disappears; by fresh additions of cocaine the blocking may be repeated blocking of conduction is obtained almost at once, but it quickly

Transcription

1 THE SELECTIVE ACTION OF COCAINE ON NERVE FIBRES. BY W. E. DIXON, M.k, M.D. (Five Figures in Text.) (From the Pharmacological Laboratory, Cambridge.) v. AN RE P first clearly showed that a localised anaesthesia is obtained if cocaine is injected subcutaneously into the tissues or applied directly to any mucous membrane, such as the mouth, pharynx, larynx, or rectum'. Two hypotheses have been advanced to account for this peripheral sensory paralysis. The first points to the fact that cocaine is a general protoplasmic poison and destroys alike all forms of livinig matter. Its exponents explain the anasthesia by pointing out how much more exposed are the sensory fibres, and assert that the motor endings are not afected because the cocaine does not reach then. The second bypothesis assumes that cocaine has a specific effect on the sensory nerve endings, and has been termed by the French school the " curare-sensitif " theory. The present note deals only with the application of cocaine directly to nerve fibres: it will be shown that far frotn its acting on all nerve fibres equally, it usuially, 'in the case of a mixed nerve, paralyses ftinctionally different fibres at different rates; and one set of fibres not uncommonly requires for conmplete paralysis a stronger percentage of the drug than another set. It has been known for a long time that cocaine directly applied to nerve reduces the irritability of the nerve fibres. Langley and Dickinson2 showed that this effect may be very transient: if the cocaine in suitable strength is cautiously applied to the nerve the blocking of conduction is obtained almost at once, but it quickly disappears; by fresh additions of cocaine the blocking may be repeated many times in suiccession. It has been shown also that the diminution of excitability, conductivity, and the action current, all run a parallel I v. Anrep. Pfluiger's Archiv, xxx. p Langley and Dickinson. This Journal, xi. p

2 88 W. E. DIXON. course not only for cocaine but for other drugs, such as chloral, phenol, and chloralosel. The present experiments were performed principally on rabbits, which were always ancesthetised by ether. Dogs and cats were anaesthetised with an A.C.E. mixture, and in the vasomotor experiments curari was also employed. Motor and sensory fibres. Cocaine forms a ready means of paralysing sensory fibres whilst leaving the motor intact. If the drug is strong and allowed to act for a sufficiently long time the motor fibres are also paralysed, but they recover their action first* when the nerve is washed with normal saline. To show this effect all that is necessary is to expose a nerve, say the sciatic of the rabbit, and paint it in a definite spot for a length of 1 or 2 cms. with 10 0/0 solution of cocaine: or to obtain an even quicker result, the brush may be placed in the solid cocaine and the adherent crystals transferred directly to the nerve. On exciting the nerve in continuity, centrally to the cocainised portion, two effects are obtained, (1) reflex movements, rise of blood-pressure and stimulation of respiration by upward conduction, (2) tetanus of the leg muscles by downward conduction through the cocainised nerve. If the nerve be now excited peripherally to the cocaine, tetanuis of the leg muscles alone results, and there are none of the signs of upward conduction. Of course if the concentrated cocaine is employed the motor nerves are also affected after a time, and paralysis of the nerve becomes complete. This type of experiment is not new and has been described by several observers2. I have also employed other drugs, such for examriple as aconitine and always find that the sensory fibres are affected before the motor. Vagus. In the case of the vagus nerve the two sets of fibres, viz., those conducting upwards and downwards respectively, may be quite clearly separated by cocaine. Fig. 1 represents an experiment in which one vagus of a rabbit was painted with a /0 solution of cocaine; the tracing shows the effect of two excitations, first on the cardiac side of the painted spot and the second on the cerebral side. The first effect A is typical both on the respiration and the blood-pressure, but at the second stimulation at B conduction downwards is blocked, though of course it is still perfect towards the brain. Fig. 2 represents another experiment in which the right vagus was treated with a solution of I in 2000 cocaine HCI, the left vagus having I Wedenski. Pfuiger's Archiv, LXXI. p Cp. Binz, Phuarmacology, translated by Latham (New Sydenham Society).

