analysis of the known glandular nerves, whether they be for the secretion autonomic system, a ganglion cell relay being placed on their path

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1 THE INNERVATION OF THE ADRENAL GLANDS. BY T. R. ELLIOTT, M.D., (From the Research Laboratories of University College Hospital Medical School.) RECENT work has proved beyond dqubt that the splanchnic nerves control the excretion of adrenalin from the adrenal glands, and that the curve of blood pressure rise caused by their electrical stimulation is the resultant of two components, namely the direct reaction of the vascular muscles to the nervous stimulus and the secondary effect on the heart and blood vessels of the adrenalin thrown into the circulation. This fact, that the splanchnics contain glandular secretor1 nerves for the adrenals, revives a question of great morphological interest. Langley's analysis of the known glandular nerves, whether they be for the secretion of sweat or saliva, proved that all conform to the type peculiar to the autonomic system, a ganglion cell relay being placed on their path between the spinal cord and the peripheral gland cell. Gland cells with such innervation naturally belong to the peripheral tissues of the body. But the embryological observations of Balfour, and their enlargement by Kohn and others, have suggested that the chromaffine cells of the medulla of the gland are derived from the same tissue as that which gives birth to the sympathetic ganglion cells, and that in consequence of this higher parentage and their habit through life of close association with the nerve cells, they should be ranked above the simple glands. If this be true, the chromaffine cell must be directly innervated by " preganglionic " primary nerve fibres from the spinal cord and there should be no intercalated ganglion cell relay. The adrenal medulla, despite its glandular functions, would not belong to the peripheral gland group but would lie on a level nearer to the central nervous system, 1 Working under the tenure of a Beit Memorial Fellowship. Towards the expenses of this work a grant was received from the Graham Research Fund of London University. PH. XLVI. 19

2 286 T. R. ELLIOTT. and be in reality a derivative of ganglion cells that had taken on secreting functions. The evidence that I wish to put forward on this point is not conclusive, but it does suggest that ganglion cell relays are not present on the glandular nerves. It is a familiar observation that the intravenous injection of nicotine into a cat completely abolishes all blood-pressure reaction to stimulation of the splanchnics'. But nicotine does not hinder the response to intravenous injection of adrenalin. Therefore nicotine must paralyse the splanchnic nerves that should cause excretion of adrenalin. It might be objected that the momentary stimulation caused by the first injection of nicotine is so intense that it completely exhausts all the available adrenalin, and leaves none to appear when the splanchnics are subsequently faradised. That cannot be upheld. It is difficult to exhaust the glands by nervous stimulation, and this certainly could not be done by the transient stimulus of nicotine. As evidence on this point may be quoted the following experiment. Both splanchnics were cut within the thorax of a cat, from which the right superior cervical ganglion had been removed three months previously. The peripheral end of the left splanclnic was then stimulated; and the pupil dilated while the ear vessels constricted in response to the adrenalini excreted. The stimulation was repeated every five minutes, being on for three and off for two minutes. After 80 minutes, that is with a total stimulation of about 50 minutes, the left splanchnic could still cause some adrenalin to be excreted and dilate the eye, though it was not so effective as the resting right splanchnic. There was no difference ultimately between the two glands in the depth of chromaffine stain. The block caused by nicotine was proved by Langley to lie in the ganglion cell relays. But that does not mean that the process of necessity takes place in the ganglion cell as such, and that the block proves the presence of a ganglion cell. It may quite well be that the stimulation and the paralysis by nicotine both occur in a part of the innervated cell which has developed a peculiar biochemical sensitiveness on accouint of the union with it of a preganglionic primary nerve from the spinal cord2, that is a receptive substance corresponding in its features with the myoneural junction at the periphery. All the primary synapses on the efferent paths outside the spinal cord show this peculiar reaction to nicotine, and nicotine will consequently block 1 Cf. details given by La n gl ey. This Journal, xx. p E ll i o t t. This Journal, xxxv. p

3 ADRENAL GLAND INNERVATION. 287 the splauichnic control of the adrenals whether the primary synapse be with a ganglion cell or directly with a chromaffine cell of the medulla. The external nerves to the cat's adrenal are derived chiefly from the splanchnics, but also from small bundles which run directly to the gland from the lumbar sympathetic chain. Small and large masses of ganglion cells can always be found closely attached to the surface of the gland, especially at the Ihilum facing the semilunar ganglion, where the medulla often extrudes a sheet of chromaffine cells almost to the surface. But the internal bundles of nerves, which run through the cortex and then break up into smaller leashes in the medulla, where they accompany the vessels and ultimately ramify among the nests of chromaffine cells, are chiefly myelinated. This can be easily recognised in frozen sections stained with haematoxylin and Scharlach, where the myelin sheath appears as a pink ring; and it is corroborated by the use of osmic acid. There is a rich supply of myelinated nerves, chiefly small and medium sized, to the medulla of the gland. Within the medtulla ganglion cells are occasionally found, but in the cat they are very rare, and their number does not correspond with that which would be expected if the myelinated nerves were destined to unite with them. The myelinated nerves might be postganglionic, for Langley has given several instances of the presence of a myelin sheath on postganglionic autonomic nerves. But this possibility was definitely excluded bv the proof that the nerves degenerate into the very heart of the medulla after section of the splanchnic trunks. By a lumbar incision the splanchnics were divided immediately below the diaphragm, that is at least a centimetre above the semilunar ganglion. The lateral nerves from the lumbar sympathetic chain were untouched. Nine to ten days later the cat was killed, and the gland, nerves, and ganglion stained with osmic acid. Fragments of the nerves were first cut out and teased: in these extra-glandular nerves degeneration was found right up to the surface of the gland. There was, therefore, no cell relay in the senmilunar ganglion. Next, an attempt was mr.ade to trace the degeneration within the gland itself. This presented difficulties, that were never quite removed. Osmic acid penetrates badly. It makes the tissue brittle, so that an entire section of the gland cannot be cut with such certainty as to give a series. Embedding in gelatine was found useless, because the process spoiled the sharpness of the osmic stain; and the same was the result with paraffin. The Marchi method also failed, insomuch as 19-2

