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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.

Vibration (150 μ × 300 Hz) of the gastrocnemius-soleus muscle was used to elicit a reflex muscle contraction (tonic vibration reflex) which was facilitated or inhibited by electrical stimulation of various areas within the central nervous system. The results obtained support previous suggestions that the principal site of action of cyclobenzaprine as a skeletal muscle relaxant agent is upon neurons of the brain stem reticular formation. Vestibular nerve and medial reticular formation-elicited responses were more sensitive to the action of cyclobenzaprine than those induced through activation of Deiters' vestibular nucleus or its spinal projection through the lateral reticular formation. Least sensitive to the action of cyclobenzaprine were responses elicited through activation of these pathways at the level of the spinal cord. It may be noted that vestibular nerve afferents as well as vestibular nuclei project to the medial reticular formation including reticulospinal neurons within the nucleus pontis oralis and caudalis. Further, stereotaxic coordinates for electrical stimulation of the medial reticular formation impinged upon these pontine nuclei. This would suggest that in the present study the muscle relaxant action of cyclobenzaprine resulted from its suppression of these latter pontine reticulospinal pathways.

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.