OPIOID RECEPTOR REGULATION IN MICE

The effect of chronic treatment with opioid agonists and antagonists o n mu opioid receptor density and opioid potency was examined in mice. Mice were implanted s.c. with osmotic mini-pumps that infused etorphin e (50-500 mug/kg/day), fentanyl (0.03-5.0 mg/kg/day) or naloxone (0.1- 10.0 mg/kg/day) for 7 to 8 days. Other mice were implanted s.c. with a morphine pellet (75 mg) for 3 or 7 days or were injected s.c. once da ily for 7 days with fentanyl (0.3 mg/kg). At the end of treatment, sat uration binding studies were conducted ([H-3]DAMGO) or antinociceptive tolerance was evaluated using the tail-flick assay. Etorphine produce d dose-dependent tolerance as well as down-regulation of mu receptor d ensity. Fentanyl infusions produced up-regulation of opioid receptors at lower (0.03 and 1.00 mg/kg/day) doses and down-regulation at the hi ghest dose (5.00 mg/kg/day). The lowest fentanyl infusion dose also pr oduced tolerance. Daily s.c. administration of fentanyl (0.30 mg/kg) i ncreased receptor density and produced tolerance to fentanyl. Morphine pellets increased (3 day) and then had no effect (7 day) on receptor density, although tolerance to morphine was observed at 7 days. Naloxo ne dose-dependently increased mu opioid receptor density. Receptor aff inity was not systematically altered by the drug treatments. Control b inding studies indicated that acute etorphine interfered with binding at mu receptors 15 min after administration, but that all drug was eli minated by 16 hr. Thus, binding and tolerance studies using etorphine were conducted 16 hr after the end of infusion, when all drug had been eliminated. These studies show that mu opioid receptors in mouse brai n can be both up- and down-regulated by opioid agonists. Furthermore, tolerance can develop independently of opioid receptor regulation. The critical determinants of the effect of chronic opioids on receptor de nsity appear to be intrinsic efficacy, dose and duration of treatment. Antagonists and low intrinsic efficacy agonists result in up-regulati on or no change in density, whereas high intrinsic efficacy compounds will down-regulate receptors if the dose is sufficiently high.