Continuous opioid agonist treatment dose-dependently regulates mu-opioid receptors and dynamin-2 in mouse spinal cord

Continuous opioid agonist treatment produces tolerance and in some cases mu opioid receptor (muOR) down-regulation. Previous studies indicate that down-regulation of muOR is more likely with high-efficacy opioid agonists (e.g., etorphine), whereas lower efficacy agonists (e.g., morphine) do not regulate muOR density. It has been suggested that muOR down-regulation may depend upon increases in Dynamin-2 (DYN-2) proteins. Therefore, the present study examined the effect of various infusion doses of etorphine on muOR density, DYN-2 protein, and DYN-2 mRNA abundance in mouse spinal cord. Mice were implanted sc with an osmotic pump that infused etorphine (50-250 microg/kg/day). Controls were implanted with inert placebo pellets. At the end of 7 days, mice were sacrificed, spinal cord removed and processed for radioligand binding, quantitative Western blotting, or RT-PCR assay. Results indicate that etorphine induced dose-dependent regulation of muOR density, DYN-2 proteins, and mRNA abundance in mouse spinal cord. Higher infusion doses significantly down-regulated muOR density, increased DYN-2 protein abundance, and decreased DYN-2 mRNA. Analysis of these results indicated a significant correlation between muOR down-regulation and DYN-2 abundance in mouse spinal cord. Taken together, muOR regulation may depend on changes in DYN-2 abundance induced by high-efficacy opioid agonists in mouse spinal cord.