Enteric nervous system and motility
The bowel runs itself on two nerve nets buried in its own wall — and when those nets are silenced by drugs and surgery, missing from birth, or no longer sweeping between meals, the gut behaves exactly as though it were blocked with nothing blocking it.
What it normally does
The gut wall carries its own nervous system, with roughly as many neurons as the spinal cord, arranged in two nets [enteric nervous system]. The outer net sits between the circular and longitudinal muscle layers and runs movement [myenteric plexus, or Auerbach plexus]; the inner net sits under the lining and runs secretion and local blood flow [submucosal plexus, or Meissner plexus]. Cut every nerve coming from the brain and the bowel still propels a bolus — sensory neurons in the wall detect stretch, interneurons relay, motor neurons act, all without leaving the gut [peristaltic reflex].
Explains how bowel can look and feel completely obstructed when nothing is physically obstructing it — ileus and pseudo-obstruction — and why a biopsy taken deep enough to include submucosa, which catches the inner net, can diagnose a disorder of movement.
Peristalsis needs a push and a permission. Behind the bolus, excitatory motor neurons release acetylcholine and substance P and the circular muscle contracts. Ahead of it, inhibitory motor neurons release nitric oxide, vasoactive intestinal peptide (VIP) and ATP, and the muscle relaxes so the bolus has somewhere to go. Relaxation is an active nerve signal, not simply the absence of contraction.
Explains why bowel with no nerve cells in it is tight and shut rather than floppy and open — the whole of Hirschsprung disease follows from losing the inhibitory half of that pair.
The brain only modulates what the gut already does. Vagal cholinergic input speeds things up; sympathetic noradrenaline acting on presynaptic alpha-2 adrenoceptors, and mu-opioid receptors sitting on the same myenteric neurons, slow things down by cutting how much acetylcholine those neurons release. Whatever the input, acetylcholine acting on M3 muscarinic receptors of smooth muscle is the final common push, and dopamine acting on D2 receptors of the myenteric neurons is a standing brake on it.
Explains postoperative ileus and opioid-induced constipation, and why every prokinetic on the ward ends up doing the same thing — getting more acetylcholine onto that one junction, or removing a brake from it.
Pacemaker cells wired between the muscle layers set the electrical rhythm [interstitial cells of Cajal] — about 3 slow waves a minute in the stomach, about 12 in the duodenum — and a contraction can only happen on a wave, which caps the maximum rate. Between meals a housekeeping wave sweeps the whole length from stomach to terminal ileum every 90 to 120 minutes, with its strong phase III driven by the hormone motilin [migrating motor complex]. Eating abolishes it and replaces it with the fed pattern; it restarts once the stomach is empty again.
Explains gastroparesis when the pacemaker cells and their neighbouring nitrergic neurons are destroyed, and bacterial overgrowth when the housekeeping wave stops running.
What goes wrong
- Postoperative ileus← from “The brain only modulates what the gut already …”
Two brakes go on at once. Handling the bowel and the peritoneal inflammation that follows trigger inhibitory sympathetic reflexes onto the myenteric plexus, and the opioids given for the pain bind mu receptors on those same myenteric neurons and cut acetylcholine release. The muscle is intact and the lumen is wide open, but no coordinated propagating wave is generated. Low potassium deepens it because smooth muscle cannot depolarise and contract properly, and low magnesium matters largely because it perpetuates the hypokalaemia; inflammatory mediators from the handled bowel spread the paralysis to segments never touched.
Ileus means gas all the way to the rectum, no transition point, silent abdomen. Mechanical obstruction means a transition point with collapsed bowel beyond it and high-pitched tinkling sounds. Treatment of ileus is subtractive — fewer opioids, correct potassium and magnesium, get the patient walking; chewing gum (sham feeding through a vagal reflex) is cheap and harmless but the evidence for it is weak. An ileus that has not settled by about day five is a mechanical cause or a leak until proven otherwise.
You would find: Two or three days after abdominal surgery: distended, tympanic, uncomfortable, no flatus, vomiting, and a quiet abdomen rather than a noisy one. The abdominal X-ray or CT shows gas spread evenly through small bowel AND colon right down to the rectum, with no transition point and no collapsed distal bowel. Recovery runs in order — small bowel within hours, stomach 24 to 48 hours, colon 48 to 72 hours — so the colon is what keeps the patient in hospital.
