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It is well known that there are individual differences in a sensitivity to analgesics. Several lines of evidence have suggested that the level of opioid-induced analgesia is dependent on the level of expression of the μ-opioid receptor (μ-OR). However, the molecular mechanisms underlying the diversity of the level of the opioid receptor and the opioid sensitivity among individuals remain to be elucidated. In the present study, we analyzed the opioid-receptor genes of CXBK recombinant-inbred mice, which show reduced sensitivity to opioids. Northern blotting, nucleotide sequencing, and in situhybridization histochemical analyses demonstrated that CXBK mice possessed μ-OR mRNA with a normal coding region but an abnormally long untranslated region (UTR). In addition, the μ-OR mRNA level in CXBK mice was less than in the control mice. Next, we produced littermate mice that had inherited two copies of the wild-type μ-OR gene, had inherited two copies of the CXBK μ-OR gene, and had inherited both copies of the μ-OR genes. In these mice, inheritance of the CXBK μ-OR gene was well correlated with less μ-OR mRNA and reduced opioid effects on nociception and locomotor activity. We conclude that the CXBK μ-OR gene is responsible for the CXBK phenotypes. Because UTR differences are known to affect the level of the corresponding mRNA and protein and because UTRs are more divergent among individuals than coding regions, the present findings suggest that opioid sensitivity may vary, depending on different μ-OR levels attributable to divergent UTR of μ-OR mRNA.

The Untranslated Region of μ-Opioid Receptor mRNA Contributes to Reduced Opioid Sensitivity in CXBK Mice