title: 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.affiliation: Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China Department of pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, China.
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Feng
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Yan
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Er-Man
authors.initials: EM
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Jing-Yuan
authors.initials: JY
authors.lastname: Fang
authors.forename: Sheng-Liang
authors.initials: SL
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D043183:Irritable Bowel Syndrome / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D059225:Nociception / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*; D059265:Visceral Pain / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D012701:Serotonin; C103505:AM 251; C078814:anandamide
keywords: Anandamide; Postinfectious irritable bowel syndrome; Serotonin; Vagal afferents; Visceral pain