Transgenic studies of pain and analgesia: Mutation or background genotype?

The application of transgenic (knockout) technology to the study of pain is rapidly expanding. Despite its power, this technique has several shortcomi ngs that complicate the interpretation of the data obtained. Although compe nsation by other genes is a well recognized problem, issues related to the background genotype of the mutant mice are less well appreciated. This revi ew describes these confounds as they apply to studies of pain and pain inhi bition. We show that the 129 and C57BL/6 mouse strains, which provide the d efault genetic background on which null mutants are constructed, display si gnificant and sometimes extreme phenotypic differences in many assays of no ciception, hypersensitivity, and analgesia. Although problems related to th e differential responsiveness of the two strains are minimized by placing k nockouts onto "pure" 129 and/or C57BL/6 backgrounds, we also illustrate tha t neither of these strains are particularly representative of inbred mice i n general. Procedures to reduce confounds and converging evidence must be u sed to accurately determine the functions of the targeted genes in pain-rel ated phenomena.