Inhibition

INHIBITION, a weakening or cessation of the external effect of excitation during the continued action of a stimulus, which is not identical to a return to rest. Examples: stimulation of the vagus nerve causes a weakening, slowing, and stoppage of heartbeats, despite the presence of automatic impulses causing heart activity. At a high frequency of stimuli applied to a motor nerve, the muscle relaxes, even though the agent causing excitation is present (see Pessimum). When a strong external stimulus is added to a conditioned stimulus, the conditioned reflex decreases and disappears despite the presence of the impulses that caused its appearance. In all these examples, the excitation effect of various tissues drops sharply. Before us is not a return to rest, but an active "bridging" of working activity, a reduction in the effect of the acting stimulus. Most authors studying this subject agree with such a characterization of inhibition as a reduction of the excitation effect distinct from rest. Views on the essence of inhibition are contradictory, and it is possible that various cases described under the name of inhibition are not identical in their mechanism. Inhibition appears to be a process just as universal as excitation and can therefore occur in all tissues and organs. Inhibition (as well as excitation) acquires its greatest development and significance in tissues with high excitability—first of all in nervous, then in muscular, and probably already to a lesser extent in glandular tissue. In the processes of normal vital activity, the most important role indisputably belongs to inhibition processes arising in the central nervous system, because they regulate the course of excitations in working apparatuses-effectors. However, it is more convenient to begin familiarization with the phenomena of inhibition with a description of its development in other tissues. Inhibition processes in the cardiovascular system. A typical case of inhibition, which first became known in physiology, is the effect of impulses from the vagus nerve on the heart (E. Weber, 1845). Upon stimulation of the vagus nerve, the heart weakens and slows its activity, reaching diastolic arrest with stronger stimulation. Upon cessation of stimulation, normal heartbeats are restored almost immediately. The inhibitory effect on the heart is exerted by excitation of the vagus nerve, which according to all modern data is qualitatively indistinguishable from excitation in other nervous apparatuses. The transmission of heart-inhibiting impulses along the vagus nerve is accompanied by the regular appearance in it of action currents, those characteristic signs of excitation (Einthoven, Fischer, Verzár). The constant appearance of these excitatory impulses in the unsectioned vagus nerve at the end of each systole has been registered by diverting action currents from the vagus nerves under normal conditions of vital activity. This is due to the fact that the nuclei of the vagus nerve in the medulla oblongata are in a state of constant, greater or lesser strong, as they say, tonic excitation. The heart thus constantly remains under the bridled influence of the vagus nerve, which is proven by the sharp acceleration of heartbeats after section of the vagus nerve or paralysis of its endings by atropine. Thanks to the constant excitation of the "center" of the vagus nerve, the heart is constantly under the influence of inhibiting impulses moderating its work. An increase in heart work (e.g., during muscular work and a number of other states) is achieved primarily by a decrease in the excitation of the vagus nerve, i.e., by a decrease in its inhibitory action. To this is added the enhancing and accelerating influence of sympathetic excitation. Regarding inhibition within the vascular apparatus, nothing definite can be said, because it is difficult to say with certainty whether the decrease in vasomotors' excitation causing vasodilation is the result of inhibition in the corresponding vasomotor centers. Such a viewpoint is not excluded, but has not been proven. It is also unknown whether the inability of dilated (during work, hyperthermia) vessels to react with constriction to the excitation of depressor nerves from the branching site of the carotid arteries (Rein) can be regarded as inhibition. Inhibition in the organs of the digestive tract is represented primarily by the inhibitory influence of the splanchnic nerve on intestinal peristalsis (Pflüger). Here the effect of the sympathetic and parasympathetic systems is the reverse of their effect on the heart; the vagus nerve enhances, while the sympathetic nerve inhibits intestinal movements. The sympathetic nerve exerts the same tonic inhibitory influence on intestinal movements as the vagus