title: Ligand-induced μ opioid receptor internalization in enteric neurons following chronic treatment with the opiate fentanyl.
abstract: Morphine differs from most opiates its poor ability to internalize μ opioid receptors (μORs). However, chronic treatment with morphine produces adaptational changes at the dynamin level, which enhance the efficiency of acute morphine stimulation to promote μOR internalization in enteric neurons. This study tested the effect of chronic treatment with fentanyl, a μOR-internalizing agonist, on ligand-induced endocytosis and the expression of the intracellular trafficking proteins, dynamin and β-arrestin, in enteric neurons using organotypic cultures of the guinea pig ileum. In enteric neurons from guinea pigs chronically treated with fentanyl, μOR immunoreactivity was predominantly at the cell surface after acute exposure to morphine with a low level of μOR translocation, slightly higher than in neurons from naïve animals. This internalization was not due to morphine's direct effect, because it was also observed in neurons exposed to medium alone. By contrast, D-Ala2-N-Me-Phe4-Gly-ol5-enkephalin (DAMGO), a potent μOR-internalizing agonist, induced pronounced and rapid μOR endocytosis in enteric neurons from animals chronically treated with fentanyl or from naïve animals. Chronic fentanyl treatment did not alter dynamin or β-arrestin expression. These findings indicate that prolonged activation of μORs with an internalizing agonist such as fentanyl does not enhance the ability of acute morphine to trigger μOR endocytosis or induce changes in intracellular trafficking proteins, as observed with prolonged activation of μORs with a poorly internalizing agonist such as morphine. Cellular adaptations induced by chronic opiate treatment might be ligand dependent and vary with the agonist efficiency to induce receptor internalization.
authors.affiliation: CURE Digestive Diseases Research Center, Digestive Diseases Division, Los Angeles, CA 90073, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Anselmi
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jaramillo
authors.forename: Michelle
authors.initials: M
authors.lastname: Palacios
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huynh
authors.forename: Catia
authors.initials: C
authors.lastname: Sternini
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004705:Endocytosis / Q000187:drug effects; D017615:Enteric Nervous System / Q000187:drug effects* / Q000378:metabolism; D005283:Fentanyl / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D017450:Receptors, Opioid, mu; D009020:Morphine; D005283:Fentanyl
references.citation: Dev Cell. 2006 Jun;10(6):839-50
references.pmid: 16740485
references.citation: Curr Opin Neurobiol. 2003 Jun;13(3):348-53
references.pmid: 12850220
references.citation: J Pharmacol Exp Ther. 1992 Jul;262(1):1-9
references.pmid: 1625189
references.citation: J Neurosci. 2002 Dec 1;22(23):10192-200
references.pmid: 12451120
references.citation: Anesthesiology. 1995 May;82(5):1226-36
references.pmid: 7741298
references.citation: Nature. 1996 Oct 31;383(6603):819-23
references.pmid: 8893006
references.citation: Annu Rev Neurosci. 2004;27:107-44
references.pmid: 15217328
references.citation: Mol Psychiatry. 2000 Mar;5(2):121
references.pmid: 10822332
references.citation: J Biol Chem. 1996 Aug 9;271(32):19021-4
references.pmid: 8702570
references.citation: Anesthesiology. 2006 Sep;105(3):574-80
references.pmid: 16931992
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G8-15
references.pmid: 11408250
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9914-9
references.pmid: 9707575
references.citation: J Biol Chem. 2003 May 23;278(21):18776-84
references.pmid: 12642578
references.citation: Mol Pharmacol. 1994 Feb;45(2):330-4
references.pmid: 8114680
references.citation: Life Sci. 2003 Dec 5;74(2-3):217-24
references.pmid: 14607249
references.citation: Mol Pharmacol. 2008 Oct;74(4):972-9
references.pmid: 18612077
references.citation: Neuroscience. 2004;123(1):101-9
references.pmid: 14667445
references.citation: Biochem J. 1997 Feb 15;322 ( Pt 1):1-18
references.pmid: 9078236
references.citation: Eur J Pharmacol. 1985 Apr 16;110(3):335-41
references.pmid: 2988984
references.citation: J Pharmacol Exp Ther. 1999 May;289(2):607-24
references.pmid: 10215631
references.citation: Neuroscience. 1999 Mar;90(3):1051-9
references.pmid: 10218804
references.citation: J Neurosci. 2002 Jul 1;22(13):5769-76
references.pmid: 12097530
references.citation: J Neurosci. 2005 Aug 24;25(34):7847-57
references.pmid: 16120787
references.citation: Curr Opin Neurobiol. 2007 Oct;17(5):556-64
references.pmid: 18068348
references.citation: Br J Pharmacol. 2012 Mar;165(6):1704-1716
references.pmid: 21564086
references.citation: Physiol Rev. 2001 Jan;81(1):299-343
references.pmid: 11152760
references.citation: Mol Pharmacol. 1998 Mar;53(3):377-84
references.pmid: 9495801
references.citation: Prog Neurobiol. 2002 Apr;66(5):285-306
references.pmid: 12015197
references.citation: Br J Pharmacol. 2008 May;154(2):384-96
references.pmid: 18414400
references.citation: Neuroscience. 1997 Nov;81(2):579-91
references.pmid: 9300443
references.citation: Neuroscience. 2003;119(1):33-42
references.pmid: 12763066
references.citation: J Biol Chem. 1999 Aug 27;274(35):24575-8
references.pmid: 10455121
references.citation: Br J Pharmacol. 2011 Oct;164(4):1322-34
references.pmid: 21434879
references.citation: Trends Pharmacol Sci. 1999 Jan;20(1):19-26
references.pmid: 10101958
references.citation: Proc Natl Acad Sci U S A. 1984 Nov;81(22):7253-7
references.pmid: 6095280
references.citation: J Biol Chem. 1997 Nov 14;272(46):28869-74
references.pmid: 9360954
references.citation: J Biol Chem. 1996 Aug 2;271(31):18302-5
references.pmid: 8702465
references.citation: Drugs. 2012 Oct 1;72(14):1847-65
references.pmid: 22950533
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9241-6
references.pmid: 8799185
references.citation: Mol Pharmacol. 1998 Oct;54(4):704-11
references.pmid: 9765514
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):7157-62
references.pmid: 9618555
references.citation: J Comp Neurol. 1996 Apr 08;367(3):375-402
references.pmid: 8698899
references.citation: Mol Pharmacol. 2005 Jan;67(1):280-7
references.pmid: 15475572
references.citation: J Comp Neurol. 2003 Apr 14;458(4):404-11
references.pmid: 12619074
references.citation: Neuroscience. 2000;98(2):233-41
references.pmid: 10854754
references.citation: Int J Clin Pract. 2007 Jul;61(7):1181-7
references.pmid: 17488292
references.citation: Neuron. 1999 Aug;23(4):737-46
references.pmid: 10482240
references.citation: Neuroscience. 2004;125(3):541-3
references.pmid: 15099667
references.citation: Gastroenterology. 2011 Feb;140(2):618-26
references.pmid: 21070774
references.citation: Pharmacol Rev. 1988 Jun;40(2):121-62
references.pmid: 3070578
references.citation: Mol Pharmacol. 2004 Jul;66(1):106-12
references.pmid: 15213301