4 288 T. R. ELLIOTT. the degenerated nerves could not be distinguished with certainty from the black stained granules of the cortical fat. The clearest staining was that given by simple osmic acid, about 03 0/0, with or without preliminary fixation in formalin. Sections were cut with the Aschoff freezing microtome, the knife being wetted with water. The myelinated nerves are then seen in conspicuous black against the light brown background of the cortical cells. The bundles run right through the cortex, and break up in the medulla. Degeneration could be recognised with absolute certainty, where the bundles chanced to be cut parallel to their length. It extended into the medulla, and it affected all the nerve fibres of a bundle'. Some bundles escaped entirely, being presumably those of the lateral fibres from the lumbar sympathetic. An attempt was made to ascertain whether any afferent fibres were present among the intra-glandular nerves, since it was possible that these might be the actual myelinated fibres in which degeneration was seen upon section of the splanchnics, whereas the efferent fibres might lose their myelin sheath below a supposed cell relay in the semilunar ganglion and so fail to be detected by the osmic stain. The latter possibility with regard to the efferent nerves could have been settled by cutting the anterior roots alone over several segments, and noting whether the degeneration extended into the gland as it does after section of the splanchnics. I preferred the direct method of tracing the afferent fibres themselves. This could not be done by Langley and Sherrington's method of cutting both posterior and anterior spinal roots and then counting the undegenerated fibres, because the total extent of the spinal root innervation of the adrenals was unknown. Instead of this, the posterior root ganglia themselves were excised without damage of the anterior roots. When the 5th, 6th, 7th and 8th thoracic ganglia were removed on one side, degeneration in the adrenal nerves did not result in two cats, although the splanchnics contained a very large number of degenerated fibres. These observations are too meagre to justify the total exclusion of afferent fibres. But they do serve to establish the important point that the intra-glandular myelinated nerves under discussion are not all afferent, and that therefore the argument from degenerative section of the splanchnics can be applied. 1 F us ari, Arch. Ital. de Biol. xvi. p , confirms the observations made by Bergmann (1839) and Gottschau (1883) that nerves may dive through the cortex of the gland, and emerging pass on to the semilunar ganglion. The degenerated bundles were not of this type.

5 ADRENAL GLAND INNERVATION. 289 CONCLUSION. Section of the splanchnic nerves causes the myelinated nerves of the adrenal gland to degenerate up to their endings in the medulla. Since few, if any, of these glandular nerves are afferent, it is clear that the primary synapse of the efferent fibres must lie in the medulla. Here ganglion -cells are rarely found', and the myelinated fibres seem to branch and run directly to the nests of chromaffine cells. So it appears probable that the latter are directly innervated fromn the primary "preganglionic" nerves without the intervention of a ganglion cell. Clear proof of this probability requires more detailed histological study than I have been able to make. It is necessary that special stains should be used to trace the degenerated nerves up to their terminal ramifications. In the descriptions that have been given by pure histologists of the innervation of these glands, attention has not, so far as I am aware, been definitely paid to the question of how the ganglion cells are related to the entering nerves. Fusari and Dogiel2 found that ganglion cells are rare in the medulla of the mouse and rat respectively, and Dogiel observed that they are rarer in the cat than in the rabbit. Giacominig, using the rapid Golgi method, described in birds a rich nervous supply to the medullary cells, while the cortical cells were almost naked of such. Numerouis sympathetic cells were seen on the outside of the gland, but few within. The question of the ganglion cell relay was not clearly considered, but Giacomini decided against Kohn's view because the nerve terminations about the chromaffine cells resembled those found in ordinary gland cells rather than those in ganglion cell synapses. I By a complete series of paraffin sections I examined the entire adrenal gland of a cat, but I failed to discover any true nerve ganglion cells within the medulla. Prejudice and the tediousness of the microscopic search make it possible that some ganglion cells were overlooked, but they must have been few; whereas the entering nerves are many. It appears, then, that in the cat a clearer separation of the chromaffine from the ganglion cells has taken place than in other animals, and consequently it becomes possible to trace the degenerated fibres to one or other type of cell. What might be regarded as a more primitive type is occasionally seen in accessory adrenals attached to one of the cat's splanchnic ganglia, where chromaffine cells and nerve cells are intermingled, but at the edge of the ganglion an offshoot of chromaffine tissue is capped by a mass of cortical cells, just as in the Monotremata. This Journal, xxxiv. p Arch. f. Anat. u. Physiol. Anat. Abtheil. p Accad. dei Fisiocritici di Siena Nov

6 290 T. R. ELLIOTT. With this reservation that the final microscopic proof is still needed, one would then place the medullary chromaffine cell on the same level as the sympathetic ganglion cell. Ganglion cell and "paraganglion" cell have a similar embryological derivation: they have a like innervation: and they have the same action on the peripheral tissue, which the one affects directly by the nervous impulse and the other by adrenalin excreted into the blood stream. Their present anatomical separation may be the index of a differentiation of functions which were once held by the two in common, when the adrenalin liberation was a part of the nervous impulse' and the "paraganglion" cell was a part of the ganglion cell. 1 E lli ot t. This Journal, xxxi. Proc. Physiol. Soc. p. xx