Principles of General Physiology

It is unnecessary to state that an actual destructive process is not spoken of as an inhibition. The possibility of return to the normal state, capable of again entering into a condition of excitation, is essential. In some cases, however, it may happen that a vicious circle is established, so that the normal state does not return, as we shall see later. As a general statement it may be taken that the processes at the basis of inhibition are of an opposite kind to those at the basis of excitation, so that the explanation of the one is involved in that of the other. If there is an increase of permeability in excitation, a decrease is to be expected in inhibition, for example. It will be found, however, that the definite knowledge we possess of the nature of the inhibitory process is still more defective than that of the excitatory process, so that all facts bearing on the question are of value.

Upper curve— volume of the tongue, obtained by a plethysmograph, so that a fall means decrease of volume, due to constriction of arterioles allowing a smaller amount of blood to be present ; and vice versa when the curve rises. Lower curve — general arterial pressure, showing that the changes in the tongue are not due to changes in the pressure at which the blood is supplied to it. Upper of the two lines— signal, marking at the first rise, stimulation of the peripheral end of the cervical sympathetic nerve, which supplies vasoconstrictor fibres ; at its second rise, that of the peripheral end of the lingual nerve, which contains the vaso-dilator fibres.

view of the kind of facts to be explained, some experimental cases will be useful. They will also serve to indicate the different kinds of inhibition to which reference was made above. Smooth Muscle. — We have already seen how the intestine shows a series of rhythmic contractions, superposed on a background of moderate tonic contraction, and how these contractions and tone can be reduced by the splanchnic nerves and increased by the vagus nerves (see Figs. 96 and 97, page 369). Since the excitation of the spontaneous contractions proceeds from the muscle itself, the action of the inhibiting and exciting nerves is exercised on the muscle cells directly. In other cases, as the muscular coat of the arterioles, there is no evidence that the plexus of nerve fibres supplying the contractile cells contains nerve cells (see Fig. 109), so that the state of tonic contraction

is clearly inherent in the muscle itself. It can be increased by nerves called vaso- The fall in the curve is produced by lengthening of the muscle, brought about by stimulation of the pelvic nerve, which inhibits the spontaneous tonic state. The rise is contraction, due to stimulation of the pudic nerve, which increases the degree of the tonic contraction. constrictor, or diminished by those called vaso-dilator. Fig. 110 shows the fact in the case of the tongue. Stimulation of the sympathetic nerve causes contraction of the small arteries and therefore decrease of the volume of blood in the organ ; that of the lingual nerve, which contains the vaso dilator fibres, causes increase of volume. We have already met with another instance in the salivary glands.

The muscle called " retractor pen is," present in certain animals, is a strip of smooth muscle arising from the anterior caudal vertebrae and inserted into the glans penis. It forms a very convenient object for the investigation of the properties of smooth muscle. Fig. Ill is a tracing obtained in some work (hitherto unpublished) in which Starling and myself were engaged. It is .seen that the initial state of the muscle is one of moderate tonic contraction, since it can be relaxed by the stimulation of the pelvic autonomic nerves, and it can also be increased by stimulation of fibres contained in the pudic nerves.

Another instructive case is that of the \a,rge. pincers of the Crayfish. There is FlO. 112. IXXERVATION OF THE CLAW MUSCLES OF THE CRAYFISH, ACCOKDIXli TO TIIK WORK OF RICHET, BIEDERMAXX, MANGOLD, ETC. — The two kinds of nerve fibres divide simultaneously and the terminal fibrils are distributed, one or more of each kind, to the same muscle fibre, passing inside the sarcolemma to end in the muscle substance. here a powerful muscle closing the forceps, and a similar one opening it (see the figure in Huxley's book, 1880, p. 93). It is clear that, if the strong closing muscle remained in a state of contraction, the weaker opening muscle would be powerless. Accordingly, it is found that, if the nerve trunk supplying the appendage be excited in such a way that the forceps is caused to open, the closing muscle is inhibited, along with the contraction of the opening muscle, and, when the forceps closes, an opposite effect on the two muscles takes place. Richet (1882) showed that a weak direct stimulation of the claw caused opening, and a strong one caused closing, while Biedermann (1887, 1) showed that a weak stimulation of the nerve caused a contraction of the opening muscle, coincidently with inhibition of tone in the closing muscle, and that a strong stimulation had the opposite effect on both. The explanation of these facts seems to lie either in the existence of four sets of fibres in the nerve trunk, exciting for the closing muscle, inhibiting for the opening muscle, exciting for the latter, and inhibiting for the former ; or two sets of fibres, each of which divides into two branches, one branch inhibiting the one muscle, while the other branch excites the antagonist muscle. The fibres causing contraction of the closing muscle and inhibition of the opening

