OLIGOGENIC DETERMINATION OF MORPHINE ANALGESIC MAGNITUDE - A GENETIC-ANALYSIS OF SELECTIVELY BRED MOUSE LINES

Two ongoing selective breeding projects have produced mice that displa y divergent analgesic responses to morphine. These two projects have s elected for similar phenotypes: high and low levorphanol analgesia (HA R/LAR lines; Portland, OR) and high and low swim stress-induced analge sia (HA/LA lines; Jastrzebiec, Poland). Evidence suggests genetic comm onalities between mice of the two projects. Using a Mendelian breeding protocol, we have recently found that one or two genetic loci predomi nantly determine the high morphine analgesia exhibited by HA mice. In the present study we demonstrate that the differential morphine analge sia (5 mg/kg, i.p.) displayed by HAR and LAR mice is similarly oligoge nic, predominantly determined by two unlinked loci. A complementation analysis, in which the analgesic responses to morphine of the recessiv e homozygotes of each project (HAR and HA) were compared to those of t heir hybrid offspring (HAR x HA), revealed that different genetic loci have been fixed in each project. An intriguing bimodal distribution w as observed in the HAR x HPL population: Some HAR x HA hybrids display ed greater morphine analgesia than either HAR or HA mice, whereas othe rs displayed minimal analgesia. LAR x LA hybrids displayed less analge sia than either LAR or LA mice. The analgesic responses of HAR x LA an d LAR x HA mice were comparable to those of their low-line parents. Th ese findings indicate not only that different loci were responsible fo r producing high morphine responders in each selection project but tha t these distinct loci can interact synergistically to produce ''superh igh'' and ''superlow'' responders.