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Role of tachykinins in castor oil diarrhoea in rats
Author(s) -
Croci Tiziano,
Landi Marco,
EmondsAlt Xavier,
Fur Gérard,
Maffrand JeanPierre,
Manara Luciano
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701130
Subject(s) - castor oil , neurokinin a , loperamide , substance p , chemistry , agonist , medicine , (+) naloxone , antagonist , endocrinology , pharmacology , receptor , zoology , biology , neuropeptide , biochemistry , diarrhea
We set out to ascertain the role of tachykinins, neurokinin A and substance P, in castor oil‐induced diarrhoea in rats as disclosed by the inhibitory effect of the non‐peptide NK 1 ‐ and NK 2 ‐receptor antagonists, SR 140333 and SR 48968, respectively. SR 48968 (0.02 to 20 μg kg −1 , s.c. or p.o.), and the opioid receptor agonist loperamide (1–10 mg kg −1 , p.o.), dose‐dependently prevented castor oil effects: % inhibition vs castor oil, diarrhoea 0 to 100, increase in faecal mass 7 to 90 and water content 16 to 90. SR 140333 (0.02 to 20 μg kg −1 , s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 μg kg −1 , p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). The R ‐enantiomers of tachykinin NK 1 and NK 2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 μg kg −1 , s.c.) had no effect other than reducing faecal mass at the highest dose tested. SR 48968 (20 μg kg −1 , p.o.) but not loperamide (10 mg kg −1 , p.o.) given 24 h before castor oil, still slightly but significantly reduced by 30% the increase of faecal mass output; both treatments significantly reduced (30 to 70%) the effect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. In castor oil‐treated rats, naloxone (2 mg kg −1 , s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg −1 , p.o.) but not of SR 48968 (20 μg kg −1 , p.o.); a similar result was obtained on faecal mass and water content. Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). In castor oil free rats, loperamide but not SR 48968 or SR 140333 significantly reduced by 50% the gastrointestinal transit of a charcoal test meal, as well as 24 h faecal mass output. Consistently, loperamide, unlike the tachykinin receptor antagonists, had a dramatic effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. Our findings suggest that castor oil diarrhoea in rats entails activation of NK 1 and NK 2 receptors by endogenous tachykinins, whose antagonists may have a potential as antidiarrhoeal agents free from the constipating action of opioids.