one require a stronger current from the induction coil than the other set do, possibly due to their excitable substances having a different optimal rate of stimulation. It is a very suggestive fact that, as was shown by Biedermann at a later date (1887, 2), the fine branching nerve fibres in the muscles are always double, a slender fibre accompanying a thicker one, even to their endings in the muscle FIG. 113. ACTION OF THE VAGUS NERVE ON THE BEATS OF THE A'ENTRICLE OF THE TORTOISE.

Upper figure — On stimulation, marked by the signal, the beats cease, after a latent period, with a decrease of diastolic tone (the tracing lever pulls downwards). The effect lasts considerably longer than the stimulation, and is followed by an increase in the magnitude of the beats. The latent period is better shown in the lower figure, where the times of stimulation are marked by white rectangles on the heart tracing itself. fibres. The same muscle fibre is supplied by a fine and a coarse fibre, and it is difficult to avoid the conclusion that one of these is excitatory, the other inhibitory, for the muscle cell. Fig. 112 is a diagram of the facts as made out by Biedermann and by Mangold (1905), who also investigated the question and found this plan of innervation to be a very general one in the Arthropods. It will be seen presently that the fact has an important bearing on the theory of inhibition.

The arrangement by which the bivalve molluscs open and close their shells was investigated by Pavlov (1885), who found that the powerful adductor muscle is supplied with two sets of nerves, exciting and inhibiting. The natural state of the muscle appears to be one of tonic contraction, which can be reduced by certain nerve fibres. It then remains in this state until a stimulation of the exciting nerve fibres sets it into contraction again. Further details with regard to these tonus phenomena will be found in Chapter XVIII. It is important to note that, as Pavlov points out (pp. 28 and 29), there are no nerve cells in the muscle itself, so that the two kinds of influence must be exercised on the muscle cells directly. In view of later theories of receptive substances, it may be added that Pavlov states that there must be special parts in the interior of the muscle fibres on which the contraction depends, and others on which the relaxation depends.

The Heart. — In Fig. 113 tracings are given of the stoppage of the heart of the tortoise by stimulation of the vagus nerve. It will be noted that, in addition to cessation of the spontaneous beats, the state of tone in diastole is reduced. In Fig. 114 a curve of the action of the opposite kind of nerves, the accelerator or augmentor nerves, from the sympathetic system, is shown. More detailed analysis of the nervous regulation of the heart will be found in Chapter XXIII.

It was remarked above/ that it is to be supposed that the phenomena asso- FIG. 114. ACTION OF THE SYMPATHETIC NERVE (AUGMENTOR) ON THE HEART OF THE TOAD. — Suspension method. Clamp in auriculoventricular groove. Sympathetic stimulated before it joins the vagus. ciated with inhibition will naturally be of an opposite kind to those associated with excitation. In this connection, the observations made by Gaskell (1887) are of much interest. We have seen that the wave of excitation in muscle is accompanied by electrical negativity of the spot actually in the state of excitation. Now Gaskell showed how a preparation can be made of the auricle of the tortoise in such a way that spontaneous beats cease for a time, owing to separation from the place where these beats arise in the sinus, while the supply of inhibitory fibres is left intact in a nerve (the coronary), which is separate from the other tissues, and can be left when they are cut. We have also seen that if one electrode is situated on an injured spot, we obtain only the electrical change taking place at the other electrode on a normal spot. When the auricle contracts, then, there is a movement of the galvanometer needle in a direction indicating negativity of the auricular muscle under an electrode on a normal spot, when the other electrode is on an injured spot. Now, suppose that we excite the vagus nerve while the auricle is in a state of rest after separation from the sinus. Gaskell saw that the muscle becomes electro-positive ; the galvanometer needle moved in the opposite direction to that associated with contraction (Fig. 115). It might, perhaps, be supposed that the explanation of this change is merely that the auricle, although showing no rhythmic beats, was in a state of slight tonic contraction, which would, of course, be associated with a permanent negative deflection of the galvanometer. If the vagus caused a disappearance of this tonus, the

