On Transmission of Stimuli in Central Nervous System With Special References to Substance P.

Abstract

Transmission of stimuli in the central nervous system in relation to the peripheral and autonomic nervous systems presents serious difficulties to the research worker trying to solve this highly complicated problem. Because of the very complex nature of the organs condemned owing to their anatomic structure we are preluded from making any simple experiments, such as those regarding the autonomic nervous system, which makes research work in this field most difficult. Hence, the results obtained are as a rule not clear enough to allow of any definite interpretation.

To illustrate the point reference is made to similar experimental methods used a research work about the peripheral nervous system (perfusion of galaiglia, work on axonal fibres and the end-plate, etc.). Any application of such methods to the central nervous system would obviously be impossible. Indeed, we were entirely successful in demonstrating the existence of a complete “order” and the peripheral and anatomic systems as regards the theoretically possible combinations of cholinergic and adrenergic neurons.

Among other methods and techniques used in research work concerned with the central nervous system, attention is drawn to the great value of Horsley-Clarsce apparatus and to the importance of modem biochemical method B, electroencephalography, etc. Novel biochemical methods have produced great results, especially as regards the function of biogenous amines. The latter peripheral amines are also to be found in the central nervous system (Ach, adrenaline, noradrenaline 5 HT, histamine, butyril choliae). This fact, and many others as well, leads to the conclusion that the latter substances are transmitters in the central nervous system and 'in the periphery alike. The extreme diversity and multiplicity of transmission of stimuli in the central nervous system cannot be accounted for by Ach alone. In addition to biogenous amines, due consideration should be given to polypeptides, SP, and Florey’s substance as possible transmitters, and to some other substance as well, including lipo-nucleotides. Such an imposing array- of transmitters makes possible an extremely \Vide range of variations and combinations. The number grows even greater when account is taken of the fact that each substance may have an excitatory and (or inhibitory action. Moreover, there are tracts that break off in places again and again, which makes the number of possible variations grow out of all proportion. In dealing with the central nervous system, this is a supposition that must of necessity be recognised. The substance mentioned above are merely those we are familiar with; there must be some others as well which we have failed to discover.

To deal adequately with each transmitter enumerated above within the limits of a single paper would obviously be impossible; as well instead confine ourselves to a discussion about the present views held on. the position of the polypeptide called Substance P, which has been the object of our special studies lately.

By way of introduction, some general properties of the substance P will need to be reported on (its isolation tin larger quantities as well as from smaller tissues, its physiological and pharmacologic properties, testing and distribution, especially in the Central nervous system).

Substance P is found distributed in large amounts in the basal ganglia and in the formatil reticularis, one region often containing much of it and the next one very little. This fact speaks for its transmitting function. The substance interferes with neither histamine nor adrenaline nor 5 HT. The substance P has been known for over twenty-five years, yet it is only since the publication of the work of Pernov and Lambeck 'in 1953 and that of Zettler in 1956 that we have learnt more about its function. Lembeck was the first to show that the substance is to be found in quantity in the dorsal roots of medulla spinalis, which suggested the possibility of it having a transmitting function in the first sensible neuron. Zettler pointed out that the substance P participates in the Central nervous system as the transmitting substance of certain inhibitory systems. After a series of experiments Zettler succeeded in testing the substance P in its relation to various neurotropic pharmacons. We have been particularly impressed by the great similarity between the properties of mephenesine — an excellent relaxar.t of musculature — and those of the substance P, as demonstrated by Zettler. He found, for instance, that the substance P has a sedative effect, preventing strychnine cramps and prolonging at the same time the evipan narcosis and latency of the onset of picrotoxin spasm, etc.

In order to complete the picture, we decided to carry out experiments with the substance P as done by Zettler with mephesine, and vice versa, experiments with mephesine as done by Zettler with the substance P only. The results went to show that the substance P reduces the intensity of cramps due to tetanus toxin as well as those provoked by W 181. Strychnine and tetanus toxin are known to act in the same way, so the prevention of cramps brought about by W 181 speaks for the synergism of substance P and that of mephenesin'e, if only because of the fact that mephenesine is the only anticonvulsant — according to Berger — that prevents convulsions due to W 181.

