Increased defecation during stress or after 5-hydroxytryptophan: selective inhibition by the 5-HT(4) receptor antagonist, SB-207266.
5-HT(4) receptor antagonism prevents the ability of exogenous 5-HT or 5-HTP to sensitize the intestinal peristaltic reflex and increase the rate of defecation, generally without affecting non-stimulated intestinal function. In this study we confirmed the ability of the selective 5-HT(4) receptor antagonist SB-207266 1 - 1000 microg kg(-1) p.o., to prevent the increase in defecation evoked over a 60 min period by 5-HTP 10 mg kg(-1) s.c. in conscious mice, in the absence of an apparent constipating action. The role of endogenous 5-HT in the mechanisms of increased defecation and/or diarrhoea was then investigated in conscious, fed rats. This was evoked by 180 min exposure to restraint stress, which increased both the number and mean weight of formed, faecal pellets excreted over the entire time period. SB-207266 1 - 1000 microg kg(-1) p.o. (dosed 30 min before restraint) did not affect the increase in defecation evoked during the first 60 min of restraint stress, but significantly and dose-dependently reduced or prevented the increased defecation during the remaining 120 min of the experiment; this action occurred in the absence of an apparent constipating action of SB-207266. In fasted rats exposed to restraint stress, watery diarrhoea developed and although there was a tendency for SB-207266 1 - 1000 microg kg(-1) p.o. (dosed 30 min before restraint) to reduce the incidence of diarrhoea, this inhibition was not complete. We conclude that selective 5-HT(4) receptor antagonism prevents disruptions in defecation behaviours caused by exogenous or endogenous enteric 5-HT and that this activity is not accompanied by a concomitant suppression of activity (constipation-like) within the intestine itself.
Sanger
G J
GJ
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, Third Avenue, Harlow, Essex, CM19 5AW.
Yoshida
M
M
Yahyah
M
M
Kitazumi
K
K
D006916:5-Hydroxytryptophan / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D003672:Defecation / Q000187:drug effects*; D003967:Diarrhea / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000502:physiology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4; D012149:Restraint, Physical; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013315:Stress, Psychological / Q000523:psychology*
D007211:Indoles; D010880:Piperidines; D011985:Receptors, Serotonin; C096919:SB 207266; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4; D006916:5-Hydroxytryptophan