The function of 5-HT3 receptors on colonic transit in rats

The function of serotonin (5-HT)(3) receptors on colonic transit was investigated in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg, s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.), corticotropin releasing factor (CRF; 1 mu g intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5-HT3 receptor antagonist, azasetron {(+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride; 0.01-10 mg/kg, p.o.} inhibited the 5-HT-, CRF- and stress-accelerated colonic transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron (1 mg/kg, p.o.) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s.c) and tetrodotoxin (0.01 mg/kg, sc.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300 mg/kg, p.o.), and metoclopramide (30 mg/kg, p.o.) did not. Azasetron (10 mu g) administered intracerebroventricularly did not inhibit the stress-induced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in stress-related colonic dysfunction like irritable bowel syndrome.