title: Visceral analgesic effect of 5-HT(4) receptor agonist in rats involves the rostroventral medulla (RVM).
abstract: The 5-HT(4) receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. In male rats, visceral pain was assessed by measuring visceromotor response (VMR) to colorectal distension (CRD). Inflammation was induced by intracolonic injection of tri-nitrobenzene sulfonic acid (TNBS). The effect of TEG on the VMR was tested by injecting intraperitoneal (i.p.), intrathecal (i.t.), intracerebroventricular (i.c.v) or in the rostroventral medulla (RVM). The effect of the drug was also tested on responses of CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons. Systemic injection of TEG attenuated VMR in naive and TNBS-treated rats. Similarly, supraspinal, but not spinal, injection of TEG attenuated the VMR. While GR113808, (selective 5-HT(4) antagonist) blocked the effect, naloxone (NLX) an opioid receptor antagonist reversed the effect of TEG. Although i.t. NLX did not block the inhibitory effect of TEG in VMR study, i.t. injection of α2-adrenergic receptor antagonist yohimbine blocked the effect of TEG when given systemically. While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT(4) receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.
authors: Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: sengupta@mcw.edu.
authors: Jyoti N
authors: JN
authors: Sengupta
authors: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Aaron
authors: A
authors: Mickle
authors: Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Pradeep
authors: P
authors: Kannampalli
authors: Procter & Gamble Pharmaceuticals Inc., Mason, OH, USA.
authors: Russell
authors: R
authors: Spruell
authors: Procter & Gamble Pharmaceuticals Inc., Mason, OH, USA.
authors: John
authors: J
authors: McRorie
authors: Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Reza
authors: R
authors: Shaker
authors: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Adrian
authors: A
authors: Miranda
mesh_terms: D000009:Abdominal Muscles / Q000187:drug effects / Q000503:physiopathology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D014302:Trinitrobenzenesulfonic Acid; D059265:Visceral Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000700:Analgesics; D007211:Indoles; D018727:Muscarinic Antagonists; D009292:Narcotic Antagonists; D058828:Serotonin 5-HT4 Receptor Agonists; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4; C105050:tegaserod; D014302:Trinitrobenzenesulfonic Acid
keywords: 5-HT(4) receptors; Colon; Descending modulation; RVM; Visceral pain