In subsequent experiments we were able to show that mephenesine prevents tremor due to harmine and catalepsy provoked by bulbocapnine, in addition to liits removing the analgetic effect due to morphine. Eventually, we carried out experiments that established the fact that SKT 525 A, which prolongs and potentiates the effect of a number of neurotropic pharmaceutical drugs, also prolongs the action of the substance P. IDNH, which is provocative of intense psyho-motor agitation, can also be removed by the substance P. As the Table shows, the results of fourteen various experiments made with mephenesine can also be obtained with the substance P. This fact speaks definitely for the synergism of the substance P and that of mephene sine. Subsequently, we compared the results of these experiments with those obtained with meprobamat, the classic tranquilliser. The latter also showed, in a great majority of cases, synergism with the substance P. Since mephenesine and meprobamat do not remove monosynajptic reflexes, while being able to do so in respect of polysynaptic reflexes, we attempted to draw a parallel in this instance also. The results went to show that the substance P does in fact remove the polysynaptic reflexes (homolateral flexoral and contralateral extensory) provoked in a decerebrated cat, while tit fails to do so when the reflexes are monosynaptic patellar. Likewise, the substance P inhibits the stimulating action of nicotine on polysynaptic reflexes.

In addition to these non-conditioned reflexes we also made experiments with a conditioned reflex on rats (stimulus of current and sound of bell). We found Substance P to have no effect on the conditioned reflex. The results of further experiments on rats — in the so-called “Irrgarten” — showed that the substance P has no appreciable influence, as a stimulant, upon nervous activity of the animals. At the same time, the substance P was found to stop vomiting, in pigeons, provoked by digitalis. This is of interest because area potstrema contains large quantities of Substance P, and the area is known to be the so-called receptor zone of the vomiting reflex. We failed to establish the existence of synergism of Substance P and mephesine only on the peripheral-afferent impulse of a hare’s ear, as shown by Lambeck in respect of the substance P. However, we did find the substance P to remove the rotatory mystagmus of the mouse, which is known to be the effect of mephesine also. Some authors were reported to have tried to test concentrations of Substance P by administration of various pharmaceutical drugs known to have an exciting or sedative effect on the Central nervous system. The results so far have been contradictory in parts, allowing of no general conclusions. For this reason, we effected stimulation of a nerve organ .in a different way, it was shown that in a darkened eye of a cow there occurs a gathering together of the substance P. This ds most interesting when related to Krlvoya’s finding that LSD has an inhibitory effect upon a ferment that acts destructively on the substance P. On the other- hand, Pfeffler is of the opinion that LSD only acts peripherally over the eye since it does not cause hallucinations in the blind.

In actual fact, all these effects are to be accounted for by the action of the substance P in the central nervous system, for we were able to show an increase in the level of the substance P in the brain of rats after intraperitoneal injection of larger doses.

Present position of Substance P and its physiology and pharmacology has thus been reviewed. The findings of Lambeck and Zettler stand confirmed. In all probability the substance P is the transmitter substance in the Central nervous system. In the main it has a rousing effect on inhibitory mechanisms. This corresponds with the findings of Perov and Euler to the effect that Substance P administered intracysterally provokes inhibition of spontaneity. A great number of experiments go to show that there is synerghm between Substance P, mephesine and meprobamat; consequently, that we are concerned with a physiological tranquilliser. Hence, the question arises what effects, if any, might the substance have on the course of mental diseases. The question is all the more interesting as mephesine has been found to produce an excellent sedative effect on hares, and also because of the hypothesis that Substance P might be the substance responsible for secretion of ACTH — knowing as we do that an accumulation of ACTH in hvpothalamus produces inhibition of the sensation of tear. It was Berger who divided tranquillisers in two major groups a) autonomic suppressors — derivatives of chlorpromazine, diphenylmethane and reserpine, and b) central relaxants — derivatives of propanediol, i. e. meprobamat and memhesine. Berger arranged them in itabular form showing their points of difference. We have added a third column to the Table introducing the substance P; the result, once more, was a complete analogy, i. e. the substance P and the Central relaxant are synergists.

It is by no means easy to formulate a definite opinion about the substance P. Further experiments and tests — more especially those with the substance purified and by methods more advanced and up-to-date, and on humans as well — are likely to results in additional data and more Information. AH that can be said with any certainty so far if that the substance P is a neurotropic agent which an all probability may be regarded as a physiological tranquilliser.