Tegaserod inhibits noxious rectal distention induced responses and limbic system c-Fos expression in rats with visceral hyper-sensitivity

摘要

AIM: 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). CONCLUSION: 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.