In 1995, James Campbell, MD, in his Presidential Address to the American Pain Society, argued that pain was undermanaged and should be evaluated as a vital sign. Since Campbell’s presentation, pain, in clinical practice, has been recognized as a 5th vital sign, and patients expect their providers to immediately respond and alleviate the pain they encounter.[1]

Vital signs are measurements of the body’s most basic functions, including body temperature, pulse rate, respiration rate, and blood pressure.  They are
used to detect or monitor medical issues and can be objectively measured in a medical setting or at home. Following Campbell’s address, now more than 25 years ago, pain, the only non-objective measurement was added as the fifth vital sign. However, being non-objective in nature, makes pain management – and pain relief not only a critical issue in medicine but also difficult to measure, which in turn, often results in effective pain management.

Ken Ng, Ph.D., a professor at the University of Windsor and adjunct professor at the University of Calgary (UCalgary). Photo Courtesy: © 2020 – 2021 CTL / University of Saskatchewan. Used with permission.

And while opiates like morphine and codeine provide many patients with relief from the ache felt after mild surgery to chronic pain experienced by cancer patients, they can cause multiple side effects and can lead to physical dependency with long-term use. Hence, improving pain medication would help millions of people to have a better health-related Quality of Life (hrQoL).

Ken Ng, Ph.D., a professor at the University of Windsor and adjunct professor at the University of Calgary (UCalgary), and Sam Carr, a Ph.D. student from UCalgary, have been working with Dr. Peter Facchini’s group at UCalgary to better understand how natural opiates are produced. The team has narrowed their focus on one enzyme in the last stage of opiate assembly, a process that occurs naturally in the poppy plant.

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“Imagine this sort of like an assembly line,” Carr said. “There are a lot of different steps in this specific pathway, and each enzyme contributes a different step from the starting product to the finished drug.”

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Sam Carr, a Ph.D. student from UCalgary. Photo Courtesy: © 2020 – 2021 CTL / University of Saskatchewan.Used with permission.

Carr and Ng are looking at the enzyme responsible for the last step in the production of the drug codeine.

Using the CMCF beamline, located at the Canadian Light Source (CLS), Canada’s national center for synchrotron research and a global center of excellence in synchrotron science and its applications at the University of Saskatchewan, Ng and Carr were able to image the structure of this unique enzyme.

The structural analysis gave the team ideas for how to modify the natural enzymes to ultimately create drugs that are more effective or have fewer side effects than natural opiates. This is part of Ng and Carr’s long-term program goals.

“If you could have this sort of understanding for many different enzymes, you could have a type of toolbox,” Carr noted. “You could modify these drugs in a specific way to produce different versions that could possibly have different pharmaceutical properties.”

The Canadian Light Source is Canada’s national center for synchrotron research and a global center of excellence in synchrotron science and its applications. Located at the University of Saskatchewan in Saskatoon, the CLS is a world-class, state-of-the-art facility that is advancing Canadian science, enhancing the competitiveness of Canadian industry, and contributing to the quality of life of people around the world. Photo Courtesy: © 2020 – 2021 CTL / University of Saskatchewan. David Stobbe / Stobbe Photography. Used with permission.

As Ng and Carr learn more about the structure and function of these enzymes, they can also transfer this knowledge to other natural drug syntheses, including enzymes that help produce anti-microbial drugs and other medicinal compounds.

“There is a really rich diversity of applications for these compounds,” Ng said. “This structure gives information, not just about opioid biosynthesis, but other natural products that include other classes of painkillers and medicinal applications like cancer treatment.”

The team’s protein crystallography research would not be possible without the use of synchrotron technology. “Due to the specific challenges with this particular project, I think it would have been impossible to solve this structure without a synchrotron,” Ng explained.

Reference
[1] Campbell JN. APS 1995 Presidential address. InPain Forum 1996 Mar 1 (Vol. 5, No. 1, pp. 85-88). Churchill Livingstone.

Featured image: Developing pain medication with fewer side effects; the structure of the enzyme studied, a molecule of codeine, and a seed capsule from the opium poppy. Photo courtesy: © 2020 – 2021 Photo Courtesy: © 2020 – 2021 CTL / University of Saskatchewan. Samuel Carr, Ph.D. Used with permission.

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