Gut, 1968, 9, 139-143

Effect of irritant purgatives on the myentericplexus in man and the mouse

BARBARA SMITH

From the Department of Pathology, St. Bartholomew's Hospital, London

Purgatives are some of the most widely used of alldrugs, particularly preparations of cascara sagradaand senna, the anthraquinone cathartics. In spiteof this comparatively little work has been done ontheir mode of action. Straub and Triendl (1937)showed that senna would act when given paren-terally but only after a latent period of up to eighthours. The authors suggested that during thisperiod it is converted into the active anthraquinoneand excreted into the large gut. They also showedthat it is active when given by mouth to an animalwith a divided intestine. Grabfield (1937) perfusedisolated coils of small and large intestine with 1 in10,000 cascara showing that it produced an increasein peristalsis in the latter but not in the former.Okada (1940) suggested that the Escherischia coliconverted senna to an oxyanthraquinone whichacted on Auerbach's plexus. He considered thatthe resulting pressure changes which he recordedwere similar to normal peristalsis. In view of thetheory then current that the anthraquinone purga-tives acted by irritating the mucosa, producing areflex muscular contraction, Douthwaite and Goul-ding (1957) gave sennakot to mice. They producedpurgation but were unable to show any evidence ofinflammation in the gut. They commented that themode of action of the drug was unknown. Thus therather scanty evidence suggests that the drug couldhave a direct effect on myenteric neurones. Corro-borative evidence for this theory comes from patientswho have been taking purgatives for many yearsand who become resistant to their effect. It isalmost impossible to wear out a physiological reflexin the presence of normal neurones so possibly theganglion cell itself is damaged. In this work thepathology of the plexus in a patient who had beentaking purgatives for over 40 years will be describedand also the effect on this structure of giving sennato mice.

CLINICAL HISTORY

The details of this patient's history were presented morefully to the Royal Society of Medicine by Dr. Avery

Jones (1967). The patient began to have increasing con-stipation from the age of 13 and frequently took aperients.She was subject to attacks of a feeling of distension andabdominal pain. She had a loop of sigmoid removed atthe age of 50 without relief and continued to takelaxatives. At the age of 57 she was passing three or fourfluid stools a day. Colectomy was done at the age of 57and resulted in relief of symptoms.

PATHOLOGY

I am indebted to Dr. Basil Morson for the followingmacroscopic description of the specimen.

'It consists of the terminal 5.0 cm of ileum with thecolon from the caecum to the rectum. The ileocaecalvalve is stenosed and incompetent. The colon shows lossof interhaustral folds throughout. The mucous mem-brane is dark brown and has the texture of snake skin,showing an appearance of reticulation with a networkof fine white intercommunicating lines. The submucosais filled with adipose tissue and at one point in thetransverse colon this is thick enough to produce apolypoid tumour 2-0 cm in diameter. The muscle layersshow obvious atrophy.'The plexus was demonstrated by silver impregnation

of sections cut parallel to the gut wall as describedpreviously (Smith, 1967). The abnormal features were avast increase in the number of Schwann cells whichfilled the plexus region, and a considerable reductionin the number of neurones and axons. The neuroneswhich remained were poorly argentophilic with irregular,ill-defined margins and only one or two swollen pro-cesses. The axons ran singly and not in bundles, theywere irregular in calibre, and a few were random indirection, apparently regenerating fibres (Figs. 1, 2, and 3).

RESULTS

In the mouse the intestinal contents are dehydratedand formed into pellets in the proximal colon andpassed distally. There is no significant storage offaeces in these animals and they are excreted quitequickly. Normally the distal colon does not containmore than two or occasionally three well-spacedpellets. If a purgative is given and the animal iskilled about eight hours later, the distal colon isempty. If a large dose is given, the colon may be

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FIG. 1. FIG. 2.

FIG. 1. Cathartic colon. A singleneurone remaining in a ganglionwith a grossly thickened axon( x 300).

FIG. 2. Cathartic colon. A poorlystaining neurone and two or threeaxons remaining in a ganglion.Schwann cell nuclei can be seen inthe background ( x 300).

FIG. 3. Cathartic colon. Twotortuous axons which areprobably regenerating. There areno neuronal nuclei in thisganglion ( x 300).

FIG. 3.

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Effect of irritant purgatives on the myenteric plexus in man and the mouse

FIG. 4. FIG. 5.

FIG. 4. Normal mousemyenteric plexus. The axonsare fine, straight and regular.Neurones are present but donot stain ( x 300).

FIG. 5. The myenteric plexusof a mouse given syrup ofsenna, 1 in 20, by mouth forfive weeks. Neurones areargentophil. The axons showbeading and fragmentation( x 300).

FIG. 6. The myenteric plexusof a mouse given syrup ofsenna, 1 in 100, intra-peritoneally for 10 dailydoses. There are a number ofdendritic enlargements whichare probably swollen boutonsterminaux (x 300).

1FH. 6.

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empty as far back as the ileocaecal valve. If there isimpaired peristalsis, the pellets will be excretedmore slowly and the distal colon will be full. In theanimals given senna for more than a fortnight, intra-peritoneally, the distal colon always contained morethan three pellets; often it was tightly packed withfive or six. Of the animals taking senna by mouth,22 out of 30 showed similar changes. In nearly allthe animals the faeces were larger and softer thannormal due to impaired water absorption.When the colon is removed from the normal

mouse it immediately undergoes segmental con-traction and the lumen is almost obliterated.Experience with other neurotoxic drugs (Smith,1968) suggest that when the plexus is damaged thisfails to occur and the gut remains flabby and open.In the animals given the senna intraperitoneally, in14 out of 20 contraction was impaired in responseto trauma, and of those taking the drug by mouth,in 20 out of thirty.

