Aggression modulates genetic influences on morphine analgesia as assessed using a classical mendelian cross analysis

Pharmacogenetic techniques allow for the examination of genetic and environmental factors underlying phenotypes associated with drug response. Initial studies of mice bred at Jackson Laboratories (JAX) indicated that C57BL/6J mice were more sensitive to morphine-induced analgesia, as measured by latency to paw lick, than SJL/J mice. A classical Mendelian cross breeding program was initiated in which F1, F2 and backcross generations were derived from C57BL/6J and SJL/J breeding pairs purchased from JAX to examine the genetic factors underlying morphine analgesia. Genetic analysis indicated significant dominance or heterosis for a reduced drug response. The F1 generation was less sensitive to morphine-induced analgesia than either parental strain. Mathematical analysis of the generation means revealed that a simple dominance model with no epistatic interaction between genes best described the data. Environmental factors also affected sensitivity to morphine analgesia, in that C57BL and SJL mice raised in our facility did not differ in latency to paw lick. SJL mice from JAX exhibit a high degree of aggression, while SJL mice raised in our facilities show little or no aggression. The levels of aggression among groups of SJL mice were characterized and found to correlate with sensitivity to morphine analgesia. Mice exposed to increasingly greater levels of aggression were the least sensitive to morphine. Thus, the changes observed in sensitivity to morphine-induced analgesia appear to be related to the degree of aggression to which these mice are exposed, possibly resulting from the stress and/or prolonged exposure to painful stimuli associated with aggressive encounters.