title: Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig.
abstract: The μ-opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut function, the cellular and subcellular distribution and regulation of MOR within the enteric nervous system are largely undefined. Herein, we defined the neurochemical coding of MOR-expressing neurons in the guinea pig gut and examined the effects of opioids on MOR trafficking and regulation. MOR expression was restricted to subsets of enteric neurons. In the stomach MOR was mainly localized to nitrergic neurons (∼88%), with some overlap with neuropeptide Y (NPY) and no expression by cholinergic neurons. These neurons are likely to have inhibitory motor and secretomotor functions. MOR was restricted to noncholinergic secretomotor neurons (VIP-positive) of the ileum and distal colon submucosal plexus. MOR was mainly detected in nitrergic neurons of the colon (nitric oxide synthase positive, 87%), with some overlap with choline acetyltransferase (ChAT). No expression of MOR by intrinsic sensory neurons was detected. [d-Ala(2), MePhe(4), Gly(ol)(5)]enkephalin (DAMGO), morphiceptin, and loperamide induced MOR endocytosis in myenteric neurons. After stimulation with DAMGO and morphiceptin, MOR recycled, whereas MOR was retained within endosomes following loperamide treatment. Herkinorin or the δ-opioid receptor agonist [d-Ala(2), d-Leu(5)]enkephalin (DADLE) did not evoke MOR endocytosis. In summary, we have identified the neurochemical coding of MOR-positive enteric neurons and have demonstrated differential trafficking of MOR in these neurons in response to established and putative MOR agonists.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: Joslyn
authors.initials: J
authors.lastname: Lay
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: Simona E
authors.initials: SE
authors.lastname: Carbone
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: DiCello
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Departments of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia; and Department of Anaesthesia and Peri-operative Medicine, Monash University, Parkville, Victoria, Australia.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia; and.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Canals
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Parkville, Victoria, Australia; and Daniel.Poole@Monash.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Poole
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism; D003106:Colon / Q000294:innervation*; D004705:Endocytosis; D004723:Endorphins / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D007082:Ileum / Q000294:innervation*; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000378:metabolism; D026602:Nitrergic Neurons / Q000378:metabolism; D021381:Protein Transport; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D013270:Stomach / Q000294:innervation*
chemical_list: D000701:Analgesics, Opioid; D004723:Endorphins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D008139:Loperamide; C028889:morphiceptin
keywords: G protein-coupled receptor; enteric nervous system; mu opioid receptor; neurochemical coding; opioid