nerve on the heart. Pavlov also described the inhibitory influence of the vagus nerve on the secretion of the stomach and especially the pancreas, attributed to the action of special inhibitory fibers running in the same trunk with secretion-stimulating fibers. This view cannot yet be considered definitively established, since it is possible that the decrease, and especially the slow development of secretion of the aforementioned juices upon stimulation of the vagus nerve, is associated not with the inhibition of secretion, but with the narrowing of the gland ducts or a vasoconstrictor action. In the urogenital system, the inhibitory influence of the erigent nerves on the tonic contraction of the urinary bladder sphincter has been described. In connection with the obscurity of the question of kidney innervation (outside of vascular effects), the question of the inhibition of renal activity must be considered open. The same applies to sweat glands, the liver, and the bile ducts. In the cases described so far (heart, intestine), the inhibitory influence is attributed by most authors to the effect on effector activity of special inhibitory nerve fibers, the excitation of which must always cause inhibition of the innervated apparatus. Another case is represented by phenomena of inhibition in skeletal muscle upon a sharp increase or enhancement of excitatory impulses applied to the motor nerve (see Pessimum). Here the assumption that the decrease in contraction upon an increase in stimulation frequency is associated with the excitation of special inhibitory nerve fibers is completely improbable. It must therefore be recognized that the development of externally opposite effects (excitation or inhibition) is determined in this case by the different frequency of exciting impulses and the state of the reacting apparatus (in some cases inhibition develops at relatively lower, in others at higher stimulation frequencies). The phenomena of the pessimum—inhibition developing within the muscle itself (probably in the nerve ending plate)—have enormous theoretical significance (see Parabiosis), but hardly occur in processes of normal vital activity, in which relaxation of excited musculature is achieved not as a result of inhibition developing in the muscle, but due to the inhibition of corresponding apparatuses of the central nervous system. The entire coordination of motor acts is based on the fact that simultaneously with excitation (contraction) of certain muscles, inhibition (relaxation) develops in other antagonistic muscles. The antagonism and synergism of various muscle groups is not something always constant; muscles that are antagonistic in one type of movement turn out to be synergists in another. However, in the vast overwhelming majority of cases of coordinated movement, it is accomplished through the dynamic distribution of excitation and inhibition in various muscle groups. A typical example is the ipsilateral relaxation of extensors upon contraction of flexors and relaxation of flexors upon contraction of extensors described by Sherrington; on the opposite limb, the reverse occurs: relaxation of extensors upon contraction of flexors of the other leg. For example, if the flexor (semitendinosus muscle) contracts on one leg, then this same muscle relaxes on the other side and the quadriceps muscle on the flexing leg. Excitation of the flexion innervation of one limb inhibits weak tonic excitation both in the ipsilateral extension apparatus and in the flexion apparatus of the opposite side. This regular inhibition of some central apparatuses upon excitation of others (antagonistic) was named reciprocal (conjugated) inhibition by Sherrington. Reciprocal inhibition is not limited to the central innervation of the limbs. The same relations are observed in the antagonistic muscles of the eyeball; they are noted further between inspiratory and expiratory musculature (Hering-Breuer reflexes) and are also shown in the field of autonomic innervation, where, for example, excitation in the central apparatuses of the vagus nerve reduces tonic excitation in the heart-stimulating sympathetic system (Brücke). This proposition can, however, be broadened without restricting it exclusively to the relationships of antagonistic reflexes, and by saying that the excitation of a certain center tends to induce inhibition in other functionally (and perhaps anatomically) connected apparatuses. This may manifest either in the above-described relaxation of the antagonistic muscle or in a drop in the excitability of the corresponding center and in the complete inhibition of one reflex act upon the execution of another (e.g., inhibition of the scratching reflex during flexion), as well as upon the application of certain afferent stimuli.

