Targeting nausea in chemotherapy patients
Nausea is one of the most distressing side-effects of chemotherapy for cancer patients—and a system that is not well understood.
While effective treatments for vomiting caused by chemotherapy exist, they unfortunately are not that effective in treating the symptoms of nausea. It can become so severe that patients stop taking their treatments.
Prof. Linda Parker from the University’s Department of Psychology and the Collaborative Neuroscience Program is studying how the brain regulates nausea. A focus of Parker’s research is the newly discovered endogenous cannabinoid (endocannabinoid) system. It plays an important role in regulating the activity of almost all neurotransmitters in the brain, including glutamate, GABA, serotonin and acetylcholine.
These endocannabinoids are produced on-demand, when and where they are needed in the brain to maintain homeostasis. The endocannabinoid system consists of two compounds, anandamide and 2-AG, that act on cannabinoid receptors (CB1 receptors) found in the brain to regulate important biological functions, such as appetite, mood, memory, nausea, and pain.
“This newly discovered endocannabinoid system offers an exciting frontier to understanding how the brain works,” says Parker.
Parker has been collaborating with universities around the world for the past 15 years, studying the effects of endocannabinoids and compounds found in the cannabis plant on the brain’s regulation of nausea. Cannabis plants have an active substance called Delta-9-tetrahydrocannabinol (THC). Interestingly, THC acts much like anandamide and 2-AG by binding to CB1 receptors to produce the typical effects of marijuana, including enhancing appetite, producing changes in mood, reducing pain and nausea. Understanding how THC and these receptors interact has helped Parker and colleagues better understand the mechanisms behind regulating nausea.
Dr. Raphael Mechoulam at the Hebrew University of Jerusalem is recognized as the “father” of the endocannabinoid system. He discovered that THC was the intoxicating compound found in the cannabis plant in 1964. Then 20 years later, in the 1980s, his group discovered both anandamide and 2-AG, sometimes called “the brain’s own THC.”
For the past 15 years, Parker and Mechoulam have worked together to evaluate the mechanisms by which cannabinoids and endocannabinoids regulate the sensation of nausea.
Parker’s group has shown that drugs that boost the activity of the endocannabinoid system have great promise as new treatments for nausea. Normally, the duration of action of endocannabinoids is short, because they are rapidly degraded (within 15 minutes) by selective enzymes.
However, when these enzymes are inhibited by drugs, the action of anandamide and 2-AG (and their anti-nausea effects) can be prolonged up to 24 hours.
Parker is collaborating with biochemists from Scripps Laboratories, LaJolla (Benjamin Cravatt), University of Irvine (Danielle Piomelli), and Northeastern University (Alexandros Makriyannis) who have developed new enzyme inhibitors which prolong the duration of action of the endocannabinoids, when and where they are produced in the brain. These drugs are highly effective in reducing nausea in Parker’s animal models of nausea, leading to new treatments for this very difficult to control symptom in chemotherapy patients.
And what about the cannabis plant? Well, it contains not only the intoxicating compound THC, but also cannabidiol (CBD) along with nearly 100 other cannabinoid compounds. However, CBD does not produce the psychoactive intoxicating effects of THC. Parker’s group has found that CBD reduces nausea and anxiety in animal models, like THC. The researchers are currently evaluating the potential of other compounds in the plant to reduce nausea and anxiety.
“Our newest CIHR-funded work is aimed at evaluating the interaction between the endocannabinoid system and the serotonin system in the regulation of nausea,” says Parker. “Our data suggest that within a specific brain region, the interoceptive insular cortex, the release of serotonin triggers the sensation of nausea. However, if we give rats treatments that boost the 2-AG levels within this region of the brain, nausea can be prevented. This suggests that 2-AG may have the function of reducing the release of serotonin in this brain region when we feel nauseated, to restore homeostatic balance.”
With these new and exciting leads into the neurobiology of nausea, more effective treatments for nausea could be developed in the future.
This research is funded by NSERC, CIHR, GW Pharmaceuticals and Prairie Plant Systems.