerebrate and decerbrate-decerebellate cats. In both preparations, reflex contractions elicited by various frequencies of longitudinal muscle vibration appeared equally sensitive to the action of cyclobenzaprine. Consequently, the slope of the line for change in muscle tension, per Hz increase in frequency of vibration in these preparations, exhibited a similar dose-related reduction after cyclobenzaprine. Reflex contractions elicited by vibration amplitudes ranging from 10 to 100μ peak-to-peak were also equally sensitive to drug action. These findings therefore support the concept that the predominant muscle relaxant action of cyclobenzaprine is at the supraspinal level reducing both γ- and α-motoneurone efferent activity. This action does not appear to involve presynaptic mechanisms. It is further suggested that cyclobenzaprine exerts its pharmacologic action upon reticulospinal rather than on vestibulospinal pathways.

Experiments were performed on decerebrate cats to determine whether CBZ acted as a general depressant to spinal cord neurones or whether the depression was selective to certain groups of neurones. At doses which appreciably affected motoneurone pools, CBZ had no depressant effect on Renshaw or IA inhibition; most spontaneously active neurones in Rexed layers V and VI, and brainstem reticular formation cells were depressed by CBZ. These results indicate that CBZ does not have a general depressant action on spinal cord neurones. Although some direct action on the spinal cord may be present, the major effects are secondary to an apparent action on specific neurones in the brainstem.

The muscle relaxant activity of cyclobenzaprine relative to chlorpromazine and diazepam in several animal models manifesting hypertonic skeletal muscle activity is described. In mice subjected to electrical and chemical induced tonic-extensor seizures, only cyclobenzaprine achieved a protective index greater than unity in all preparations. Cyclobenzaprine also appeared to be highly potent and selective in abolishing local tetanus in rabbits. Relative to the other compounds, cyclobenzaprine was consistently active in γ- and α-decerebrate as well as in ischemic spinal cord rigid cat preparations, at doses which produced no signs of motorincoordination (ataxia) or behavioural depression. Consequently, only cyclobenzaprine exhibited high protective indices and those of greater than unity for all three cat preparations. Furthermore, in contrast with chlorpromazine and diazepam, repeated administration of cyclobenzaprine to ischemic spinal cord rigid cats failed to induce tachyphylaxis. Cyclobenzaprine was also well absorbed orally in mice and cats. These observations suggest that cyclobenzaprine may be useful in the treatment of human pathological conditions manifested by excessive tonic skeletal muscle activity. The potential usefulness of cyclobenzaprine as a pharmacological tool for further studies involving somatic motor systems is also suggested.

The effects of cyclobenzaprine on spinal synaptic transmission were studied in spinal unanesthetized cats. The drug, in cumulative doses up to 20 mg/kg, depressed monosynaptic reflexes evoked by stimulation at 0.2 Hz to a moderate degree. Polysynaptic reflexes were depressed to a similar extent. Monosynaptic reflexes evoked repeatedly at 5 and 10 Hz were depressed even after 5 mg/kg of cyclobenzaprine. Maximum potentiation of monosynaptic responses after tetanization was not affected. Neither direct postsynaptic nor recurrent inhibition was influenced by the drug. Presynaptic inhibition was slightly reduced. It is suggested that direct effects of cyclobenzaprine at the spinal level do not represent the primary site of action responsible for its antispastic activity.

Tissue slices 400 μ thick were taken from the brain stem, at the level of the locus coeruleus, of 150–250 g Sprague-Dawley rats. Microe1ectrodes were placed in the locus coeruleus under visual control, and a cell whose discharge rate would decrease with microiontophoretic application of norepinephrine or clonidine was sought. Cyclobenzaprine (CBZ) was then introduced into the perfusion medium at a concentration equivalent to 1 mg/kg body weight of the whole animal. Discharge rates before and during CBZ administration were compared. The six cells with initial discharge rates between 2 and 10 Hz decreased firing with CBZ, whereas the four cells with initial rates between 0.5 and 1.5 Hz increased their rates with CBZ.

Cyclobenzaprine, a new centrally acting skeletal muscle relaxant, was compared with diazepam as to their effects on several brainstem motor systems. Precollicular decerebrate cats were used to investigate intervestibular, vestibulo-spinal and reticulo-spinal effects. Both cyclobenzaprine and diazepam were without significant effect at less than high doses on the vestibular system as assessed by the monosynaptic response recorded in the median longitudinal fasciculus to vestibular nerve stimulation. The effects on brainstem reticular formation was assessed by the vestibulo-reticulo-spinal, spinal-bulbo-spinal and reticulo-spinal responses. In every case cyclobenzaprine had a strong blocking effect on reticular-produced inhibition of the spinal cord monosynaptic reflex. Diazepam was without effect or enhanced the inhibition. The evidence supports the notion that cyclobenzaprine depresses spinal cord interneurone activity by disfacilitation from a reticulo-spinal pathway.