This includes, for example, the inhibition of pendulum-like movements of the limb of a spinal animal when squeezing the tail (Sherrington), the inhibition of the effects of irritation of the motor zone of the cerebral cortex during the act of defecation or swallowing (Ukhtomsky; compare dominant); the drop in excitability to temperature irritations when applying painful ones (Gellhorn and Northup). Such "induction" of inhibition in some apparatuses during the excitation of others, also covering cases of reciprocal inhibition, was named by Sherrington negative induction. The latter was also described by Pavlov in the cerebral cortex in the form of the inhibition of certain nervous apparatuses during the development of excitation in neighboring ones. Thanks to the mechanism of negative induction, excitation is limited to the place of its origin, without irradiating through the entire mass of the central nervous apparatus. To these same phenomena belongs Pavlov's "external" inhibition, i.e., the decrease or disappearance of a conditioned reflex upon exposure to an extraneous stimulus. It should be noted that, depending on as-yet-unclarified regularities, the mechanism of negative induction is often not observed. In this case, irradiation of excitation is also noted. This takes place, for example, in strychnine poisoning, in a sharp increase in the excitability of the spinal cord as a result of prolonged irritation of sensory nerves (see Asterios), in the initial execution of complex motor acts in the absence of trainability, generally in unreinforced conditioned reflexes and in that constitutional or acquired state of the brain which Pavlov characterizes as the weakness of the inhibitory process (in a number of cases this state yields to therapeutic action of bromine). All cases where excitation "irresistibly" spreads through the cerebral mass can be recognized as defective for the organism, reflecting either functional insufficiency of the central nervous system or being the result of pathologically strong influences. It is completely indisputable that in human activity as well, a certain regularity in the distribution of both excitation and inhibition is an obligatory condition for the soundness of his activity. Here we also note Sechenov's idea that the processes of consciousness are necessarily connected with the restraint, inhibition of corresponding motor and other reactions. For more details on the significance of inhibition in conditioned reflex activity, as well as on the participation of inhibition in the mechanism of sleep, see Conditioned reflexes, Sleep. Along with the dynamic change of excitation and T. in the same central apparatuses in the central nervous system, special centers of inhibition have repeatedly been described. The idea of them belonged to Sechenov, who in general first discovered central inhibition (1863) and showed that irritation of the thalami optici in a frog with a microcrystal of common salt sharply lengthens the time of the flexion reflex of the hind legs upon chemical irritation of the skin (according to the data of the Orbeli-Tonkikh laboratory, Sechenov inhibition is due to impulses transmitted to the spinal cord via the sympathetic system, which regulates the excitability and state of the spinal cord; Sechenov inhibition can also be observed during transection of the spinal cord and is not observed after transection of the sympathetic rami communicantes). The question of the presence of inhibition centers still does not leave the pages of physiological periodicals, having not yet received its resolution. It is indisputable, apparently, that the excitation of certain parts of the central nervous system (especially in the region of the diencephalon) extremely easily leads to the inhibition of a number of locomotor and other acts. Whether this is the result of the excitation of "centers" of inhibition or a particularly sharp manifestation of the same mechanisms of negative induction has not yet been clarified. It has been shown, for example, that brain transection anterior to the red nuclei leads to an extreme increase in extensor tone. Whether this is due to the exclusion of apparatuses that constantly inhibit tone, or is caused, conversely, by the traumatic excitation of the red nuclei and other centers, has not yet been established. Neither has the correctness of Goldstein's hypothesis, which views the cerebellum as an organ of innervation inhibition of extensors, been proven. But in any case, the fact is that the removal or damage of the cortex, and especially of certain parts of the diencephalon, often entails an exorbitant excitation of the animal. Close examples are also described by neurology. It can therefore be asserted that the activity of the cerebral cortex and the diencephalon (and perhaps also the midbrain) regulates the distribution of inhibition and enhances it in lower-lying parts. When discussing the problem of inhibition in centers, it must always be remembered that the conditions for its occurrence are determined not only by the innate properties of certain apparatuses, but also by the state of the central nervous system, depending on the entire state of the organism. It has been shown, for example, that the activity of the vegetative nervous system sharply changes the conditions for the occurrence of inhibition in centers. The same applies to the action of hormones. However, since the internal mechanism of inhibition has not been completely elucidated, and the interactions of various parts of the central nervous system have been elucidated very little, we are only very rarely in a position to predict under what exact state of the nervous centers a state of inhibition will develop in them, what significance it will have, and what its final result will be in the integral manifestation of nervous activity. Turning to theoretical attempts to explain the phenomena of inhibition, it should be pointed out that its internal nature is even less studied than the phenomena of excitation. Theories of inhibition can be artificially divided into two groups: theories that consider inhibition as some derivative of the state of excitation, and theories that consider it as a completely special