Pharmacogenetic evidence for the involvement of 5-hydroxytryptamine (serotonin)-1B receptors in the mediation of morphine antinociceptive sensitivity

Morphine antinociception has been shown to be influenced significantly by g enetic factors, now beginning to be identified in mice. A recent quantitati ve trait locus analysis revealed a significant statistical association betw een morphine antinociceptive magnitude and a region of mouse chromosome 9. This region contains the Htr1b gene, which encodes the 5-hydroxytryptamine (serotonin)-1B (5- HT1B) receptor subtype. To investigate the possibility t hat Htr1b represents the quantitative trait locus, C57BL/6 and DBA/2 inbred strains, the progenitors of the original quantitative trait locus mapping populations, were administered a novel 5- HT1B receptor antagonist (GR12793 5) concomitant with morphine. These mice are known to differ in morphine an tinociceptive sensitivity on thermal pain assays (DBA/2 high; C57BL/6 low). GR127935 caused a dose-dependent antagonism (both reversal and prevention) of morphine antinociception in DBA/2 mice but had no effect in C57BL/6 mic e. However, a 5-hydroxytryptamine-1A subtype (5- HT1A) receptor agonist, 8- hydroxydipropylaminotetralin, reversed morphine antinociception equally in the two strains. DBA/2 mice also exhibited significantly greater antinocice ption than did C57BL/6 mice from the administration of a 5- HT1B agonist, C GS12066. These data collectively support a role for 5- HT1B receptors in th e mediation of morphine antinociception and support the contention that pol ymorphisms in the Htr1b gene may underlie individual differences in morphin e sensitivity.