Recently, we described the generation of two humanized mouse lines in which the native MOR’s exon 1 was replaced with human exon 1 that encompasses the polymorphism25. Our initial study presented evidence for the 118G allele to be a gain-of-function variant with regard to dopamine response to an alcohol challenge, but did not address whether it moderates morphine responses relevant to analgesia. Thus, the present study examined the pharmacological profile of MOR in sensory neurons isolated from homozygous mice expressing either 118AA or 118GG allele. The main finding was a differential response of 118GG sensory neurons to morphine when compared to 118AA neurons. Neurons expressing the variant allele exhibited a five-fold decrease of the morphine-mediated Ca2+ current inhibition potency (IC50) as well as a 26% decrease in efficacy. Furthermore, when both groups of mice were tested for morphine requirement on a hotplate assay, the 118GG homozygous mice displayed a diminished response for up to 3 hours when compared to 118AA mice. These behavioral assays strongly support our electrophysiological observations which suggest that the mutant MOR exhibits an altered morphine pharmacological
