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One or two genetic loci mediate high opiate analgesia in selectively bred mice
Jeffrey S Mogil1, Przemyslaw Marek, Pamela Flodman
1Research Service (151W), VA Medical Center, Portland, OR 97201 USA Oregon Health Sciences University, Portland, OR 97201 USA ACEA Pharmaceuticals, Plumwood House 1003, Health Sciences Road West, Irvine, CA 92715 USA Division of Human Genetics and Birth Defects, Department of Pediatrics, University of California at Irvine, Irvine, CA 92717 USA Department of Psychology and Brain Research Institute, University of California at Los Angeles, Los Angeles, CA 90024 USA Department of Behavioural Physiology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec Poland.
Abstract:
The analgesic responses of humans and laboratory animals are characterized by substantial individual differences. The genetic basis of this variability can be studied experimentally in rodents using a program of selective breeding. One such program selected for high (HA) and low (LA) swim stress-induced analgesia (SSIA) on the hot-plate (56 degrees C) test in Swiss-Webster mice. These lines, which have been selectively bred for more than 25 generations, display markedly divergent opioid-mediated SSIA (3-min swims in 38 degrees C water), morphine analgesia (10 mg/kg, i.p.), and analgesia to the kappa-receptor agonist, U-50,488H (30 mg/kg, i.p.). The present study investigated the mode of inheritance of these opioid analgesias in HA and LA mice, using Mendelian genetic analyses. We report that the differential sensitivity of HA and LA mice to each of these analgesic manipulations appears to be determined oligogenically, by one or at the most two major genetic loci. The loci associated with each type of analgesia do not co-segregate, however, indicating that three distinct oligogenic effects have been identified. These findings suggest that the genetic determination of analgesic mechanisms may have simple components and as such may be amenable to further analysis using molecular genetic techniques.