tissue would naturally become less negative, that is, it would appear to become electro-positive. It is of some importance, therefore, to note that Gaskell was unable to detect the slightest change in tonus, although using a very sensitive lever to magnify any possible movement. It is evident that inhibitory action is accompanied by some kind of change, which is of the opposite nature to that which is responsible for the negativity of a tissue in the state of excitation.

With regard to some doubts that have been expressed as to these results, I should like to state chat I have myself on two separate occasions shown the fact %,s a lecture experiment and have obtained the electro-positive change without difficulty. It should be borne in mind that the magnitude of the change is much less than that of the negative change occurring on contraction, so that observers who have attempted to observe it with the capillary electrometer have been unable to do so. Recently, however, both Meek and Eyster (1912) and Samoilov (1913) have photographed it by aid of the string galvanometer, made especially sensitive. The advantage of the use of this instrument is that the positive effect can be seen in the beating heart, both of the frog and of the tortoise (see Fig. 116).

Gaskell has also shown that, after the heart of the tortoise has been brought to a standstill by the application of the alkaloid muscarine to the sinus, stimulation of the vagus nerve produces the same change as that recorded above ; moreover, stimulation of the augmentor nerves of the toad, which in the beating heart causes increase in the rate or height of the contractions of the ventricle, produces in the ventricle of the heart at rest under the action of muscarine or otherwise, an electrical change of the same sign as that associated with contraction of the muscle (Fig. 117).

ON THE CURVE. — At the arrow, muscarin was applied to the sinus to arrest its contractions. This has no effect on the subsequent stimulation of the vagus. Note that the electrical change is opposite in sign to that associated with contraction, and also to that produced by the augmentor nerve in quiescent muscle (see Fig. 117 below). to the response to direct stimulation. M'William showed (1885, 1) that the sinus, auricles and ventricle of the newt's heart are inexcitable under vagus inhibition,

Although this phenomenon could not be demonstrated in other animals, it shows that the action of inhibitory nerves is excited on the muscle itself. The work of Dorothy Dale and G. R. Mines (1913) shows that the action of the vagus on the heart, as investigated by the string galvanometer, is to produce increased resistance to transmission from auricle to ventricle and to shorten the duration of the electrical disturbance. That of the accelerator nerves is to improve the rate of conduction and to increase the duration of the electrical response in the ventricle.

Since the effects of the excitatory and inhibitory nerves on smooth muscle are of an opposite nature, it is to be expected that the effect of one could be balanced by the simultaneous stimulation of the other. Experiments of this kind were made by llrid Hunt (1H97), who found that the result on the heart beat of simultaneous stimulation of the vagus and accelerator nerves was nil or minimal, if the effects when separately stimulated were equal and opposite. If the stimulation of the one was interpolated in the middle of that of the other, the rate of the beat was brought back towards that of the normal. In other words, the nerves are purely antagonistic and " the statement that a minimal stimulation of the one can completely overcome a maximal stimulation of the other is undoubtedly incorrect."

On the other hand, the experiments of von Frey (1876) are sometimes quoted in support of the opposite view. These experiments showed that, on maximal stimulation of chorda tympani and sympathetic nerves at the same time, the rate of blood flow througli the submaxillary gland was slowed, showing that the constrictor effect overpowered the dilator one. When the stimulation ceased, the dilator effect of the chorda tympani showed itself to last longer than the constrictor effect of the sympathetic. By appropriate choice of the relative strength of the stimulation of the two nerves, Asher (1909) showed, however, that the effect of either dilator or constrictor nerves can be made to preponderate. Anrep and Cybulski

FIG. 116. POSITIVE VARIATION OF THE DEMARCATION CURRENT OF THE FROG'S VENTRICLE IN CONSEQUENCE OF STIMULATION OF THE VAGUS. One electrode leads off from an injured sjx>t. String galvanometer. Upper tracing— the monophasic electrical changes. The tops are too high to be included on the plate. Below it — reference line. Lower tracing — spontaneous heart beats, recorded by a lever. On stimulation of the vagus, marked by the signal, there is a gradual fall in the diastolic level of the galvanometeil ine ; that is, there is an electrical effect in the opposite direction to that associad <l with contraction. After this effect has passed off, there is a temporary rise in the level of the diastolic position of the string. Note that the diastolic position of the lever marking the beats shows no alteration during the course of the vagus inhibition.

