Biomarkers of morphine tolerance and dependence are prevented by morphine-induced endocytosis of a mutant mu-opioid receptor.
Growing evidence shows that trafficking of the mu-opioid receptor (MOR) is a critical process in functional recovery from desensitization following activation and plays important roles in morphine tolerance and dependence largely because of the failure of morphine to promote such trafficking. However, morphine tolerance and dependence are believed to be mediated by multiple mechanisms, including well-documented biochemical changes in cAMP activity, N-methyl-D-aspartate receptors (NMDARs), glucocorticoid receptors (GRs), and c-fos. Here, we assess the consequences of promoting morphine-induced endocytosis on these biochemical changes utilizing a knock-in mouse model, RMOR, in which MORs undergo morphine-induced endocytosis. Chronic morphine treatment of wild-type (WT) mice promoted superactivation of adenylyl cyclase, alterations in NMDARs, and up-regulation of GR and c-fos in distinct brain regions. Notably, none of these biochemical changes occurred in the RMOR-knock-in mice. Together, these data demonstrate that morphine tolerance and dependence are mediated by multiple biochemical mechanisms and that MOR endocytosis plays a critical role in each of these mechanisms.
He
Li
L
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California-San Francisco, Emeryville, CA 94608, USA.
Kim
Joseph A
JA
Whistler
Jennifer L
JL
D000818:Animals; D015415:Biomarkers; D004361:Drug Tolerance; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D055879:Gene Knock-In Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology*; D009154:Mutation; D010147:Pain Measurement; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; D017450:Receptors, Opioid, mu; D009020:Morphine
Eur J Pharmacol. 2008 May 13;585(2-3):473-82
18417120
Mol Pharmacol. 1996 Apr;49(4):636-45
8609891
Curr Biol. 2008 Jan 22;18(2):129-35
18207746
Science. 1991 Jan 4;251(4989):85-7
1824728
Eur J Neurosci. 1995 Aug 1;7(8):1700-6
7582124
J Pharmacol Exp Ther. 1993 Oct;267(1):145-52
7901389
Neuron. 2001 Dec 6;32(5):829-39
11738029
Anesthesiology. 1995 May;82(5):1226-36
7741298
Neuron. 1996 May;16(5):897-900
8630245
J Neurochem. 1996 Jan;66(1):369-77
8522977
J Neurosci. 1996 Jan;16(1):274-82
8613793
J Neurosci. 2000 Dec 1;20(23):8578-84
11102461
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9241-6
8799185
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1544-9
9037090
Eur J Pharmacol. 2007 Jun 1;563(1-3):92-101
17349996
Neurochem Res. 2008 Apr;33(4):691-707
17960478
Proc Natl Acad Sci U S A. 1975 Aug;72(8):3092-6
1059094
Anesthesiology. 2005 Apr;102(4):832-7
15791114
J Clin Invest. 2008 Mar;118(3):1065-73
18246198
Cell. 2002 Jan 25;108(2):271-82
11832216
Neuron. 2008 Jul 10;59(1):11-34
18614026
Brain Res Mol Brain Res. 1998 Oct 30;61(1-2):51-61
9795131
J Neurosci. 2002 Sep 15;22(18):8312-23
12223586
Nature. 2000 Dec 7;408(6813):720-3
11130073
Psychopharmacology (Berl). 2000 Aug;151(2-3):121-41
10972459
Physiol Rev. 2001 Jan;81(1):299-343
11152760
Mol Pharmacol. 1998 Mar;53(3):377-84
9495801
J Clin Invest. 2007 Nov;117(11):3185-7
17975665
Neuropsychopharmacology. 2004 Sep;29(9):1664-74
15138436
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7742-7
9636221
J Neurochem. 1995 Jul;65(1):176-83
7790859
Pain. 2005 Mar;114(1-2):81-92
15733634
J Neurosci. 2003 Jul 23;23(16):6529-36
12878694
Nature. 1996 Oct 31;383(6603):819-23
8893006
J Neurosci Res. 2006 Mar;83(4):532-7
16453311
Curr Biol. 2005 Jun 7;15(11):1028-33
15936273
J Neurosci. 2004 Mar 10;24(10):2412-20
15014116
Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8537-41
8078918
Brain Res Mol Brain Res. 1999 Sep 8;72(1):1-16
10521594
J Biol Chem. 2001 Aug 17;276(33):31408-14
11359768
Mol Pharmacol. 2005 Jan;67(1):280-7
15475572
Psychopharmacology (Berl). 2006 Jun;186(2):177-84
16572262
J Neurosci. 1990 Jul;10(7):2308-17
2115910
J Neurosci. 2005 Nov 30;25(48):11145-54
16319314
Trends Neurosci. 1992 May;15(5):186-91
1377426
J Biol Chem. 1996 Aug 30;271(35):21309-15
8702909
Neuron. 1999 Aug;23(4):737-46
10482240
J Neurosci. 2006 Nov 15;26(46):12033-42
17108177
Neuropsychopharmacology. 2008 Jun;33(7):1746-59
17895918
Stress. 2008 Sep;11(5):321-38
18609295