1 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 e ect of the non-peptide NK 1 -and NK 2 -receptor antagonists, SR 140333 and SR 48968, respectively. 2 SR 48968 (0.02 to 20 mg kg 71 , s.c. or p.o.), and the opioid receptor agonist loperamide (1 ± 10 mg kg 71 , p.o.), dose-dependently prevented castor oil e ects: % 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 mg kg 71 , s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 mg kg 71 , p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3 The R-enantiomers of tachykinin NK 1 and NK 2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 mg kg 71 , s.c.) had no e ect other than reducing faecal mass at the highest dose tested. 4 SR 48968 (20 mg kg 71 , p.o.) but not loperamide (10 mg kg 71 , p.o.) given 24 h before castor oil, still slightly but signi®cantly reduced by 30% the increase of faecal mass output; both treatments signi®cantly reduced (30 to 70%) the e ect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. 5 In castor oil-treated rats, naloxone (2 mg kg 71 , s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg 71 , p.o.) but not of SR 48968 (20 mg kg 71 , p.o.); a similar result was obtained on faecal mass and water content. 6 Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this e ect being signi®cantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). 7 In castor oil free rats, loperamide but not SR 48968 or SR 140333 signi®cantly 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 e ect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8 Our ®ndings 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.
