CONSTIPATION EVOKED BY 5-HT3-RECEPTOR ANTAGONISM - EVIDENCE FOR HETEROGENEOUS EFFICACY AMONG DIFFERENT ANTAGONISTS IN GUINEA-PIGS

The abilities of selective 5-HT3-receptor antagonists to evoke constipation were examined in conscious guinea-pigs and in preparations of guinea-pig isolated colon. Compared with vehicle-treated guinea-pigs, acute doses of granisetron (0.1, 1 and 10 mg kg(-1), i.p.) and tropisetron (10 mg kg(-1), i.p., but not 1 and 0.1 mg kg(-1), i.p.) significantly (P < 0.05) reduced the total number of faecal pellets excreted during a 12-h observation period. By contrast, BRL 46470 (0.1-10 mg kg(-1), i.p.) had no significant effect on the incidence of defecation. Mid-to-distal lengths of guinea-pig isolated colon spontaneously expelled faecal pellets. Granisetron (0.1 and 1 mu M) and tropisetron (1 mu M) reduced or prevented the rate at which they were spontaneously expelled. Morphine (0.1 mu M) and clonidine (10 nM) also slowed faecal pellet transit time. Naloxone (0.1 mu M) had no effects alone, but reversed the actions of granisetron, morphine and clonidine. BRL 46470 (1 mu M) had no significant effect on the transit of faecal pellets in guinea-pig isolated colon. In segments of guinea-pig isolated colon which did not contain faecal pellets, granisetron, tropisetron and BRL 46470 antagonized the ability of 5-HT to evoke cholinergically-mediated contractions of the longitudinal muscle. The respective pA(2) values and slopes of the Schild plots were 8.5 +/- 0.05, slope 1.06 +/- 0.03; 8.5 +/- 0.1, slope 0.91 +/- 0.04; and 7.9 +/- 0.1, slope 0.93 +/- 0.05. Our experiments suggest that not all 5-HT3-receptor antagonists are the same. In particular, BRL 46470 does not prevent defecation or faecal pellet expulsion in guinea-pig colon, even though this compound is an effective 5-HT3-receptor antagonist in the same tissue. For the 5-HT3-receptor antagonists which did cause constipation, the effects can be at least partly attributed to an indirect opioid-dependent action within the colonic enteric nervous system.