IN-VIVO HOMOLOGOUS REGULATION OF MU-OPIOID RECEPTOR GENE-EXPRESSION IN THE MOUSE

Regulation of the mu-opioid receptor gene by opioid analgesic drugs ha s not been observed in rats and mice following in vivo treatments that produce tolerance. Although in vivo heterologous regulation of mu-opi oid receptor mRNA by non-opioid compounds has been reported, the failu re to observe changes in mu-opioid receptor mRNA levels in vivo after treatment with opioid agonists raised the possibility that in vivo hom ologous regulation by agonists may not occur. Therefore, in the presen t study, the effect of a high intrinsic efficacy opioid receptor agoni st on opioid receptor density, gene expression and tolerance was deter mined. Mice were infused with etorphine for 7 days using an osmotic mi nipump, then the pump was removed and studies conducted 16-168 h later . Etorphine (50-250 mu g/kg/day) infusion produced significant dose-de pendent tolerance to the analgesic (tailflick) effects of etorphine, a s well as dose-dependent mu-opioid receptor downregulation in brain at 16 h following the end of the infusion. mu-opioid receptor density re turned to control levels over a 168 h period following the end of etor phine (250 mu g/kg/day) infusion. Similarly; the magnitude of toleranc e decreased over the same period. Evaluation of changes in brain mu-op ioid receptor mRNA 16 h following etorphine infusion indicated that th ere was dose-dependent increase in steady-state levels, with no signif icant change in GAPDH mRNA. The increase in mu-opioid receptor mRNA wa s similar to 55-65% over control at the highest etorphine infusion dos e. mu-opioid receptor mRNA returned to control levels over a 168 h per iod following the end of etorphine (250 mu g/kg/day) infusion. These d ata suggest that the increase in mu-opioid receptor mRNA following the termination of etorphine treatment may drive the recovery of mu-opioi d receptors. These data are the first demonstration of in vivo homolog ous regulation of mu-opioid receptor gene expression in the mouse by a n opioid receptor agonist that produces tolerance and receptor downreg ulation. (C) 1997 Elsevier Science B.V.