The irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more common in women compared to men. 5-Hydroxytryptamine (5-HT, serotonin) signaling is disrupted in some IBS patients possibly due to polymorphic variations in the gene encoding the serotonin transporter (SERT) which result in increased extracellular 5-HT availability. Female SERT knockout (KO) rats exhibit visceral hypersensitivity to colonic distention that mimics colonic hypersensitivity known to occur in female IBS patients. Studies performed herein focused on understanding the role of 5-HT3 receptor signaling in SERT KO rats. The visceromotor response (VMR) to colorectal distension (CRD) was determined following inhibition of peripheral and central 5-HT3 receptors in SERT KO and WT rats. In female SERT KO rats spinal 5-HT3 receptor inhibition with alosetron caused an increase in VMR to CRD. In Male SERT KO rats activation of spinal 5-HT3 receptors increased VMR to CRD. Depletion of descending serotonergic input from the brainstem reversed the effects of 5-HT 3 receptor inhibition in SERT KO female rats and activation in SERT KO male rats. Based on these studies, I concluded that this sex specific response observed in SERT KO rats is due to differential pattern of 5-HT3 receptor expression in male and female SERT KO rats. The effects of ovarian hormone on VMR to CRD were also investigated in SERT KO and WT female rats. Ovariectomy and estrogen receptor (ER) antagonist studies were performed in SERT KO and WT female rats. VMR to CRD was enhanced in the proestrus phase of the estrous cycle in SERT KO but not WT female rats. Ovariectomy increased discomfort to CRD in SERT KO female rats in a time dependent manner. VMR to CRD increased on day 7 post-ovariectomy and lasted for up to 3 weeks. Intrathecal administration of ICI 182 780 (ER-α and ER-β) antagonist increased VMR to CRD in SERT KO female rats. The G-protein coupled ER (GPR30) antagonist, G15, did not affect VMR to CRD in SERT KO and WT female rats. These studies suggest that in SERT KO female rats classical ERs (ERα and ERβ) play an antinociceptive role in the presence of serotonergic dysfunction.
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