Faculty Collaboration Database

Visceral analgesic effect of 5-HT(4) receptor agonist in rats involves the rostroventral medulla (RVM). Neuropharmacology 2014 Apr;79:345-58

Date

12/18/2013

Pubmed ID

24334068

Pubmed Central ID

PMC4321751

DOI

10.1016/j.neuropharm.2013.12.006

Scopus ID

2-s2.0-84891619998 (requires institutional sign-in at Scopus site)   17 Citations

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.

Author List

Sengupta JN, Mickle A, Kannampalli P, Spruell R, McRorie J, Shaker R, Miranda A

Authors

Adrian Miranda MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Jyoti N. Sengupta PhD Professor in the Medicine department at Medical College of Wisconsin
Reza Shaker MD Assoc Provost, Sr Assoc Dean, Ctr Dir, Chief, Prof in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abdominal Muscles
Analgesics
Animals
Colon
Indoles
Male
Medulla Oblongata
Muscarinic Antagonists
Narcotic Antagonists
Neurons
Neurons, Afferent
Periaqueductal Gray
Rats
Rats, Sprague-Dawley
Receptors, Serotonin, 5-HT4
Serotonin 5-HT4 Receptor Agonists
Serotonin Antagonists
Spinal Cord
Trinitrobenzenesulfonic Acid
Visceral Pain