- Acute colonic pseudo-obstruction (Ogilvie syndrome)← from “The gut wall carries its own nervous system, w…”
In a sick inpatient — after a fractured hip, a caesarean, sepsis, a spinal injury, or with deranged electrolytes, opioids and anticholinergics on board — the input balance to the colon tips heavily sympathetic and the sacral parasympathetic supply to the left colon is thought to drop out. The local nerve net alone cannot generate a propagating wave through that segment, so the colon behind it dilates enormously. There is no lesion anywhere: the bowel is functionally obstructed at a segment that will not relax.
It is not a surgical obstruction, and operating on it is a disaster. Start conservative for 24 to 48 hours — correct potassium and magnesium, stop the opioids and anticholinergics, nasogastric and rectal tubes, nil by mouth. If that fails and there is no ischaemia or perforation, neostigmine is the next step and usually works within minutes; colonoscopic decompression is reserved for neostigmine failure or contraindication. Sudden severe pain with peritonism, fever and tachycardia means it has perforated.
You would find: Massive abdominal distension appearing over a day or two in a patient already in hospital for something else, tympanic to percussion, often still passing some flatus, with surprisingly little tenderness unless the wall is failing. CT shows a grossly dilated colon with no mechanical cause. Caecal diameter is the number that matters: as the widest segment it carries the highest wall tension (Laplace), so above roughly 12 cm the caecum is the part that becomes ischaemic and perforates.
- Hirschsprung disease← from “Peristalsis needs a push and a permission. Beh…”
Neural crest cells migrate down the gut in fetal life and, in this disease, stop short. The last segment of bowel — always continuous from the internal anal sphincter and rectum, extending a variable distance proximally — has no ganglion cells in either plexus. With no inhibitory nitrergic neurons, that segment never receives permission to relax: it stays tonically contracted and narrow, while the normally innervated bowel above it hypertrophies and balloons trying to push past. A functional obstruction sitting at a narrow segment, with the dilated bowel proximal to it.
About 1 in 5000 births, four times more common in boys, and roughly 1 in 10 cases has trisomy 21. No drug fixes it — the aganglionic segment is resected and normal bowel pulled through. The killer is Hirschsprung-associated enterocolitis: fever, foul explosive diarrhoea and distension in a known or undiagnosed case, which can go to sepsis within hours. In an older child, chronic severe constipation from birth with an empty rectum on examination and no soiling separates it from ordinary functional constipation, where the rectum is loaded and overflow soiling is common.
You would find: A term newborn who has not passed meconium within the first 48 hours, with abdominal distension and bile-stained vomiting. Explosive gas and liquid stool the moment a finger or tube is withdrawn from the rectum (squirt sign). Contrast enema shows a narrow distal segment with a cone of dilated bowel above it. The diagnosis is a suction rectal biopsy: no ganglion cells, hypertrophied nerve trunks, and supporting stains — increased acetylcholinesterase and absent calretinin.
- Diabetic gastroparesis← from “Pacemaker cells wired between the muscle layer…”
Years of hyperglycaemia damage the vagus, but the bigger lesion is inside the wall: pacemaker cells are depleted and the nitric-oxide-producing inhibitory neurons of the antrum and pylorus are lost. The antrum grinds weakly and out of rhythm, and the pylorus fails to relax, so solid food is neither broken down to small enough particles nor let through. Acute hyperglycaemia itself slows the stomach further, so the problem feeds itself.
Diabetes is roughly three to four times more common in Aboriginal and Torres Strait Islander Australians and develops at a younger age, so the autonomic complications including gastroparesis fall disproportionately on those communities and appear in younger patients than expected. Before blaming the diabetes, check the medication list: opioids, anticholinergics and GLP-1 receptor agonists all slow gastric emptying as a direct consequence of their mechanism. The GLP-1 point is also an anaesthetic one — retained gastric contents despite standard fasting is why current Australian peri-procedural guidance addresses these drugs specifically.
You would find: Fullness after a few mouthfuls, nausea, and vomiting of recognisable food eaten hours earlier. A splash audible over the epigastrium when the patient is rocked (succussion splash) hours after a meal. Glucose control becomes erratic and unpredictable, because injected insulin acts before the meal is absorbed. Confirmed on gastric emptying scintigraphy, but only after endoscopy has excluded a mechanical blockage — the symptoms are identical.
