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Comparative Study of the Effects of Strychnine and Megimide on the Reflex Activities of Spinal Cord in Rabbit

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Comparative Study of the Effects of Strychnine and Megimide on the Reflex Activities of Spinal Cord in Rabbit COMPARATIVE STUDY OF THE EFFECTS OF STRYCHNINE AND MEGIMIDE ON THE REFLEX ACTIVITIES OF SPINAL CORD IN RABBIT MASAO MORITA, MOTOHIRO YASUHARA, TOSHIKO KIMURA, CHIEKO ITO AND NORIKO KITAO Department of Pharmacology, Kansai Medical School,Hirakata, Osaka Received for publication September 10, 1958 Concerning the mechanism of action of strychnine on the central nervous system, Dusser de Barenne (1) and others have made various reports. Recently Bradley et al. (2) and Eccles (3) observing strychnine suppresses the direct inhibitory action and depresses the polysynaptic inhibition in the spinal cord through electrophysiological studies have expressed a new opinion that this is related to the mode of central excitatory action of strychnine. Morita et al. (4) caught the muscle discharge originating in Golgi's tendon organ. which has been considered to be inhibitory on motoneuron in the spinal cord. Next, Takeuchi (5), one of our colleagues investigated the effects of ether, barbiturate and myanesin on this discharge and other spinal reflex discharges and Kimura (6) that of chlorpromazine on these muscle discharges. We have been able to observe two or three discharges at the same time when the same methods as described in the previous reports were used. Ac cordingly, we have considered it significant to investigate the mechanism of strychnine action on the spinal cord in the electromyography of rabbit's hindlimb. It was found by Shaw et al. (7) that megimide (ƒÀ-ƒÀ-ethyl-methyl glutarimide) has an antagonism towards barbiturates, and Cass (8) comparing megimide with picrotoxin or pentylenetetrazol to its potency of antagonistic action against barbiturates, concluded that megimide is more effective barbiturate antagonist than these analeptics. It has generally been said that such medullary stimulants have different loci of action from that of stry chnine and though strychnine produces predominant responses by the functional changes of neuron in the spinal cord, on the contrary, medullary stimulants have strong action at a higher center than the spinal level. Therefore, the authors studying the comparative effect of strychnine and megimide on spinal reflex activities, have tried to discover the difference in spinal action of these two drugs. METHOD Adult rabbits were used in these experiments whose spinal cord had been transected between Th 12 and L 1 without any anesthetic agents. These spinal rabbits had their skin cut open at fossa poplitea ; peroneal nerve and tibial nerve were exposed and the latter one resected. In all cases, ipsilateral transaction was made on Achilles tendon to relax gastrocnemius and soleus muscle. Animals were put on experimentation three hours after the transection of their spinal cord. Rabbits were fixed on supine position on the metal instrument designed in our laboratory whose photograph was put in Kimura's paper (6). In the nociceptive reflex experiment, electric stimulation• was given to the central end of the ipsilateral, cut tibial nerve to induce twitch of tibialis anterior muscle. In the pro prioceptive reflex experiment, a certain amount of stretch was given to tibialis anterior muscle by bending the ankle joint dorsally. The strength of electrical stimuli was always kept constant with the frequency of 1.5 c/sec. The lead off electrode was coaxial needle type. An insulated Copper wire of 0.1 mm was sealed as active electrode in a 1/3 hypo dermal needle. The tip of wire was left exposed. The electrode was inserted into the tibialis anterior muscle. Thus, obtained action potential of tibialis anterior muscle was observed by GR coupled cathode ray oscillograph and recorded with a magnetic oscillo graph. In this paper, "after-discharge" and "delayed discharge" are being used as well as "evoked discharge" in electromyogram of nociceptively induced reflex twitch. Evoked discharge was considered to develop through excitation of polysynaptic reflex arcs and after discharge through the reverberating neuron circuit in spinal cord and delayed discharge to originate from proprioceptive reflex arcs. In proprioceptively induced reflex discharges in spinal rabbits, larger discharge (hereafter to be abbreviated as "GIb discharge") is of Golgi's tendon organ origin and smaller one (hereafter to be abbreviated as Gla discharge) originates from muscle spindle. Therefore, the effects of central drugs on these nocicep tively or proprioceptively induced discharges may be presumed to correspond to those on some functions of spinal reflex arcs. Strychnine nitrate as well as megimide were given intravenously in all samples. Megimide was used as 0.5 per cent solution in Ringer's solution. RESULTS 1. Effect of Strychnineon the Proprioceptirel y Induced Reflex Discharges Strychnine, in a dose of 0.03 to 0.04 mg/kg given intravenously to spinal rabbit, increased the frequencies and the voltages in both GIb and