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)