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 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.
Hain
H S
HS
Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon, USA. heather.hain@wl.com
Belknap
J K
JK
Mogil
J S
JS
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009020:Morphine / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000235:genetics* / Q000502:physiology; D012680:Sensitivity and Specificity; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013045:Species Specificity; D013997:Time Factors
D000700:Analgesics; D010069:Oxadiazoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C090701:GR 127935; D009020:Morphine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin