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

Objective 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. Methods 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, NA, PGN2, and SWN. We also performed full sequencing of the 5' flanking region and exons of the mouse p opioid receptor gene Oprm1 and analyzed the association between genotypes and phenotypes in these mice. Results 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. Conclusion These results suggest that the short tandem repeats in the 5' flanking and 3' untranslated regions of the It 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. Pharmacogenetics and Genomics 18:927-936 (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.