Inflammation-associated changes in DOR expression and function in the mouse colon

DiCello, JJ; Saito, A; Rajasekhar, P; Eriksson, EM; McQuade, RM; Nowell, CJ; Sebastian, BW; Fichna, J; Veldhuis, NA; Canals, M; Bunnett, NW; Carbone, SE; Poole, DP

Author(s): DiCello, JJ; Saito, A; Rajasekhar, P; Eriksson, EM; McQuade, RM; Nowell, CJ; Sebastian, BW; Fichna, J; Veldhuis, NA; Canals, M; Bunnett, NW; Carbone, SE; Poole, DP;
Details: Publication Year 2018-10,Volume 315,Issue #4,Page G544-G559
Journal Title: American Journal of Physiology. Gastrointestinal and Liver Physiology
Publication Type: Journal Article
Abstract: Endogenous opioids activate opioid receptors (ORs) in the enteric nervous system to control intestinal motility and secretion. The mu OR mediates the deleterious side effects of opioid analgesics, including constipation, respiratory depression and addiction. Although the delta OR (DOR) is a promising target for analgesia, the function and regulation of DOR in the colon are poorly understood. This study provides evidence that endogenous opioids activate DOR in myenteric neurons which may regulate colonic motility. The DOR agonists DADLE, Deltorphin II and SNC80 inhibited electrically-evoked contractions and induced neurogenic contractions in the mouse colon. Electrical, chemical and mechanical stimulation of the colon evoked the release of endogenous opioids, which stimulated endocytosis of DOR in the soma and proximal neurites of myenteric neurons of transgenic mice expressing DOR fused to eGFP. In contrast, DOR was not internalized in nerve fibers within the circular muscle. Administration of dextran sulfate sodium induced acute colitis, which was accompanied by DOR endocytosis and an increased density of DOR-positive nerve fibers within the circular muscle. The potency with which SNC80 inhibited neurogenic contractions was significantly enhanced in the inflamed colon. This study demonstrates that DOR-expressing neurons in the mouse colon can be activated by exogenous and endogenous opioids. Activated DOR traffics to endosomes and inhibits neurogenic motility of the colon. DOR signaling is enhanced during intestinal inflammation. This study demonstrates functional expression of DOR by myenteric neurons and supports the therapeutic targeting of DOR in the enteric nervous system.
Publisher: APS
Research Division(s): Population Health And Immunity
PubMed ID: 29927325
Publisher's Version: https://doi.org/10.1152/ajpgi.00025.2018
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-06-27 09:13:24

Last Modified: 2018-10-11 01:31:29