Association of morphine-induced antinociception with variations in the 5′ flanking and 3′ untranslated regions of the μ opioid receptor gene in 10 inbred mouse strains

Abstract

Genetic factors are hypothesized to be involved in interindividual differences in opioid sensitivity. Inbred mouse strains that are genetically different and isogenic within each strain are useful for elucidating the genetic mechanisms underlying the interindividual differences in opioid-induced analgesia. We examined the effects of morphine in 10 inbred mouse strains, including wild-derived strains that have a wide range of genetic diversity, including BLG2, CHD, KJR, MSM, NJL, PGN2, and SWN. We also performed full sequencing of the 5' flanking region and exons of the mouse mu opioid receptor gene Oprm1 and analyzed the association between genotypes and phenotypes in these mice. The effects of morphine on locomotor activation and antinociception varied among the inbred strains. The nucleotide differences that cause amino acid substitutions were not found in the Oprm1 gene in the inbred strains analyzed in this study. In the 5' flanking region and 3' untranslated region of the Oprm1 gene, four highly variable regions containing novel short tandem repeat polymorphisms (GA, T, TA, and CA/CT) were identified. The GA, T, and TA repeat numbers were significantly associated with morphine-induced antinociception. These results suggest that the short tandem repeats in the 5' flanking and 3' untranslated regions of the mu opioid receptor gene are involved in interstrain differences in opioid sensitivity in mice. Wild-derived inbred mouse strains with different numbers of these repeats may be useful models for examining interindividual differences in opioid sensitivity.