Lasers and a light-sensitive protein from algae are helping scientists at the University of Calgary unlock the reasons why about a third of Albertans suffer from chronic, often life-altering pain.
It could potentially lead to new painkilling drugs that aren’t addictive, says Gerald Zamponi, PhD, senior associate dean for research at the Cumming School of Medicine and a member of the faculty’s Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute.
In a study published Dec. 13 in Cell Reports, a research team led by Zamponi detailed how certain biochemical processes in nerve cells that control the normal sensation of pain can instead cause animal models to become hypersensitive to it. “Our hypothesis was that chronic pain is actually not a direct result of the original injury, itself, but is instead due to nerve cells at the site of the injury simply becoming more active,” he says.
Unlike normal or acute pain, which is like a short-lived protective “alarm” that alerts the body about an injury until it heals, chronic pain can be like a constant, unwanted siren that continues to blare long after the initial cause, persisting for months and even years. It can lead to depression and suicide, says Zamponi, who is also a professor in the Department of Physiology and Pharmacology at the Cumming School.
Chronic pain is a major health challenge
“There are some people who are in chronic pain their whole lives and there is little that can be done to treat them effectively without resorting to highly addictive drugs such as opioids,” he says, adding that almost half of diabetics experience chronic neuropathic pain. It is caused by nerve damage due to high blood sugar.
“They are in constant, burning pain that gets even worse when they go to sleep because they just focus on their pain as they’re lying in bed.
"For a lot of people with chronic pain, they can’t go to work because they are in such intense pain. Their quality of life suffers, and it’s just not something that I would want in my life, I can tell you that.”
Chronic pain has a massive impact on the economy, he says. “In Canada alone, pain causes $40 billion per year in lost productivity and health-care costs. It is absolutely essential for us to understand the mechanism by which acute pain becomes chronic.”
'Does the exact opposite'
His research team’s study involved optogenetics, a lab technique that uses a light-sensitive protein called channelrhodopsin, derived from algae. The protein was incorporated into the nerve cells of animal models, making them fire when exposed to blue light.
A low-intensity laser was directed on to the skin of the animal models, says Zamponi. “Just by activating the nerve cells with the laser, in ways that that did not damage the skin, was enough to induce changes in the expression of a protein called USP5 — and that was enough to give them a hypersensitivity to pain, even though they weren’t injured.”
USP5 is short for ubiquitin specific peptidase 5. It’s an enzyme in cells that eliminates ubiquitin, a protein that cells add to other proteins so they can be targeted for destruction.
Ubiquitin helps control the effect of proteins by modifying how much is present in cells, including certain proteins in nerve cells called calcium channels that help create pain signals. Fewer of these means less sensitivity to pain, says Zamponi, who is a Canada Research Chair as well as a Fellow of the Royal Society of Canada.
“What USP5 does is the exact opposite,” he says. “It actually removes these ubiquitin groups, and then the cell looks at the calcium channel as something it likes. More and more of these calcium channels start to accumulate — and the more calcium channels you have, the more pain signalling you get.”
Assay to test for new drugs
Getting a clearer understanding of the mechanism behind chronic pain in animal models opens up the possibility that a new drug may eventually be found to treat such conditions in humans. It would potentially avoid side-effects such as addiction caused by opioids like fentanyl, a painkiller originally intended for cancer patients that has become a deadly street drug.
Besides constipation, another problem with opioids is that repeated use builds up tolerance in patients, rendering them useless for people with chronic pain. “The idea is that a new drug would be for a completely different pathway,” Zamponi says.
His research team has created an assay to help test for such drugs and has successfully used a chemotherapy drug to treat chronic pain in animal models to prove the idea works. It would likely take years to create a treatment for humans.
“They would wholly target calcium channels that are dysregulated by USP5, and so that means that all the other calcium channels we have in our heart, muscles and the rest of the brain are not affected by targeting this particular process,” he says. “There’s a reduced risk of side-effects just for that reason.”
The study was funded by the Foundation Grant Program at the Canadian Institutes of Health Research (CIHR) and the Vi Riddell Program in Pediatric Pain at the Alberta Children’s Hospital Research Institute.