Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction.
Opiate analgesia, tolerance, and addiction are mediated by drug-induced activation of the mu opioid receptor. A fundamental question in addiction biology is why exogenous opiate drugs have a high liability for inducing tolerance and addiction while native ligands do not. Studies indicate that highly addictive opiate drugs such as morphine are deficient in their ability to induce the desensitization and endocytosis of receptors. Here, we demonstrate that this regulatory mechanism reveals an independent functional property of opiate drugs that can be distinguished from previously established agonist properties. Moreover, this property correlates with agonist propensity to promote physiological tolerance, suggesting a fundamental revision of our understanding of the role of receptor endocytosis in the biology of opiate drug action and addiction.
Whistler
J L
JL
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, USA.
Chuang
H H
HH
Chu
P
P
Jan
L Y
LY
von Zastrow
M
M
D019393:Arrestin / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004361:Drug Tolerance; D004594:Electrophysiology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005048:Etorphine / Q000494:pharmacology; D005434:Flow Cytometry; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000503:physiopathology*; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic / Q000096:biosynthesis / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D019393:Arrestin; D004745:Enkephalins; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006150:Guanine Nucleotides; D008024:Ligands; D009294:Narcotics; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005048:Etorphine; D009020:Morphine