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Difenoxin and loperamide: studies on possible mechanisms of intestinal antisecretory action
1Monash University, Unit of Addictive Drug Research, School of Pharmacology, Victorian College of Pharmacy, Parkville, Australia.
Abstract:
Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) actions of difenoxin and loperamide are mediated by enteric neurones. An iso-osmotic perfusion solution was circulated around the lumen of the jejunum of anaesthetised rats. Vasoactive intestinal peptide was infused intra-arterially to induce net fluid secretion which was inhibited by difenoxin (ED50, 0.23 mg/kg) and loperamide (ED50, 0.5 mg/kg). However, neither were able to restore the fluid transport rate to the control level of absorption. The antisecretory effects of difenoxin (0.77 mg/kg) and loperamide (0.6 mg/kg) were blocked by the opiate receptor antagonist naloxone (2 mg/kg). Their effects were also abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA; 200 mg/kg; with desmethylimipramine given beforehand to protect noradrenergic nerves and enhance 5-HT depletion). The effect of difenoxin was blocked with methiothepin (1 mg/kg) and methysergide (30 micrograms/kg) but not ketanserin (30 micrograms/kg), ritanserin (30 mg/kg), ondansetron (10 micrograms/kg) or ICS 205-930 (3 mg/kg). None of the above 5-HT receptor antagonists modified the antisecretory effect of loperamide. The antisecretory effect of difenoxin but not loperamide was prevented by phentolamine (2 mg/kg) and by pretreatment with 6-hydroxy-dopamine (150 mg/kg total). It is concluded that both difenoxin and loperamide inhibit net fluid secretion by indirect mechanisms. It is proposed that the initial action is on enteric mu-opiate receptors and that this results in the release of 5-HT. In the case of difenoxin, the 5-HT may act on 5-HT1-like receptors to release noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Difenoxin and loperamide reduce fluid secretion in the jejunum by acting on enteric nerves. Their antisecretory effects involve opiate receptors and serotonin release, with difenoxin also engaging noradrenergic pathways.
Area of Science:
- Pharmacology
- Gastroenterology
- Neuroscience
Background:
- Antidiarrhoeal drugs like difenoxin and loperamide are known to affect fluid transport in the intestine.
- The precise mechanisms underlying their antisecretory actions, particularly their interaction with enteric neurons, require further elucidation.
Purpose of the Study:
- To investigate whether the antisecretory effects of difenoxin and loperamide are mediated by enteric neurons.
- To explore the roles of opiate receptors, serotonin (5-HT), and noradrenergic pathways in mediating these drug actions.
Main Methods:
- Experiments were conducted using an isolated rat jejunum model perfused with an iso-osmotic solution.
- Net fluid secretion was induced by vasoactive intestinal peptide infusion and inhibited by difenoxin and loperamide.
- The involvement of specific receptors and neurotransmitters was assessed using antagonists such as naloxone, p-chlorophenylalanine (PCPA), methiothepin, methysergide, phentolamine, and 6-hydroxy-dopamine.
Main Results:
- Both difenoxin and loperamide demonstrated significant antisecretory effects, inhibiting VIP-induced fluid secretion.
- These effects were blocked by the opiate receptor antagonist naloxone and by inhibiting serotonin synthesis with PCPA.
- Difenoxin's antisecretory action was further blocked by 5-HT1-like receptor antagonists (methiothepin, methysergide) and by agents affecting noradrenergic pathways (phentolamine, 6-hydroxy-dopamine), suggesting a complex mechanism involving serotonin and noradrenaline release.
Conclusions:
- Difenoxin and loperamide exert their antisecretory effects through indirect mechanisms involving enteric neurons.
- The primary action appears to involve enteric mu-opiate receptors, leading to the release of serotonin.
- Difenoxin's action additionally involves serotonin acting on 5-HT1-like receptors to release noradrenaline, highlighting distinct pathways for these related drugs.