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 act ivation of the mu opioid receptor. A fundamental question in addiction biol ogy is why exogenous opiate drugs have a high liability for inducing tolera nce 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 demonstra te that this regulatory mechanism reveals an independent functional propert y of opiate drugs that can be distinguished from previously established ago nist properties. Moreover, this property correlates with agonist propensity to promote physiological tolerance, suggesting a fundamental revision of o ur understanding of the role of receptor endocytosis in the biology of opia te drug action and addiction.