A recipe of one part science and one part surprise has led researchers at the University of Toronto, The Hospital for Sick Children and the Amgen Institute to discover that the mice in their study were displaying some unusual characteristics.
The team’s persistent study of genetically engineered mice lacking a gene called DREAM (downstream regulatory element antagonistic modulator) identified little out of the ordinary until further testing produced a novel find. The mice were responding to pain with a dramatic loss of pain sensitivity compared to mice who had the DREAM gene.
The unexpected discovery of a gene associated with pain may lead to an entirely new approach to pain control and offers potential for those plagued with the constant pain of diseases such as cancer or arthritis. Traditionally such ailments are aided with the use of pain relievers that can be addictive and have serious side effects.
“This is an exciting development,” said study co-author Dr. 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 Dr. Josef Penninger at Amgen by graduate student Mary Cheng and post-doctoral fellow Graham Pitcher, lead authors of the study. Dr. Salter’s interest was piqued when he was presented with the initial findings and the team plunged ahead to begin to understand the workings of this genetic mechanism. The results of the research were published in the January 11 issue of the scientific journal Cell.
Part of the puzzle was already clear as the DREAM gene’s role in reducing production of the chemical dynorphin has 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,” said Dr. Salter.
By most indications the mice with the absent DREAM gene were completely normal and showed no reduction in their motor function, learning or memory. But on further investigation, the mice underwent a series of humane tests measuring their threshold for pain. They were discovered to have an increased production of dynorphin in the region of the spinal cord involved in transmitting and controlling pain messages. Displaying an amazing resilience, the mice had dulled reactions and sensed less pain than the mice with the gene present. In fact, these mice 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,” said Dr. 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.”
The study points the way to alternative forms of treatments than those currently in existence. Typically pain management has focused on drugs like morphine which stimulate cell receptors for proteins called the endogenous opioid system, or on drugs such as aspirin that block the enzyme cyclo-oxygenase. The DREAM gene works differently 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,” said Dr. Salter.
One of the challenges of such a potential treatment would be to create a drug that is able to penetrate deep inside specific cells, in order to hone in on the DREAM function. Such a drug might also take longer to work but ultimately have longer lasting effects.
These future treatments may have another significant advantage over long-time pain relievers like morphine; the mice in the study lacking the DREAM gene did not become addicted to the pain control chemicals their bodies produced.
“Those of us working in the area of pain research have a vision that what we are doing will have direct relevance to what happens to patients. By figuring out new ways to suppress pain signaling to the brain without affecting other sensations or cognitive functions, we will be able to design new therapies that stop pain but don’t produce the side effects associated with present treatments,” added Dr. Salter.