title: Antagonist-induced micro-opioid receptor up-regulation decreases G-protein receptor kinase-2 and dynamin-2 abundance in mouse spinal cord.
abstract: Chronic treatment with opioid receptor antagonists has been shown to increase the density of micro-, delta- and kappa-opioid receptors in cell culture and in the intact animal. Although opioid receptor antagonist-induced up-regulation is a robust phenomenon, the mechanisms responsible for the increase in receptor density remain unclear. In the present study, changes in a kinase and a GTPase that have been implicated in G-protein-coupled receptor regulation were examined following opioid receptor antagonist treatment. Mice were implanted s.c. with a naltrexone pellet or placebo pellet. On the eighth day following implantation, spinal cord was removed and G-protein receptor kinase-2 (GRK-2) and dynamin-2 abundance were determined using a quantitative immunoblot approach. Changes in micro-opioid receptor density were also determined. Naltrexone treatment produced a significant (145%) increase in micro-opioid receptor density. Naltrexone treatment was associated with a significant 36% decrease in GRK-2 and 30% decrease in dynamin-2 abundance in spinal cord. These data raise the possibility that opioid receptor antagonist-induced micro-opioid receptor up-regulation in the intact animal may be due to a reduction in constitutive internalization of opioid receptors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
authors.forename: Minesh
authors.initials: M
authors.lastname: Patel
authors.forename: Benedict
authors.initials: B
authors.lastname: Gomes
authors.forename: Chintan
authors.initials: C
authors.lastname: Patel
authors.forename: Byron C
authors.initials: BC
authors.lastname: Yoburn
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D034285:Dynamin II / Q000378:metabolism*; D054770:G-Protein-Coupled Receptor Kinase 3; D020558:GTP Phosphohydrolases / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000494:pharmacology*; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D017450:Receptors, Opioid, mu; D009271:Naltrexone; D017868:Cyclic AMP-Dependent Protein Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517850:GRK3 protein, mouse; D051552:beta-Adrenergic Receptor Kinases; D020558:GTP Phosphohydrolases; D034285:Dynamin II