Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats.

Abstract

Serotonin (5-HT) plays pivotal roles in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5-HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2-arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT 3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD, the anandamide-synthesizing enzyme) protein gradually declined from day 1 to 5. The time-dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS.

• Authors: Chen-Chen Feng, Xiu-Juan Yan, Xin Chen, Er-Man Wang, Qing Liu, Li-Yan Zhang, Jun Chen, Jing-Yuan Fang, Sheng-Liang Chen
• Journal: Pain (Pain) Vol. 155 Issue 8 Pg. 1591-1604 (Aug 2014) ISSN: 1872-6623 [Electronic] United States
• PMID: 24813296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• Arachidonic Acids
• Cannabinoid Receptor Antagonists
• Endocannabinoids
• Piperidines
• Polyunsaturated Alkamides
• Pyrazoles
• Receptor, Cannabinoid, CB1
• Serotonin
• AM 251
• anandamide

Topics

• Adult
• Animals
• Arachidonic Acids (metabolism)
• Cannabinoid Receptor Antagonists (pharmacology)
• Endocannabinoids (metabolism)
• Female
• Humans
• Intestinal Mucosa (metabolism)
• Irritable Bowel Syndrome (metabolism)
• Male
• Middle Aged
• Nociception (physiology)
• Piperidines (pharmacology)
• Polyunsaturated Alkamides (metabolism)
• Pyrazoles (pharmacology)
• Rats
• Receptor, Cannabinoid, CB1 (metabolism)
• Serotonin (pharmacology)
• Vagus Nerve (drug effects, metabolism)
• Visceral Pain (metabolism)