W1729 Volume Dependent Recruitment of Adaptive Esophageal Peristaltic and Upper Esophageal Sphincter Contractile Reflexes Is Preserved in Sleep State in Healthy Premature Infants

Abstract

Background: Serotonin (5-HT) plays a major role in gastrointestinal (GI) functions. Of several subtypes of 5-HT receptors, 5-HT3 and 5-HT4 are involved in GI motility and pain. 5-HT4 receptor agonist tegaserod (TEG) has been shown to modulate visceral pain in both humans and animals. However, its underlying mechanism of action remains unknown. Aim: The objective of the present study is to examine the site of action of this drug in colorectal distension (CRD)-induced visceral pain in naive and post-inflamed sensitized rats. Methods: In each of 47 male Sprague-Dawley rats under fully anesthetized state, a bipolar electrode was implanted surgically into the external oblique muscle of the abdomen to measure the visceromotor response (VMR) represented as electrical activity (EMG) of the muscle to graded CRD (10-80mmHg). VMR was recorded in fully awake rats 72 hours following the surgery. To induce colonic inflammation, 0.5ml of tri-nitrobenzene sulfonic acid (TNBS) in 50% ethanol was infused into the colon under the influence of anesthesia and rats were tested 7days after TNBS injection. Drugs were injected either intraperitoneally (ip), intravenously (iv) or subcutaneously (sc). Electrophysiological recordings were made from the S1 sacral dorsal root receiving pelvic nerve innervating the colon. Responses of pelvic afferents to CRD were recorded before and after TEG injection. Results: Rats exhibited linear increasing VMR to graded CRD. TNBS-treated rats exhibited significantly (p<0.05 vs naive) greater VMR suggesting the sensitization following inflammation. High doses of TEG (5 and 10mg/ kg, ip) resulted in severe CNS effect including agitation, motor impairment and sedation (n=4). CNS effects were delayed in atropine (5mg/kg, ip) pretreated rats (n=4). Lower doses (0.5 and 1mg/kg, ip) of TEG did not produce any visible CNS effect. TEG (1mg/kg) significantly attenuated VMR in both naive and post-inflamed rats. Atropine failed to block the effect of TEG, suggesting that visceral analgesia was not mediated via muscariniccholinergic system. Selective 5-HT4 antagonist GR113808 (5mg/kg, sc) significantly reversed the effect of TEG. Similarly, opioid receptor antagonist naloxone (5mg/kg, iv) significantly reversed the effect of TEG. In electrophysiology experiments, TEG (1mg/kg, ip) did not attenuate the mechanotransduction of colonic pelvic nerve afferents in either naive or postinflamed rats. Conclusion: Results suggest that TEG produces visceral analgesia via the activation of central 5-HT4 receptors. Since opioid antagonist naloxone blocks the effect of TEG, it suggests that the central opioidergic system is linked to 5-HT4 mediated visceral analgesia.