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

J Pharmacol Exp Ther. 1999 Nov;291(2):444-9.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Analgesics / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Morphine / pharmacology*
  • Oxadiazoles / pharmacology*
  • Piperazines / pharmacology*
  • Receptors, Serotonin / genetics*
  • Receptors, Serotonin / physiology
  • Sensitivity and Specificity
  • Serotonin Antagonists / pharmacology*
  • Species Specificity
  • Time Factors

Substances

  • Analgesics
  • Oxadiazoles
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • GR 127935
  • Morphine
  • 8-Hydroxy-2-(di-n-propylamino)tetralin