3 COCAINE ON NERVE FIBRES. been severed. On stimulating the nerve above the painted spot the heart is not inhibited butt the blood-pressure rises from vaso-constriction. Stimulation below the cocainised portion has the normal effect both on the respiration and heart. Section of the opposite vagus therefore exerts no effect on the result. ~89 Fig. 1. Fig. 2. Fig. 1. Rabbit: ether, respiration, and blood-pressure. 1 cm. of the left vagus nerve has been painted with a /i, solution cocaine HCI. A represents the 'effect of excitation at the cardiac end, and.8 the effect of excitation at the cerebral end. Coil at 17 cms. Time =seconds. Fig. 2. Rabbit: ether, respiration, and blood-pressure. Left vagus cut. 1 cmi. right vagus,painted with a /i, solution cocaine HCIL Shows the effect of stimulation above and below the painted spot. Coil at 15 cms. Time= seconds. In. the dog the same division of the vagal fibres may be brought about, although owing to the comparatively large size of this animal's nerves the separation is not so clearly defined : for this purpose any strength of cocaine up to 0-4 0/,, may be necessary, accordinig to the size of the animal In Fig. 3 the record is shown of an experiment in which the left vagus was painted with a 0-3 0/0 solution of the drug. Excitation at A, below the painted spot affects both the respiration and ci'rculatilon, whilst stimulation at B., above the cocaine regioni, shows only the effect on the respiration. One other use for cocaine may be mentioned : it forms a ready

4 t9o W. E. DIXON. means of producing a temporary block in the vagus, phrenic or other nerve, for all fibres and without an initial excitation such as occurs when the nerves are- severed. For this purpose a i 0/0 solution is appropriate in the rabbit, whilst a 5 0/0 solution applied to the phrenic of a dog produces paralysis lasting about 10 minutes. I venture to suggest that painting the vagi with cocaine may be of value in cases of "suddeni Fig. 3. Dog. A.C.E. 1 cm. of left vagus painted 0 3 0/0 cocaine HC1. A represents period of stimulation below, and B that above the painted spot. Coil at 15 cms. Time= seconds.,death" in the early stage of chloroform narcosis. It is almost certain that these deaths occur from a great excitation (direct or reflex) of the medulla which results in inhibition of the heart. If the va&i are cut Embley and Martin' have shown that the blood-pressure bounds up, and the heart immediately recovers its activity: in a single experiment which I have performed on a morphinised and pithed dog which had received no volatile ansesthetic I obtained the same result by painting with cocaine. Strong chloroform was first given to the dog until there was marked cardiac inhibition, when the vagi were painted with 2 0/. cocaine; almost immediately the blood-pressure rose and the heart recovered. In man, section of the vagi is of course impossible, but I know of no reason why the conduction in these nerves should not be temporarily blocked by cocaine. I Embley and Martin. Brit. Med. Journ. i. p

5 COCATINT ON NER.VE FIBRES. Vasomotor nerves. Experiments with vasomotor nerves were performed on the dog, cat, and rabbit. In dogs and cats the sciatic nerve was chosen and the animals were either anesthetised or killed by pithing, but in either case curari was intravenously administered and artificial respiration kept up. The nerve was exposed and cut high uip so as to allow as long a piece of nerve as possible for manipulation. A glass plethysmograph was then applied to the limb and a volume record obtained either by a bellows or tambour. Blood-pressure was simultaneously recorded. If a 10/0 solution of cocaine is painted over about 1 cm. of the sciatic nerve of the cat the vaso-constrictor uerve fibres are paralysed before the vasodilator. It is not always easy to make this experiment satisfactory, for if the cocaine is too strong or allowed to act too long a time both sets of fibres are paralysed. The details of the experiment are simple; the drug is painted on the central portion of the free nerve- and electrical excitation is then applied both above and below the painted spot Ẇith the dog the large size of the nerve presents difficulties. In the experiment recorded in Fig. 4 the sciatic nerve was painted with a 1 0/0 solution of cocaine 3 minutes previotusly to stimulation, and in 91 Fig. 4a. Dog. A.C.E. Curari. Blood-pressure and limb plethysmograph. 10/0 cocaine HCI applied to about 1 cm. of the sciatic nerve. Effect of excitation below painted spot. Coil at 5 cms. Time=seconds. Fig. 4a the nerve was stimulated below the cocaine, and typical vasoconstriction results. In Fig. 4b the excitation was repeated with the same strength of current above the painted spot, and verv gradual vasodilatation results, which is perhaps most readily recognised by the augmented volume pulse.