- Small intestinal bacterial overgrowth← from “Pacemaker cells wired between the muscle layer…”
Anything that stops the fasting housekeeping wave leaves the small bowel unswept — scleroderma, long-standing diabetes, chronic opioid use, a blind loop left behind after surgery, adhesions, or a resected ileocaecal valve that lets colonic bacteria track back up. Colonic-type bacteria colonise the small bowel and ferment carbohydrate to gas before the mucosa can absorb it, and deconjugate bile salts so fat is malabsorbed too.
Low B12 with high folate is the fingerprint. Antibiotics clear it — rifaximin has the best evidence but in Australia it is registered for hepatic encephalopathy and its use in SIBO is off-label and unsubsidised, so amoxicillin-clavulanate, metronidazole or a tetracycline are commonly used instead. Whichever is used, it returns within months unless the stasis itself is fixed — the antibiotic treats the consequence of a dead migrating motor complex, not the cause.
You would find: Bloating, audible wind and watery diarrhoea coming on within hours of eating, with weight loss if it has run long. The bloods are the giveaway: low vitamin B12, because the bacteria consume it, with a normal or high folate, because the bacteria make it. Breath testing after glucose or lactulose supports the diagnosis but is unreliable enough that a response to antibiotics is often the real test.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- The D2 dopamine receptor on myenteric plexus neurons. Metoclopramide adds weak agonism at the 5-HT4 receptor on those same neurons (and 5-HT3 antagonism at higher doses); domperidone has neither and is a pure D2 antagonist.
- Which does
- Dopamine released within the plexus normally holds down acetylcholine release from the excitatory motor neurons. Blocking D2 takes that brake off, so more acetylcholine reaches M3 receptors on the smooth muscle; metoclopramide's weak 5-HT4 agonism pushes the same neurons in the same direction. Antral contractions strengthen and coordinate with the pylorus.
- So you see
- The stomach empties faster, fullness and nausea settle, and vomiting stops — the antiemetic part coming from D2 blockade in the chemoreceptor trigger zone rather than from anything happening in the stomach.
- And the same mechanism causes
- The D2 receptor is not only in the gut, and metoclopramide crosses into the brain. Block it in the nigrostriatal pathway and you get exactly what a dopamine-blocking antipsychotic does: an acute dystonic reaction, often within hours of the first dose — eyes rolled upwards, neck twisted, jaw locked — plus restlessness the patient cannot sit still through (akathisia), parkinsonism with longer use, and tardive dyskinesia after months. Block the same receptor on pituitary lactotrophs, where dopamine from the tuberoinfundibular pathway is the brake on prolactin release, and prolactin rises: galactorrhoea, breast tenderness, amenorrhoea. Nothing here is a random side effect — it is one receptor in three tissues.
- Handling
- Courses are kept short: since the 2015 TGA review, metoclopramide is limited to a maximum of five days in every age group. It is contraindicated under 1 year of age, and in children and young adults under 20 it is restricted to second-line use in narrow indications, because that group has by far the highest risk of a dystonic reaction. An acute dystonia is reversed with an anticholinergic such as benztropine, not with more antiemetic.
Catches people out: Domperidone blocks the same D2 receptor but does not enter the brain parenchyma, so movement problems are rare — instead it blocks cardiac potassium (hERG) channels and prolongs the QT interval, which is its own limiting risk and the reason it is used at the lowest effective dose and avoided in significant cardiac disease. Prucalopride is the cleaner version of the other half of metoclopramide's mechanism: a selective 5-HT4 agonist used for chronic constipation, without the dopamine blockade and without the movement disorder.
- Binds
- The motilin receptor on enteric neurons and gastric smooth muscle
- Which does
- It mimics motilin and triggers phase III of the migrating motor complex out of turn — the strong, sweeping housekeeping contraction that normally only happens between meals — regardless of whether the stomach has just been fed. At the lower, prokinetic doses this works largely through motilin receptors on cholinergic enteric neurons, so it too ends up putting more acetylcholine onto the muscle.
- So you see
- Powerful antral contractions with better antroduodenal coordination, and the stomach empties. It is the fastest-acting prokinetic there is, working within minutes when given intravenously.
- And the same mechanism causes
- Motilin receptors are spread along the upper gut, so the same forceful sweeping contraction that empties the stomach produces cramping abdominal pain, nausea and diarrhoea further down. And a receptor that is stimulated constantly disappears: motilin receptors downregulate within days to weeks, so the drug simply stops working (tachyphylaxis). That is a mechanistic ceiling, not a tolerance the patient can push through.
