Oligogenic determination of morphine analgesic magnitude: A genetic analysis of selectively bred mouse lines |
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Authors: | Jeffrey S. Mogil Pamela Flodman M. Anne Spence Wendy F. Sternberg Benjamin Kest Bogdan Sadowski John C. Liebeskind John K. Belknap |
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Affiliation: | (1) Research Service (151W), VA Medical Center and Oregon Health Sciences University, 97201 Portland, Oregon;(2) Division of Human Genetics and Birth Defects, Department of Pediatrics, University of California, Irvine, 92717 Irvine, California;(3) Department of Psychology and Brain Research Institute, University of California, Los Angeles, 90024 Los Angeles, California;(4) Department of Behavioural Physiology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland |
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Abstract: | Two ongoing selective breeding projects have produced mice that display divergent analgesic responses to morphine. These two projects have selected for similar phenotypes: high and low levorphanol analgesia (HAR/LAR lines; Portland, OR) and high and low swim stress-induced analgesia (HA/LA lines; Jastrzebiec, Poland). Evidence suggests genetic commonalities between mice of the two projects. Using a Mendelian breeding protocol, we have recently found that one or two genetic loci predominantly determine the high morphine analgesia exhibited by HA mice. In the present study we demonstrate that the differential morphine analgesia (5 mg/kg. i.p.) displayed by HAR and LAR mice is similarly oligogenic, predominantly determined by two unlinked loci. A complementation analysis, in which the analgesic responses to morphine of the recessive homozygotes of each project (HAR and HA) were compared to those of their hybrid offspring (HAR x HA), revealed that different genetic loci have been fixed in each project. An intriguing bimodal distribution was observed in the HAR x HA population: Some HAR x HA hybrids displayed greater morphine analgesia than either HAR or HA mice, whereas others displayed minimal analgesia. LAR x LA hybrids displayed less analgesia than either LAR or LA mice. The analgesic responses of HAR x LA and LAR x HA mice were comparable to those of their low-line parents. These findings indicate not only that different loci were responsible for producing high morphine responders in each selection project but that these distinct loci can interact synergistically to produce superhigh and superlow responders. |
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Keywords: | Opiate levorphanol analgesia pain inhibition complementation genetic segregation selection |
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