Selective breeding for levorphanol-induced antinociception on the hot-plate assay: commonalities in mechanism of action with morphine, pentazocine, ethylketocyclazocine, U-50488H and clonidine in mice.

Selective breeding (selection) was used to bidirectionally alter gene frequencies affecting levorphanol antinociception on the hot-plate assay in mice. After 12 generations of selective breeding, the high antinociceptive response line exhibited about 7 times steeper dose-response curve than did the low antinociceptive response line whereas only small differences were seen with saline alone. The authors sought to determine whether these large, genetically mediated differences in sensitivity bred into the high and low antinociceptive response lines (lineages) with levorphanol would also be evident with other analgesics. Should this occur with any particular drug, this would imply common mechanisms of action between that drug and levorphanol mediated by common gene action. This was found to be the case with morphine, but progressively less similarity to levorphanol was seen with other analgesics with the following rank order: morphine greater than pentazocine greater than ethylketocyclazocine greater than U-50488H greater than clonidine. Thus, the mechanisms of action for the latter compounds are different from levorphanol in varying degrees. The role of sedation produced by some of these drugs was also evaluated and was found to be independent of the antinociceptive effects. Thus, the latter was not confounded by the former in these genetic lines of mice.