- Handling
- A single dose to clear the stomach before endoscopy sits on exactly the same mechanism as its use in gastroparesis — one drug, one receptor, two clinical problems.
Catches people out: It is still an antibiotic, so prolonged prokinetic use drives resistance. It also blocks cardiac potassium channels and is a potent CYP3A4 inhibitor — QT prolongation and interactions matter as much as the gut effect.
- Binds
- The active site of acetylcholinesterase, the enzyme that destroys acetylcholine in the synaptic cleft
- Which does
- Acetylcholine that is released is no longer broken down, so it accumulates and keeps activating M3 receptors on colonic smooth muscle. The parasympathetic push that had dropped away is restored chemically, and the colon starts generating propagating contractions again.
- So you see
- Dramatic decompression — a rush of flatus and stool, often within minutes, and a visibly flatter abdomen. Most patients respond, which is why it is the definitive medical treatment before anything invasive.
- And the same mechanism causes
- The acetylcholine it spares is not confined to the colon. The same accumulated acetylcholine reaches M2 receptors on the sinoatrial node and slows the heart — bradycardia within minutes, occasionally to asystole — and hits M3 receptors elsewhere, causing salivation, sweating, watery eyes, and bronchoconstriction that matters in asthma. Every one of these is the same molecule at the same receptor family in a different tissue, which is why atropine is the antidote and why it is sitting ready before the infusion starts.
- Handling
- Only after mechanical obstruction, ischaemia and perforation have been excluded on imaging. Give it with continuous ECG monitoring and atropine drawn up at the bedside.
Catches people out: Absolutely contraindicated if mechanical obstruction, ischaemia or perforation is suspected — driving strong contractions against a closed or dead segment perforates it. Avoid too in significant bradyarrhythmia and active bronchospasm, both of which its own mechanism will worsen.
- Binds
- The mu-opioid receptor on enteric neurons of the myenteric plexus
- Which does
- Opioids bind these receptors, hyperpolarise the neuron and cut acetylcholine release, so propulsive waves are replaced by non-propulsive segmenting contractions, transit slows, more water is reabsorbed, and sphincters tighten. Blocking the receptor in the gut restores acetylcholine release and normal propulsion, while the analgesic receptors in the brain and spinal cord stay occupied.
- So you see
- The bowels open, often within a day and sometimes within hours, with no loss of pain relief and no systemic withdrawal — which is the entire point of the class. The same trick can be played with plain naloxone, but only by mouth: swallowed naloxone acts on the gut and is then almost entirely destroyed on first pass through the liver, which is exactly how the oxycodone-with-naloxone combination (Targin) works. Injected naloxone reaches the brain and reverses the analgesia, so it can never be used this way.
- And the same mechanism causes
- Pulling opioid off receptors that the gut has adapted to gives the bowel a withdrawal of its own: cramping abdominal pain, wind and diarrhoea, without any systemic withdrawal at all. If the blood-brain barrier is damaged — head injury, some intracranial tumours — enough drug can cross to precipitate genuine central withdrawal and unmask the pain the opioid was treating.
- Handling
- For established postoperative ileus, the useful moves are subtractive: cut the opioids, replace potassium and magnesium, mobilise the patient early, and use regional or non-opioid analgesia so the brake is never applied.
Catches people out: Contraindicated where mechanical obstruction is known or suspected: restoring strong contractions proximal to a blockage risks perforation, and gastrointestinal perforation has been reported in advanced illness where the bowel wall is already compromised.
Every motility drug on this page does one of two things at the junction where the myenteric neuron meets smooth muscle — it adds a push, or it removes a brake. Metoclopramide removes the dopamine brake, naloxegol and methylnaltrexone remove the opioid brake, neostigmine stops the acetylcholine being destroyed, erythromycin borrows the motilin signal that already drives the housekeeping wave. Once you can say which brake or which push, the adverse effects write themselves, because the same receptor sits somewhere else: D2 in the basal ganglia gives dystonia and D2 in the pituitary gives galactorrhoea, M2 in the sinoatrial node gives bradycardia, mu in the gut being unblocked gives cramps. And the two diseases with no drug at all — Hirschsprung, which needs the aganglionic segment cut out, and postoperative ileus, which needs the opioids taken away — are the ones where naming the mechanism tells you not to reach for a prescription.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.