They show that one of those genes in particular has a long evolutionary history, as evidenced by the fact that it plays a role in pain sensing in flies, mice and humans. At least in mice, the newly described gene is also linked to a condition known in humans as synesthesia, in which one sensory experience triggers the perception of another sense.
"We found lots of new genes and pathways that have never been implicated in pain before," said Josef Penninger of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.
"From a helicopter view, this shows that there are evolutionarily conserved contributors to pain in flies, mice and humans," added Clifford Woolf of Harvard Medical School, a finding that underscores the importance of pain as a protective mechanism.
Detailed studies in mice show another intriguing feature of the pain gene; it acts in the brain, not in the peripheral nerves, as most known pain genes do.
In what the researchers say is the first genome-wide screen for a complex behavior in flies, thousands of fly genes were silenced using tiny bits of RNA in a method known as RNA interference. Those flies were then tested for their response to noxious heat. In this case, if the flies failed to move away from the heat, they would die.
"We wanted to get as complete a list of genes as possible," Penninger said. "We were almost too successful." The exercise turned up hundreds of genes with a potentially important role in the insects' sense of heat-induced pain.
The research team then focused their attention on one of those genes in particular, known as a2d3 or straightjacket. That gene had no previously known role in pain but was of interest in part because it is related to another gene that is the target of existing analgesic drugs, they explained.
Much like the behavior observed in the flies, mice lacking activity of the gene took longer to jump off of a hot plate. Rare variants of a2d3 were also found in humans with reduced sensitivity to both heat and chronic back pain, they report.
But the researchers were in for another surprise. In the mice, they were able to trace where a2d3 was acting and they saw activity primarily in the brain, not in the nerve endings that are immediately responsible for sensing heat. "We had no idea what it might be doing," Woolf said.
Through functional MRI studies of the brains of sleeping mice as they were exposed to heat, the researchers found that the pain signal in mutants goes to the thalamus of the brain as it should. But that signal is then not sent on properly to higher order pain centers.
Rather, the signal goes instead to other sensory parts of the brain involved in smell, sight and hearing. "Of course, we cannot ask the mouse, but it appears they see, hear and smell the pain signal," Penninger said.
"Here, we found a [pain] gene in the fly that, in the mouse, led us to synesthesia. It was completely unexpected," Woolf said.
The discovery makes the mutant mouse the first model of synesthesia, a condition affecting some four percent of the human population. "There was a famous composer who said he could see his music because each note was a different color," Penninger said. "It's been difficult to study because there had been no model and no genes had been identified."
The researchers also now have hundreds of other pain-related genes that turned up in their initial screen left to explore. In a broad sense, the study shows the power of fly genetics, the researchers say.
"One can really model even complex behaviors like the experience of pain in organisms like the fly and come up with novel pathways that can be translated back to mice and humans," Penninger said. "It works quite well and we learn something entirely new."
But, Woolf added, "the greatest outcome is that we will use this knowledge to identify targets for new analgesics, not just to understand pain." Many of today's pain therapies are relatively ineffective or have severe side effects, he explained. Drug companies are working with perhaps 10 or 20 potential targets for new drugs. "Now, we have hundreds of potential targets, most of them completely novel."
The primary authors for this research are Clifford J. Wolf, Children’s Hospital Boston and Department of Neurobiology, Harvard Medical School, and Josef M. Penninger, Institute of Molecular Biotechnology of the Austrian Academy of Sciences.
In additional to Woolf and Penninger, this paper was co authored by: G. Gregory Neely, Andreas Hess, Michael Costigan, Alex C. Keene, Spyros Goulas, Michiel Langeslag, Robert S. Griffin, Inna Belfer, Feng Dai, Shad Smith, Luda Diatchenko, Vaijayanti Gupta, Cui-ping Xia, Sabina Amann, Silke Kreitz, Cornelia Heindl-Erdmann, Susanne Wolz, Cindy V. Ly, Suchir Arora, Rinku Sarangi, Debasis Dan, Maria Novatchkova, Mark Rosenzweig, Dustin Gibson, Darwin Truong, Daniel Schramek, Tamara Zoranovic, Shane J.F. Cronin, Belinda Angjeli1 Kay Brune, Georg Dietzl, William Maixner, Arabella Meixner, Winston Thomas, J. Andrew Pospisilik, Mattias Alenius, Michaela Kress, Sai Subramaniam, Paul A. Garrity and Hugo J. Bellen.
Journal
Cell