(1884) found it easy to make either effect show itself in the case of the tongue. It is to be noted that von Frey's experiments were made to test a particular hypothesis, that of interference in ganglion cells, and the results are not in disagreement with the view of the supply of the same individual muscle fibre by two separate nerve fibres of opposite action. Secretion. — If the view taken in our chapter on Secretion be correct, namely, that, up to a certain stage, this process is an automatic one on the part of the cell mechanisms, there is some reason to suppose that there might be nerves inhibiting the process. In the case of the pancreas we have met with some evidence, brought forward by Pavlov and his co-workers, that the vagus nerve contains inhibitory fibres for this gland. One way in which this influence can be seen is the following : suppose that we have, by repeated periods of stimulation of the vagus, obtained a flow of juice; this flow outlasts the actual period of stimulation, and, if the stimulation be applied to the vagus afresh before the effect of the preceding stimulation has ceased, it will be seen that the first effect is a cessation of the flow, which is afterwards followed by an increase. The reader may remember that this is very similar to the phenomenon seen in the action of the same nerve on the

movements of the intestine, so that it is not unnatural to imagine that the effect on the pancreas might be due to the relaxation and contraction of muscular fibres in the ducts. That this is the explanation is shown by the experiments of von Anrep, described on page 349 above. Jappelli (1908) states that, if an attempt is made to produce reflex salivary secretion by exciting the central end of the lingual nerve, no effect is produced as long as the stimulation lasts, but that the secretion appears subsequently. If secretion is in progress when the nerve is excited, a temporary cessation occurs. Before we can accept these results as evidence of inhibitory fibres, experiments on the blood flow through the gland must be made under the conditions of the experiment. It is practically certain that reflex vaso-constriction was produced in the gland by stimulation of the sensory nerve and the failure of blood supply would be quite sufficient to account for the results. Reference was made previously (page 349) to the " anabolic " nerves supposed to supply the gland cells ; the function of these fibres is supposed to be to excite the building-up process in these cells. According to the theory proposed by Gaskell, to be discussed presently, anabolic nerves are inhibitory. When the chorda tympani is cut, these tonic inhibitory impulses are removed and we have "paralytic secre- ,tion." The basis of this theory will be found not to be a very solid one.

Nerve Centres. — We come now to a very important region in which inhibitory processes play as fundamental a part as those of excitation. A few examples will be given here, and the nature of the phenomena discussed later. The necessity of the process will be apparent, if we consider the state of affairs in a complex co-ordinated act, in which the nerve cells of centres governing various muscles are called upon. Some or all of these cells are certain to be occupied in other ways at the time ; that is, they are already in a state of excitation due to the arrival of messages from other sources. If they are to perform the new process properly, they must be freed from this previous state of excitation, so as to be accessible to the fresh one. Further, the activity of certain centres sets into contraction muscles which oppose those required in the new act and which must be relaxed.

In Fig. 107, on page 388 (from Sherrington and Sowtx>n, 1911, p. 443), we saw that a state of tonic reflex contraction is produced in the vasto-crureus muscle, by stimulation of the central end of the popliteal nerve with rheonome currents. This tonic excitation of the nerve cells continues after the stimulus has ceased, as shown by the line of the signal at the base of the figure. At the second mark of the signal, a weak tetanising stimulation was applied to the same nerve. The tonic state of the nerve cell is completely abolished, but returns when the inhibiting stimulus ceases.

