Tegaserod inhibits noxious rectal distention induced responses and limbic system c-Fos expression in rats with visceral hypersensitivity.
OBJECTIVE
To examine the effects of tegaserod, a serotonin (5-HT) 4 receptor partial agonist, on abdominal withdrawal reflex (AWR) to rectal distention (RD) and c-Fos expression in limbic system.


METHODS
Neonatal Sprague-Dawley rats randomly received colonic irritation by acetic acid from postnatal day 8 to d 21 as a visceral hypersensitive model (group H) or by intrarectal saline as a control group (group C). When they became adults, rectal distention (RD) was performed by a balloon (6F; Fogarty arterial embolectomy catheter; length, 20 mm; diameter, 2 mm) which was rapidly inflated with increasing volumes of saline (0.4, 0.8 and 1.2 mL) for 20 s at five-minute intervals. Five subgroups of group H (H-saline, H-vehicle, H-Teg0.1, H-Teg0.3 and H-Teg1.0) were injected randomly with saline, vehicle (1-methyl-2-thpyrrolidone) or tegaserod at doses of 0.1, 0.3 and 1.0 mg/kg ip, respectively. Two subgroups of group C (C-Saline and C-Teg1.0) were injected with saline or tegaserod (1.0 mg/kg) ip. RD was performed 10 min after injection, AWR was recorded and c-Fos expression in limbic system was analyzed quantitatively by immunohistochemistry.


RESULTS
Compared to saline, tegaserod significantly inhibited AWR in group H (0.4 mL: from 2.0 to 0.5; 0.8 mL: from 3.5 to 1.5; 1.2 mL: from 4.0 to 3.0, P<0.01), but had no significant effect on group C. Tegaserod dose-dependently attenuated the number of c-Fos positive neurons in limbic structures, anterior cingulate cortex (ACC) showed the greatest attenuation. In group H, tegaserod (1.0 mg/kg) resulted in a significant overall decrease to 57% of H-saline (283+/-41 vs 162+/-16, P<0.01), in ACC to 42% of H-saline (72+/-10 vs 31+/-8, P<0.01). In group C, tegaserod (1.0 mg/kg) resulted in an overall decrease to 77% of C-saline (214+/-13 vs 164+/-22, P<0.01), in ACC to 65% of C-saline (48+/-8 vs 31+/-7, P<0.01).


CONCLUSIONS
Tegaserod inhibits the response to rectal distention in rats with visceral hypersensitivity and dose-dependently attenuates c-Fos expression in limbic system, especially in anterior cingulate cortex.
Jiao
Hong-Mei
HM
Department of Gastroenterology, First Hospital of Peking University, Beijing 100034, China.
Xie
Peng-Yan
PY
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000502:physiology*; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects / Q000502:physiology*
D005765:Gastrointestinal Agents; D007211:Indoles; D016760:Proto-Oncogene Proteins c-fos; C105050:tegaserod; D009195:Peroxidase