Differential Genetic Mediation of Sensitivity to Morphine in Genetic Models of Opiate Antinociception: Influence of Nociceptive Assay

Several genetic mouse models of opiate sensitivity have been identified or produced in an attempt to investigate mechanisms underlying individual variation in responses to opiate drugs like morphine. The major models in use presently are the DBA/2 (DBA) versus C57BL/6 (C57) inbred strains, the recombinantly inbred CXBK strain, and mouse lines selectively bred for high- and low-magnitude antinociception after swim stress (HA and LA lines, respectively) or levorphanol administration (HAR and LAR lines, respectively). The hot-plate test, an assay of acute, thermal nociception, was used in the selection of the HA/LA and HAR/LAR lines, and has largely been used to characterize the differential opiate sensitivity of the DBA (high) and C57 (low) strains and the deficient sensitivity of the CXBK strain. There exist, however, many other nociceptive assays used with murine subjects; the most common are the tail-flick/withdrawal test, the acetic acid abdominal constriction test and the formalin test. In the present experiment, baseline nociceptive sensitivities and morphine antinociceptive dose-response relationships (0.1-10 mg/kg i.p. or s.c.) were investigated in mice of all four genetic models and in all four major nociceptive assays, with identical parameters. Results indicate a high degree of dissociation between different genetic models, which suggests that these strains differ in their nociceptive and antinociceptive sensitivities due to the effects of very different genetic and physiological mechanisms. In addition, the present findings suggest that morphine inhibits different modalities of nociception via separate mechanisms that can be genetically dissociated and independently altered. Strikingly, in HA/LA and HAR/LAR mice, we find that an inverse relationship exists with respect to morphine antinociceptive sensitivity in the hot-plate and acetic acid abdominal constriction tests, respectively.