Opioid receptor upregulation in mu-opioid receptor deficient CXBK and outbred Swiss Webster mice

Chronic in vivo treatment with opioid antagonists increases opioid receptor density and the potency of opioid agonists without altering receptor mRNA levels. To determine if basal receptor density affects opioid receptor upregulation, we examined the effect of chronic naltrexone treatment on mu-opioid receptor density and mRNA in two mice strains that differ in mu-opioid receptor density. CXBK mice (mu-opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c. with a placebo or 15 mg naltrexone pellet for 8 days, the pellets removed and 24 hr later opioid receptor density (mu, delta) and receptor mRNA level (mu) determined in whole brain; or morphine dose-response studies conducted. In placebo-treated CXBK mice, mu-opioid receptor density was approximately 40% less than in Swiss Webster mice, although mu-opioid receptor mRNA abundance was similar in both strains. In placebo-treated CXBK mice, morphine potency was approximately 6-fold less than Swiss Webster mice. Naltrexone treatment increased morphine potency (1.7-fold) and mu- (approximately 90%) and delta- (approximately 20-40%) opioid receptor density in CXBK and Swiss Webster mouse brain similarly. Mu-opioid receptor mRNA was unchanged by naltrexone treatment in either strain. There was no difference in the basal or naltrexone-treated whole brain G(i alpha2) protein levels in CXBK or Swiss Webster mouse. These data indicate that a deficiency in mu-opioid receptors does not alter the regulation of opioid receptors by opioid antagonists in vivo, and suggest that adaptive responses to chronic opioid antagonist treatment are independent of opioid receptor density.