ROLE OF TACHYKININS IN CASTOR-OIL DIARRHEA IN RATS

1 We set out to ascertain the role of tachykinins, neurokinin A and su bstance P, in castor oil-induced diarrhoea in rats as disclosed by the inhibitory effect of the non-peptide NK1- and NK2-receptor antagonist s, SR 140333 and SR 48968, respectively. 2 SR 48968 (0.02 to 20 mu g k g(-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: % in hibition 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 mu g kg(-1), s .c.) and the platelet activating factor antagonist SR 27417 (5 to 500 mu g kg(-1), p.o.) did not prevent the increase in faecal water conten t, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3 The R-enantiomers of tachykinin NK1 and NK2 receptor antagonists, SR 1406 03 and SR 48605 (both at 2 or 20 mu g kg(-1), s.c.) had no effect othe r than reducing faecal mass at the highest dose tested. 4 SR 48968 (20 mu g 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% th e increase of faecal mass output; both treatments significantly reduce d (30 to 70%) the effect of castor oil on faecal water content, althou gh the incidence of diarrhoea was only slightly less than in controls. 5 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 mu g kg(-1), p.o.); a similar result was obtai ned on faecal mass and water content. 6 Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contraction s (500 to 1000% over control values) of transverse and distal colon, t his effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transvers e colon). 7 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 dramati c effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8 Our findings suggest that castor oil diarrhoea in rats entails activation of NK1 and NK2 receptors by endo genous tachykinins, whose antagonists may have a potential as antidiar rhoeal agents free from the constipating action of opioids.