Histologically the normal myenteric plexus of themouse is a geometrical pattern of nerve trunks withcollections of ganglion cells at their junctions andto some extent running along their length. When itis impregnated with silver the neurones are usuallyunstained, the axons are smooth, straight and ofregular calibre (Fig. 4). Sometimes collections ofdendrites can be seen in the ganglia. In animalsgiven neurotoxic drugs the abnormalities consist ofswelling and argentophilia of neurones, axonal frag-mentation, retraction balls, and dendritic masseswhich are probably swollen boutons terminaux(Hoff and Hoff, 1934) and neurofibrillary tanglesprobably representing hypertrophy of the autonomicground plexus (Smith, 1968). In the animals givensyrup of senna by mouth, there was little changefor about a month. After this there was slight neu-ronal argentophilia with swelling of axons and someneuro-fibrillary tangles. After four months, therewas evidence of axonal fragmentation and den-dritic swelling (Fig. 5). In the animals given thedrug intraperitoneally, there was considerabledamage evident after a fortnight. There was a littleargentophilia of neurones but a more striking featurewas the presence of large numbers of axon swellingsand boutons terminaux (Fig. 6).

DISCUSSION

The histological changes produced in the myen-teric plexus in animals by neurotoxic drugs aresomewhat variable. Some substances, such as thevinca alkaloids, seem to produce gross argento-philia with axonal fragmentation; others, such asmepacrine, produce much less argentophilia butlarge numbers of axonal and dendritic swellings

(Smith, 1968). The appearances in the animals givensenna, particularly by the parenteral route, whichgives a higher dose, are very similar to those pro-duced by mepacrine. It is interesting that mepacrine,which is fluorescent, can be shown to have a specificaffinity for neurones rendering them visible whenviewed by ultraviolet light. The acridines and theanthraquinones are chemically allied and it ispossible that they may affect neurones in a similarway. The rather specific affinity of senna for thelarge intestine may be due to the fact that it issecreted into it, and very small doses will affect theneurones in the gut wall because it is concentratedthere. It has thus been shown that senna has ahistologically damaging effect on myenteric neuroneswhen given to mice. It is therefore suggested thatthe drug has an affinity for these cells and actsin the pharmacological situation bystimulating them.The patient who had been taking purgatives for

many years also had marked damage to the plexus.However, here the situation is more complicated,because she had been taking a number of differentdrugs and it is not really known why she started totake laxatives originally. Acquired organic diseaseof the plexus producing failure of gut motilitydoes exist and such patients will inevitably takeaperients. Thirty years later it is impossible to saywhether the damage is entirely due to purgativesor whether there was a primary plexus lesion.Patients who have an inflammatory destructioni ofthe plexus both in Chagas' disease and in idiopathicmegacolon have a considerable hypertrophy of thesmooth muscle particularly the inner coat (personalobservation). This is possibly a true work hyper-trophy due to increased segmentation not mediatedneurologically in the absence of coordinated peri-stalsis. This patient had a definite atrophy of thebowel wall which is perhaps against a primaryorganic lesion.

In the cathartic syndrome, several fluid motionsa day are passed. The myenteric plexus in the distalcolon is not only responsible for peristalsis but alsoby active relaxation for storage. If the damage issufficiently severe, the colon may be converted intoan inert tube through which small intestinal contentspass, helped along by segmentation and a push frombehind, and no storage occurs. Hence, these patientslose considerable quantities of water and potassium.

SUMMARY

Myenteric plexus damage is described in a patientwith the cathartic syndrome.Damage to the myenteric plexus was produced in

mice by the administration of syrup of senna.

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Effect of irritant purgatives on the myenteric plexus in man and the mouse 143

It is suggested that senna acts pharmacologicallyby its effect on myenteric neurones, and if takenlong enough may damage them.

This work was assisted by a grant from The MuscularDystrophy Group of Great Britain. I am grateful toMr. P. Crocker for the photographs.

REFERENCES

Douthwaite, A. H., and Goulding, R. (1957). Action of senna.Brit. med. J., 2, 1414-1415.

Grabfield, G. P. (1937). New experiments on some old cathartics.J. Pharmacol. exp. Ther., 60, 108.

Hoff, E. C., and Hoff, H. E. (1934). Spinal terminations of the pro-jection fibres from the motor cortex of primates. Brain, 57,454-474.

Jones, F. A. (1967). Cathartic colon. Proc. roy. Soc. Med., 60, 503-504.Okada, T. (1940). OJber den Mechanismus der Sennaabfuhrung.

Tohoku J. exp. Med., 38, 33-44.Schofield, G. C. (1960). Experimental studies on the innervation of

the mucous membrane of the gut. Brain, 83, 490-514.Smith, B. (1967). Myenteric plexus in Hirschsprung's disease. Gut,

8, 308-312.(1968). The myenteric plexus in drug-induced neuropathy.J. Neurol. Neurosurg. Psychiat., 30, 506-510.

Straub, W., and Triendl, E. (1937). Theorie der Abfuhrwirkung derFolia Sennae und ihrer wirksamen Inhaltstoffe. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 185, 1-19.

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