Exendin-4,an analogue of Glucagon-like peptide-1,attenuates hyperalgesia through serotonergic pathways in rats with neonatal colonic sensitivity

Glucagon-like peptide-1 (glp-1) analogue rose-010 can provide effective pain relief from irritable bowel syndrome (ibs). however,the underlying biological mechanism is still unknown. here,we investigate the effect of glp-1 analogue exendin-4 on visceral hypersensitivity in colonic sensitized rats. rat models of visceral hypersensitivity were established by intra-colonic infusion of acetic acid in 10-day-old sprague-dawley rats. visceral sensitivity was assessed by measurement of abdominal withdrawal reflex (awr) and electromyography (emg). exendin-4 with doses of 1,5,and 10 ∞g/kg were intraperitoneally administered,respectively. the expressions of serotonin transporter (sert) and tryptophan hydroxylase-1 (tph-1) in colonic tissues were detected by rt-pcr and western blot,respectively. the levels of serotonin (5-ht) and glp-1 were measured by elisa assay. visceral hypersensitivity after neonatal colonic sensitization was verified. the colonic sensitized rats showed low levels of glp-1 in plasma and high levels of 5-ht in plasma and colonic tissue (p<0.05). exendin-4 dose-dependently reduced visceral hypersensitivity in colonic sensitized rats. the awr scores in colonic sensitized rats with exendin-4 (5 ∞g/kg) reduced to 1.56±0.53 (p=0.013 vs. 2.33±0.50),2.23±0.45 (p=0.008 vs. 3.0±0.5) during crd at 40,and 60 mmhg,respectively. similar findings were showed at dose of 10 ∞g/kg. exendin-4 (5 ∞g/kg and 10 ∞g/kg) reduced the emg during crd at 40,60,80 mmhg (p<0.01). exendin-4 (5.0 ∞g/kg or 10.0 ∞g/kg) significantly decreased the 5-ht colonic levels (2.343±0.447,2.175±0.360 ng/100 mg vs. 3.607±0.628 ng/100 mg,p<0.05). the sert protein expressions in colonic tissues in colonic sensitized rats were significantly increased with exendin-4 at doses of 1,5 or 10 ug/kg (0.759±0.068,0.942±0.037,0.944±0.097 vs. 0.552±0.047,p<0.05,respectively),and the sert mrna expression also increased after treatment with exendin-4. the colonic sensitized rats showed lower tph-1 levels after treatment with exendin-4 (p<0.05). these findings suggest that exendin-4 reduce visceral hypersensitivity and this may be associated with up-regulating sert expression,and down-regulating tph-1 expression.