Vol. 291, Issue 2, 444-449, November 1999

Pharmacogenetic Evidence for the Involvement of 5-Hydroxytryptamine (Serotonin)-1B Receptors in the Mediation of Morphine Antinociceptive Sensitivity¹

Heather S. Hain, John K. Belknap and Jeffrey S. Mogil

Department of Behavioral Neuroscience, Oregon Health Sciences University (H.S.H., J.K.B.); Veterans Affairs Medical Center, Portland, Oregon (J.K.B.); and Department of Psychology and Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, Illinois (J.S.M.)

Morphine antinociception has been shown to be influenced significantly by genetic factors, now beginning to be identified in mice. A recent quantitative trait locus analysis revealed a significant statistical association between morphine antinociceptive magnitude and a region of mouse chromosome 9. This region contains the Htr1b gene, which encodes the 5-hydroxytryptamine (serotonin)-1B (5-HT_1B) receptor subtype. To investigate the possibility that 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-HT_1B receptor antagonist (GR127935) concomitant with morphine. These mice are known to differ in morphine antinociceptive 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 mice. However, a 5-hydroxytryptamine-1A subtype (5-HT_1A) receptor agonist, 8-hydroxydipropylaminotetralin, reversed morphine antinociception equally in the two strains. DBA/2 mice also exhibited significantly greater antinociception than did C57BL/6 mice from the administration of a 5-HT_1B agonist, CGS12066. These data collectively support a role for 5-HT_1B receptors in the mediation of morphine antinociception and support the contention that polymorphisms in the Htr1b gene may underlie individual differences in morphine sensitivity.