GIa discharges, in a dose of 0.05 to 0.06 mg/kg gradually decreased GIb discharges and in a dose of more than 0.07 mg/kg eliminated GIb discharges and only GIa discharges remained. When a much larger amount of strychnine is given, the burst of discharges of high voltage may be observed in tibialis anterior muscle (See Fig. 1). On the muscle discharges under strychnine action, we checked the influence in this case when the a Terent nerve impulse is blocked by injection of procaine in the concentration of 2 per cent in Ringer's solution around the tendon of tibialis anterior muscle. After this procedure. we found that when both GIb and (;la discharge-, arc augmenting the GIb discharges was eliminated and ~%-hen(;la discha ge eni obsei,,t'd iindri th( :tt vrhntnr action, procaine did not have any influ ence on the discharge. However, when we apply procaine in the concentration of 2 per cent in Ringer's solution on peroneal nerve, both GIa and GIb discharge were eliminated. It has been found by the authors that proprioceptive reflex dis charges are in general easily affected by procaine and GIb discharges are elimi nated by injection of procaine around the tendon. Then, according to the effects of procaine on the changes in discharges caused by strychnine, it has been clear that the discharges increased by strych nine should be put with GIa and GIb discharges. FIG. 1. Effect of strychnine on proprioceptive reflex discharges from tibialis anterior muscle Next, we investigated the influence of during stretch of ankle joint in spinal rabbit. myanesin on the reflex discharges under A : Control, B : after intravenous injection of 0.03 mg/kg of strychnine, C : after 0.07 the strychnine action. When GIa and mg/kg of strychnine, D : after 0.1 mg/kg of GIb discharge are increasing after stry strychnine, burst of discharges appeared. chnine, 10 to 20 mg/kg of myanesin given Time scale, 60 c/sec. intravenously, depressed these discharges and 50 mg/kg of myanesin suppressed the discharges entirely. When the burst of discharges after strychnine action is observed, 50 mg/kg of myanesin eliminated the burst and yielded the GIa discharge instead of the burst and even 80 mg/kg of myanesin did not eliminate this GIa discharge. But in this situation, by applying procaine in the concentration of 2 per cent in Ringer's solution on peroneal nerve the GIa discharge was easily eliminated. On the central action of myanesin, detailed pharmacological studies have been made by Berger (9), Henneman et al. (10), Kaada (11), King and Unna (12) and it has been found that polysynaptic spinal reflexes are readily inhibited by small doses of myanesin while monosynaptic reflexes are resistant to the acion of the drug, and both supraspinal suppression and facilitation of spinal reflexes are readily abolished . Therefore the burst of discharges after strychnine action may be considered as the different discharges from GIa or GIb discharge, resulting from the excitation of interneurons of the spinal cord . II. Effect of Strychnine on the NociceptivelyInduced Reflex Discharges In most cases the nociceptive reflex discharges in tibialis anterior muscle of spinal rabbit consist of evoked discharges and delayed discharges. When strychnine was given intravenously in the amount of 0.05 mg/kg or more, first the voltage of evoked discharges increases and the duration is prolonged, and then delayed discharges augment . Even in the case on which the delayed discharges were not ob served before the application of the drug, the delayed discharges were newly showen. Increasing the dose up to more than 0.1 mg/kg the after-discharges could be observed (See Fig. 2 A, B). Such after-discharges and delayed discharges pro duced by strychnine were scarcely influenced by ap plication of procaine on the tendon or peroneal nerve. However, when 20 mg/kg of myanesin or 5 mg/kg of pentothal sodium is administered intravenously, though the evoked discharges were not influenced, these after as well as delayed discharges were elimi nated (See Fig. 2 C). Therefore it is considered that after-discharges or delayed discharges which became FIG. 2. Effect of strychnine on nocicep active after strychnine are not caused by the activities tive reflex discharges from tibialis of small motor nerve system but are caused as a result anterior muscle following electrical stimulation of the central end of of activities of the interneuron structure in the spinal ipsilateral, cut tibial nerve in spinal cord which consists of a chain of many interneurons, rabbit and antagonistic action of for they have a strong susceptibility to myanesin or myanesin against strychnine. A : Control, B : after intravenous pentothal sodium. injection of 0.1 mg/kg of strych nine, C : after intravenous injec III. Effect of Megimide on the Proprioceptively tion of 20 mg/kg of Myanesin in B, D : after intravenous injection Induced Reflex Discharges of 50 mg/kg of myanesin in B. Time scale, 60c/sec. Concerning the influence of megimide upon the activity of small motor nerve system, Soderberg (13) has found that the muscle spindle activity is increased by a subconvulsive dose of megimide.
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