Intestinal motor stimulation by the 5‐HT₄ receptor agonist ML10302: differential involvement of tachykininergic pathways in the canine small bowel and colon

Abstract

5-Hydroxytryptamine (5-HT)4 receptor agonists stimulate gut motility through cholinergic pathways, although there are data suggesting that noncholinergic (tachykininergic) excitatory pathways may also be involved. Differences may exist between the small bowel and colon. Our aims were: (i) to compare the prokinetic effect exerted by the 5-HT4 receptor agonist ML10302 in the canine small bowel and colon in vivo; and (ii) to investigate the role of tachykininergic pathways in mediating this response. In fasting, conscious dogs, chronically fitted with electrodes and strain-gauge force transducers along the small bowel and colon, intravenous injection of ML10302 (35 microg kg-1) immediately stimulated spike activity and significantly increased propagated myoelectrical events at both intestinal levels. In the small bowel, the effects of ML10302 were unchanged by previous administration of the selective NK1 tachykinin receptor antagonist SR140333, the NK2 tachykinin receptor antagonist SR48968, or the NK3 tachykinin receptor antagonist SR142801. In the colon, all tachykinin receptor antagonists significantly inhibited stimulation of spike and mechanical activity by ML10302, without affecting ML10302-induced propagated myoelectrical events. Atropine (100 microg kg-1 i.v.) suppressed the stimulatory effect of ML10302 at both intestinal levels. In conclusion, the 5-HT4 receptor agonist ML10302 induced significant prokinesia both in the small bowel and colon through activation of cholinergic pathways. Tachykininergic pathways are not involved in the ML10302-induced prokinesia in the small bowel, but they play an important role in mediating the colonic motor response to ML10302.

Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain

“…Further, close intra‐arterial injections of NK 1 receptor agonists stimulate giant migrating contractions of dog colon ( Tsukamoto et al , 1997 ) and antagonism at the receptor blocked increased defaecation induced by restraint stress in rats ( Ikeda et al , 1995 ) and blocked substance P‐ and stress‐induced defaecation by Monglolian gerbils, without affecting increases in defaecation evoked by 5‐HT or carbachol ( Okano et al , 2001 ). In conscious dogs, De Ponti et al (2001) found that NK 1 (or NK 2 or NK 3 ) receptor antagonism had no effects on propagated colonic myoelectrical events induced by 5‐HT 4 receptor activation, but reduced the associated increase in electrical spike or mechanical activity, an effect not observed with these antagonists in the small intestine. Together, these studies are consistent with an action of NK 1 receptors within the large bowel, although for the studies in vivo , a spinal site of action cannot always be ruled out.…”

Pharmacology of serotonin: what a clinician should know

“…105 An in vivo study in dogs showed that tachykininergic pathways play an important role in mediating the colonic motor response to administration of the 5-HT 4 receptor agonist ML10302 whereas they are not involved in ML10302 induced prokinesia in the small bowel. 106 Besides these actions, 5-HT 4 receptors also affect secretory processes at the mucosal level. 107 There are animal 21 and human 108 data suggesting that 5-HT released by mucosal stimulation initiates a peristaltic reflex by activating 5-HT 4 receptors on sensory neurones containing calcitonin gene related peptide.…”

Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome

“…Indeed, MEN10627 reduced restraint stress‐induced output of faecal pellets in rats (Evangelista, 2001). Finally, it should be noted that intestinal motor effects induced by the stimulation of other receptors (e.g., serotonin or protease‐activated receptors PAR‐2 and PAR‐4) are mediated in part by TKs acting through NK2 receptors ( De Ponti et al , 2001 ; Zhao & Shea‐Donohue, 2003; Mulè et al , 2004 ).…”