Difenoxin and loperamide: studies on possible mechanisms of intestinal antisecretory action.
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)
Monash University, Unit of Addictive Drug Research, School of Pharmacology, Victorian College of Pharmacy, Parkville, Australia.
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D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D004157:Diphenoxylate / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism*; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000145:classification; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D000930:Antidiarrheals; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D012702:Serotonin Antagonists; D012701:Serotonin; D014660:Vasoactive Intestinal Peptide; C100010:difenoxin; D008139:Loperamide; D004157:Diphenoxylate; D009020:Morphine