process. The first theories, which necessarily connect inhibition processes with the refractory phase mechanism, include the parabiosis theory (see), the nutritive concept, and the decrement theory. The nutritive theory of inhibition sees in inhibition the result of a sharp increase in dissimilation caused by excitation. In this case, some (Hering, Gaskell, Verworn, initially Beritov with us, partly Pavlov, Folbort) see in inhibition a manifestation of enhanced compensatory assimilation, a kind of protective reaction of living tissue, while others (Verworn's later variant), conversely, consider inhibition to be a manifestation of the exhaustion of the energy potentials of tissues. In the first variant, the processes of dissimilation and assimilation are inevitably separated in time, which contradicts modern biochemical data. In addition, it is completely unclear why enhanced assimilation is connected with inexcitability. The second variant is based on the unproven assumption that each bout of excitation entails the complete destruction of the tissue's dynamogenic resources. At the same time, one must logically and inevitably appeal to the so-called "all-or-none" law (see), since only upon its recognition can the refractory phase, the manifestation of the lengthening of which inhibition is then considered to be, be considered an expression of dissimilation. The decrement theory (Lucas, Adrian, Brücke) attributes the occurrence of inhibition to the tissue's increased resistance during the refractory phase in relation to exciting impulses. This theory, which gives a logically consistent interpretation of the phenomena of inhibition, suffers from the fact that it introduces a completely artificial notion of decrement as a resistance analogous to the weakening of the strength of a nerve impulse in an altered section of a nerve. In the centers, changing resistances are attributed from this point of view to the synapse—a hypothetical membrane between neurons, the resistance of which determines the passage of excitation. The factual side of this theory has been strongly criticized in Kato's work in relation to the nerve fiber and Samoilov, who showed that the duration of inhibition in the centers greatly exceeds the duration of the refractory phase. Acknowledging that a number of (but perhaps not all) cases of inhibition are connected with the refractory phase mechanism, we must say that until its nature is clarified, the nature of these cases of inhibition cannot be clarified. The key to the problem here undoubtedly lies in the study of the chemistry and physical chemistry of nervous activity. Other theories of inhibition consider it as an expression of a special process, not connected with excitation, always and invariably caused by the activity of certain nerve fibers or the action of specific "inhibition substances." After Loewi showed that substances are formed in the heart during vagal stimulation that cause the arrest of another, even atropinized heart, all these theories began to consider inhibition as the result of the action of special chemical substances (for the case of the vagus nerve, very likely close to acetylcholine). For inhibition carried out by the vegetative nerves, such a theory is very probable with the reservation that the specificity of the inhibitory influence is by no means proven. Physiology has proven with numerous examples that the same substance, depending on the concentration and the state of the reacting substrate, can have a directly opposite effect. It is therefore quite probable that "inhibitory" substances can also have an excitatory effect, although practically they may not manifest it, since they usually reach an "inhibitory" concentration.

Let us also point out that during vagal stimulation the chronaxie (see) of the heart is clearly lowered (Frederik, Brücke; cf. the opposite data of Orbeli's school), probably precisely as a result of the accumulation of the "vagal substance" (Vagusstoff) of Loewi, produced by the endings of the vagus nerve. If we assume that the automatic impulses arising in the heart as a result of this turn out to be excessively strong, we have before us a typical example of parabiosis. The question of the formation of "inhibitory" substances in nerve centers has not yet gone beyond the bounds of a hypothesis (Sherrington, Samoylov). Experimental proofs of their formation have not been provided. Theoretically, one can repeat here what has just been said about the action of the vagus nerve on the heart, emphasizing that here, in view of the variability of the appearance of inhibition, the inhibitory or excitatory effect of these "substances" is unquestionably determined by the state of the nerve tissue. We note also that, according to Kato, as well as Mathews, inhibition in the centers of the spinal cord is caused by the excitation of specific inhibitory nerves. The proofs of this proposition still seem to us insufficient. Here it must also be pointed out that, according to Lapicque, the presence of inhibition is determined by a change in the ratio of the chronaxies of the apparatuses conducting excitation. The factual side of this proposition, however, is disputed, and it by no means explains the genesis of inhibition, since it does not answer the question of the cause of this shift between chronaxies. Finally, let us emphasize the incorrectness of identifying inhibition and fatigue, since the concept of fatigue encompasses only the final result of the most diverse shifts, among which a disorder of inhibition is frequently observed. From what has been said, it is evident that at the present time there is no theory of inhibition that satisfactorily and unquestionably encompasses all its cases. This is understandable, since the processes of inhibition are the most "intimate," specific activity of excitable tissues, and a complete solution of this question would signify a complete solution of all questions of general physiology. It is undoubtedly for this reason that the investigation of the nature of the inhibition process, increasingly clarifying its nature, will continually pose new questions related to the characterization of vital phenomena in the broadest sense of the word.