Opioid receptor internalization

The activation of Erkl/2 by opioid receptor has been shown to occur through the G(5y subunits in a Ras-dependent manner [101]. However, whether the delta opioid receptor activation of the Erkl/2 requires the receptor being internalized is controversial. Coscia and coworkers suggested that delta opioid receptor internalization is a prerequisite for the agonist activation of the Erkl/2 [102]. However, several laboratories have since reported that opioid receptor activation of Erkl/2 did not depend on the receptor internalization [103,104]. Dominant negative dynamin mutant that would block the agonist-induced receptor internalization would not attenuate the Erkl/2 stimulation. Such data support the observation that morphine could stimulate the Erkl/2 activity but could not induce receptor internalization [105], Thus, the delta opioid receptor stimulates the Erkl/2 activities prior to the receptor internalization processes. 

Keith, D.E., et al, mu-Opioid receptor internalization opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. Molecular Pharmacology, 1998, 53, 377-384. 

Receptor desensitization, internalization, and/or down-regulation may play a role in the development of tolerance to opioid receptor agonists (Clark et al. 

Dhawan BN, Cesselin F, Raghubir R et al. International Union of Pharmacology XII. Classification of Opioid Receptors. Pharmacol Rev 1997 48 567-592. 

Keith DE, Murray SR, Zaki PA et al. Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 1996 271 19021-19024. 

Blake AD, Bot G, Reisine T. Molecular pharmacology of the opioid receptors. In Molecular Neurobiology of Pain. Progress in Pain Research and Management, Vol. 9 (Borsook D, ed), International Association for the Study of Pain Press, USA, 1997 259-273. 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

Cvejic, S. and Devi, L. A. (1997) Dimerization of the delta opioid receptor implication for a role in receptor internalization. J. Biol. Chem. 272,26959-26964. 

Pfeiffer, M., Koch, T., Schroder, H Laugsch, M., Hollt, V and Schulz, S. (2002) Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J. Biol. Chem. 277,19762-19772. 

In case of the P -adrenergic receptor, phosphorylation of serine and threonine residues in the carboxyl tail can be shown to be involved in desensitization and internalization (141,156). Other GPCRs—such as the p- and 5-opioid receptors... 

Hasbi, A., Allouche, S., Sichel, F., et al. (2000) Internalization and recycling of delta-opioid receptor are dependent on a phosphorylation-dephosphorylation mechanism. J. Biol. Chem. 293, 237-247. 

Lee PHK, Me Nutt RW, Chang K-J. A non-peptide delta-opioid receptor agonist BW 373U86 suppresses naloxone-precipitated morphine abstinence. In Meeting of the International Narcotics Research Conference, Keystone, Colorado, USA, 1992, Abstract 34. 

In addition to in vitro cell models, opioid agonists could induce the rapid endocytosis of the receptor in organo cultures or primary neuronal cultures, and also neurons in vivo. Treatment of longitudinal muscle-myenteric plexus preparation or the primary hippocampal neuron cultures with DAMGO resulted in internalization of the mu opioid receptor [146,147]. Similar observation was obtained with fluorescently labeled opioid peptides Fluo-dermorphin and Fluo-deltorphin [148]. Within 15 min of an intra-peritoneal injection of etorphine, mu opioid receptor immunoreactivity was observed in the endosomal structures of the myenteric neurons of guinea pig ileum [149]. Again, rapid clustering of a spliced variant of mu opioid receptor MOR-1C was observed in the lateral septum of the mouse after intracere-... 

However, it is clear that opioid receptor endocytosis is critical for the receptor to resensitize. Wolf et al. [170] reported the mutation of Thr394 of mu opioid receptor to Ala resulted in the rapid internalization and resensitization of receptor. Similar observations were reported with various spliced variants of mu opioid receptor, in which the rate of desensitization appears to correlate inversely with the resensitization properties of receptor [169]. Such observations and others have led to a hypothesis proposed by Whistler et al. [140] that the ability of various opioid agonists to produce tolerance is dependent on their RAVE values. In their hypothesis, agonist that induces rapid receptor internalization, e.g., etorphine, would develop less tolerance in animals than agonist such as morphine, which does not produce receptor... 

Daniels DJ, Kulkarni A, Portoghese PS. Bivalent ligands designed to probe receptor heterodimers/hetero-oligomers pharmacological evidence for interactions between opioid receptor types. International Narcotic Research Conference, Monterey, CA, 2002 S47. 

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