Antagonist-induced μ-opioid receptor up-regulation decreases G-protein receptor kinase-2 and dynamin-2 abundance in mouse spinal cord

Chronic treatment with opioid receptor antagonists has been shown to increase the density of mu-, 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 p-opioid receptor density were also determined. Naltrexone treatment produced a significant (145%) increase in mu-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 mu-opioid receptor up-regulation in the intact animal may be due to a reduction in constitutive internalization of opioid receptors. (C) 2002 Elsevier Science B.V. All rights reserved.