FIG. 117. ELECTRICAL CHANGE PRODUCED IN THE QUIESCENT VENTRICLE OF THE TOAD BY STIMULATION OF THE AUGMENTOR NERVE. — The first two stimulations, after the heart had been^ brought to a standstill by application of muscarin to the sinus. The last one, on another heart after the ventricle had ceased to beat owing &o block of impulses from the sinus by application of a clamp between the auricle and ventricle. The sign of the electrical effect is similar to that of spontaneous contraction, and opposite to that produced by the vagus.

case, the reflex contraction of the muscle was brought about by stimulation of the skin of the foot of the opposite side, indicated by the lower signal. At the rise of the upper signal, the foot of the same side as that of the muscle observed was stimulated. The excitation of the centre disappears, and it is to be noted that it falls below the level at which it was before the reflex contraction was induced. The cells of the centre were, therefore, already in a state of partial tonic excitation before the exciting stimulus was applied, and this was abolished along with that due to the stimulation of the afferent nerve.

Fig. 119 (Veszi, 1910) is a somewhat simpler case, being a reflex from the spinal cord separated from the higher centres. The gastrocnemius muscle of the frog is put into continuous reflex tetanus, by stimulation of the afferent dorsal root of the 9th spinal nerve, during the mark of the lower signal. At the se.veral marks of the upper signal, the central end of the 8th root was stimulated. There is complete FIG. 118. REFLEX INHIBITION OF DECEREBRATE TONE. — The tone was induced by stimulation of the skin of the foot of the opposite side, marked by the lower signal and by lines cutting the myogram. During the time marked by the upper signal, the foot of the same side as the muscle was stimulated. Note that the muscle was, to begin with, in some degree of tonic contraction, and that this is inhibited together with that due to the reflex from the contralateral foot. The muscle falls to the position of complete relaxation.

inhibition of the centre, although the stimulation causing reflex contraction was continued. We may take another example from a different group, the vasomotor reflexes. In Fig. 120 (from an experiment of my own), the uppermost curves represent the volume of one of the hind legs of a dog, a rise in the curve meaning increase of volume due to the presence of more blood in the limb. The vaso-dilator supply had been cut off from the centre by section of the spinal cord in the upper lumbar region. Between the two parts of the tracing, the vaso-constrictor supply was also cut off by section of the abdominal sympathetic chain. The effect of this, as will be seen, was to cause an increase in the volume of the limb, although there was no change in the blood pressure (the first part of the tracing was interrupted before the blood pressure had returned to its normal level, which, at the time of section of the sympathetic, was at its initial height as at the beginning of the figure). The only way in which this vaso - dilatation could have happened was that the vasoconstrictor centre was in a state of tonic excitation, and sending impulses to the limb, keeping its arterioles in a state of tonic contraction. Section of the efferent nerves conveying these impulses re- (After Veszi.)

vessels from this tonic excitation, and pressure of the blood inside them caused expansion. At the two marks on the signal line, the central end of the vagus nerve was stimulated. In the dog there are, in this nerve, fibres which excite and also fibres which inhibit the vaso-constrictor centre, but the fall of blood pressure, in the lower curve, shows that in this case the effect of the latter, the " depressor " fibres, was present alone. Owing to inhibition of the tonic state of excitation of the vasoconstrictor centre, the limb dilates in the first stimulation, since the arterioles are freed from the constrictor impulses, just as by the subsequent section of the nerve fibres themselves. The second stimulation, after section of the sympathetic

INHIBITION OF SPINAL REFLEX IN THE FROG.— All sensory roots of the sciatic nerve cut. Lower signal — continuous stimulation of the central end of the 9th dorsal root. Upper signal — intermittent stimulation of the central end of the 8th dorsal root. The reflex contraction due to the stimulation of the one root is inhibited every B, Similar experiment in which the action of the 10th root is inhibited by The first and last contractions on the myogram show that stimulation of the 8th root by itself alone causes reflex contraction, although brief.

chain, is merely to show the absence of any direct effect on the vessels of the limb, the fall in the curve being due to the diminution in the blood content, owing to the lowered blood pressure produced by dilatation in the blood vessels of those other parts of the body still under the dominion of the vaso-constrictor centre. Experiments on balanciny excitation against inhibition in nerve centres show FIG. 120. DEPRESSOR REFLEX ON THE ARTERIOLES OF THE HIND LEG FROM