The mutant mice didnt make sense. Josef M. Penninger of the University of Toronto and his colleagues had disabled a rodent gene that they thought controlled another gene, one involved in the immune system. Yet the mice had no immune defects or any other obvious problems. The more we went into the project the more confused we got, recalls Penninger.
When the mice were subjected to an array of behavioral tests, however, the scientists noticed that the rodents werent as sensitive to acute and chronic forms of pain, including pain caused by heat, toxic substances, and nerve damage. The gene that Penningers team had mutated encodes a protein called DREAM (downstream regulatory element antagonistic modulator), which is a so-called transcription factor. As such, it binds to DNA and regulates the activity of genes.
Instead of controlling an immunity-related gene, as Penningers team expected, DREAM appears to suppress the production of a natural opioid called dynorphin. The mice lacking DREAM overproduce this opioid in spinal cord nerve cells, where it affects pain perception, Penningers group reports in the Jan. 11 Cell.
These results add to a growing puzzle. In contrast to the new work, some experiments have shown that dynorphin actually promotes pain. The new work is sort of counterintuitive, says Robert M. Caudle of the University of Florida. Dynorphin is probably more complicated than we realized.
Penninger suggests that dynorphin has either a pain-killing or pain-enhancing action depending on which cell-surface protein it binds. Although drugs that target transcription factors are rare, the team is developing inhibitors of DREAM to test if they are a new class of pain relievers. DREAM is an intriguing target, he says.