DIFFERENTIAL GENETIC MEDIATION OF SENSITIVITY TO MORPHINE IN GENETIC MODELS OF OPIATE ANTINOCICEPTION - INFLUENCE OF NOCICEPTIVE ASSAY

Several generic mouse models of opiate sensitivity have been identifie d or produced in an attempt to investigate mechanisms underlying indiv idual Variation in responses to opiate drugs like morphine. The major models in use presently are the DBA/2 (DBA) versus C57BL/6 (C57) inbre d strains, the recombinantly inbred CXBK strain, and mouse lines selec tively bred for high-and low-magnitude antinociception after swim stre ss (HA and LA lines, respectively) or levorphanol administration (HAR and LAR lines, respectively). The hot-plate test, an assay of acute, t hermal nociception, was used in the selection of the HA/LA and HAR/LAR lines, and has largely been used to characterize the differential opi ate sensitivity of the DBA (high) and C57 (low) strains and the defici ent sensitivity of the CXBK strain. There exist, however, many other n ociceptive assays used with murine subjects; the most common are the t ail-flick/withdrawal test, the acetic acid abdominal constriction test and the formalin test. In the present experiment, baseline nociceptiv e sensitivities and morphine antinociceptive dose-response relationshi ps (0.1-10 mg/kg i.p, or s.c.) were investigated in mice of all four g enetic models and in all four major nociceptive assays, with identical parameters. Results indicate a high degree of dissociation between di fferent genetic models, which suggests that these strains differ in th eir nociceptive and antinociceptive sensitivities due to the effects o f very different genetic and physiological mechanisms. In addition, th e present findings suggest that morphine inhibits different modalities of nociception via separate mechanisms that can be genetically dissoc iated 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 abdomina l constriction tests, respectively.