6 92 W. E. DIXON. A physical explanation is compatible with these facts. The vasoconstrictor nerves having no sheath would be more rapidly attacked than the vasodilator; the latter according to Bayliss' are identical with the ordinary sensory afferent posterior root-fibres and possess a sheath. Sensory fibres, however, are very susceptible to cocaine, and hence there is an explanation of the difficulty in separating these two sets of fibres. Fig. 4b. Reduced Same. Effect of stimulation above the painted spot. Excitation begins at A and ends at B. Coil at 5 ems. In the rabbit a similar separation of fibres has been obtained by stimgulating the sympathetic nerve whilst measuring the ear-volume. Bronchomotor fibres. Prof. Brodie and myself have already attempted to separate bronchomotor fibres by means of cocaine but only with slight success, perhaps because in our earlier experiments we used anwesthetics which we subsequently showed invalidated the results by partially paralysing the nerve endings. Cocaine, then, whilst paralysing all nerve fibres when it is applied to them in concentrated solutions, yet exerts a selective action in dilute solutions, picking out some fibres and paralvsing them before or to the exclusion of others. Three explanations might be offered to account for these facts. First, the distribution of the fibres in the bundle may be such that those conducting one form of impulse are more exposed to the action of the drug than those conducting another. Such however is not the case, for sensory and motor fibres are freely mixed up together in the mixed nerve; and in the vagus Prof. Langley informs me there is a similar mixing together of the fibres. A second hypothesis accounts for the facts by supposing some fibres to possess a more efficient protection in their sheath than others, and the fact that moderate injury to a nerve is more likely to lead to sensory affections than motor would appear to favour it. Histology however gives I Bayliss. This Journal, xxvi. p

7 COCAINE ON NER VE FIBRES. no support to this view. Thirdly, cocaine may have a greater specificity for some fibres than for others, that is, the chemistry of the two sets of fibres may be slightly different. A fact which appears to favour the latter hypothesis is the extraordinary way in which drugs of all kinds attack not only sensory nerve fibres but sensory nerve cells before the motor, and this fact obtains, no matter whether the effect is one of stimulation or depression. Thus caffeine may be regarded as an example of a typical stimulant to the cerebrum, and the most characteristic effect of the drug is increased perception, a more perfect consciousness (i.e. the sum total of sensory impulses both as regards intensity and number at any one moment), and hence the wakefulness. Morphine on the other hand depresses sensory cells; perception and object consciousness are diminished, and hence the train of mental symptoms characteristic of the drug. Or to take the cord, we have again the strongest evidence to show that stimulants such as strycbnine exert their effect entirely on the sensory cells' and that depressants such as CHCI32 certainly attack the sensory cells before the motor. If cocaine is injected into the spinal canal of a man between the second and third lumbar vertebrse complete sensory paralysis of the lower extremities quickly follows; and if the dose is moderate (15 mgrs.) a partial motor paralysis is also later developed, consciousness of course being retained. Recovery begins with motion, and sensation is the last to revive. As regards nerve fibres I have already pointed out that the sensory are invariably affected both more easily and with smaller doses than the motor, not only with cocaine as has been shown by several observers, but by other drugs, such as aconitine, carbolic acid, chloroform, ether, etc. When we come however to the nerve endings this rule certainly does not hold: many drugs have a specific action on the motor nerve endings without in any way influencing sensory. This however is of little significance to our argument, since the term " nerve ending in no way means that the structure is nervous. Further, we have no evidence that cocaine paralyses the sensory nerve endings: all we can say is that a subcutaneous injection paralyses some part of the peripheral sensory apparatus, and quite possibly the fine nerve fibrils before the endings. At all events it is quite impossible, as far as we can judge by administering cocaine internally, to affect sensory endings, although it must be remembered that we have no very good way of testing the activity of 3 Houghton and Muirhead. Med. News, z. p Bernstein. Moleschott's Untersuch. x. p

8 .94 W.. E. DIXON. sensory endings when the sensory cells become paralysed, as in the case after big doses of cocaine. Mosso, after strongly cocainising a dog's foot, excited it electrically and obtained visual refle'xes, from which he attempted to show that the nerve endings were not essentially affected1. His experiments were not valid on account of the diffusible stimulus he employed. Sympathetic motor nerve endings cannot be paralysed with cocaine. If artificial perfusions are performed through the limb vessels of cats it is found that before adrenalin ceases to produce constriction of the vessels 50/G of cocaine must be added to the blood; when this amount is reached the muscle is killed, since such drugs as BaCl, induce no contraction. That is to say, the cocaine does not specially act on these endings, nor do I know of any evidence tending to show that it has a paralysing action on any form of nerve ending in the body in such dosage as would entitle it to the name specific. CONCLUSIONS. Cocaine locally applied to nerve fibres picks out and paralyses some fibres before others; sensory before motor, vagal fibres conducting upwards, before those conducting downwards, vaso-constrictor fibres before vaso-dilator, broncho-constrictor before broncho-dilator. It is suggested that the local application of cocaine to the vagi may be a means of combating death during early chloroform narcosis. Drugs which attack the central nervous system, brain, or spinal cord or nerve fibres almost invariably attack the sensory cells and fibres before the motor. There is no reason to suppose that cocaine has a specific action on sensory nerve endings. [The expense of this research has been defrayed by a grant from the Royal Society.] I Mosso. Arch. Ital. de Biol. xiv. iii