Researchers at the University of Toronto, The Hospital for Sick Children and the Amgen Institute have discovered a genetic mechanism involved in pain modulation that could lead to an entirely new approach to pain control. The results of their research are published in the Jan. 11 issue of the journal Cell.
In the study, genetically engineered mice lacking a gene called DREAM (downstream regulatory element antagonistic modulator) showed a dramatic loss of pain sensitivity compared to mice who had the DREAM gene.
"This is an exciting development," says study co-author Professor Michael Salter, director of the University of Toronto Centre for the Study of Pain and a senior scientist at The Hospital for Sick Children. "There's a great interest in this finding because it's so different from the traditional approaches researchers have been taking to pain management."
The work was done in the laboratory of principal investigator Professor Josef Penninger at Amgen by graduate students Mary Cheng and Graham Pitcher, lead authors of the study.
The DREAM gene's role in reducing production of the chemical dynorphin had been previously identified.
DREAM produces a protein that suppresses the genetic machinery that reads the DNA code for dynorphin, which decreases dynorphin production. Dynorphin is a peptide normally produced in the body. Known as an endorphin, it is produced in response to pain or stress. "We knew about DREAM and its role in dynorphin expression, but the purpose of this study was to determine DREAM's actual physiological function," says Salter.
When the DREAM gene was absent in mice, the researchers discovered increased production of dynorphin in the region of the spinal cord involved in transmitting and controlling pain messages.
The mice, they discovered, had decreased sensitivity to acute, inflammatory and neuropathic pain. "The attenuated pain response was evident for all types of pain in all types of tissue tested," says Salter. "The fact that even mice with neuropathic pain-the kind of sharp, chronic pain resulting from nerve injury-experienced this effect is exciting because the medical community currently doesn't have any widely effective treatments for this debilitating type of pain."
Current approaches to pain management focus on drugs such as morphine that stimulate cell receptors for the endorphin family of proteins, also called the endogenous opioid system, or drugs such as aspirin that block the enzyme cyclo-oxygenase.
The DREAM gene, however, works in an entirely different way by binding directly to DNA and regulating the expression of a protein in the endogenous opioid system. "These findings point to a novel pharmacological approach to pain management where researchers will be looking for drugs that could block the ability of DREAM to bind to DNA or simply prevent the production of DREAM," says Salter.
The mice in the study who lacked the DREAM gene were otherwise completely normal and showed no reduction in their motor function, learning or memory. They also did not become addicted to the pain control chemicals their bodies produced, which may prove to be an advantage over the potentially addictive drugs such as morphine that act on opioid receptors.
"Pain is a huge, silent public health crisis that is only beginning to be addressed by researchers," Salter says.
"Evidence of the severity of this crisis can be found in the fact that the U.S. government has declared 2001-2010 the Decade of Pain Research and Management. This declaration highlights a growing awareness of the vast problem of untreated or under-treated pain, and we hope this research will contribute in a significant way to current efforts by scientists to confront this challenge."
The study was funded by CANVAC, the National Cancer Institute of Canada, the Canadian Institutes of Health Research and Amgen Inc.
Journal
Cell