Abstract

The effect of chronic treatment with opioid agonists and antagonists on mu opioid receptor density and opioid potency was examined in mice. Mice were implanted s.c. with osmotic mini-pumps that infused etorphine (50-500 micrograms/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 daily for 7 days with fentanyl (0.3 mg/kg). At the end of treatment, saturation binding studies were conducted ([3H]DAMGO) or antinociceptive tolerance was evaluated using the tail-flick assay. Etorphine produced dose-dependent tolerance as well as down-regulation of mu receptor density. Fentanyl infusions produced upregulation of opioid receptors at lower (0.03 and 1.00 mg/kg/day) doses and down-regulation at the highest dose (5.00 mg/kg/day). The lowest fentanyl infusion dose also produced tolerance. Daily s.c. administration of fentanyl (0.30 mg/kg) increased 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. Naloxone dose-dependently increased mu opioid receptor density. Receptor affinity was not systematically altered by the drug treatments. Control binding studies indicated that acute etorphine interfered with binding at mu receptors 15 min after administration, but that all drug was eliminated 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.(ABSTRACT TRUNCATED AT 250 WORDS)