Sep. 24, 1998 Researchers at the University of California San Francisco have shown in rats that a synthetic drug that mimics the principal active ingredient in marijuana has an effect similar to that of morphine on an area of the brain that modulates pain.
The finding, reported in the September 24 issue of Nature, raises the possibility that marijuana-like drugs could be used to treat pain, said the lead author of the study, Ian Meng, PhD, a postdoctoral fellow in the laboratory of Howard Fields, PhD, a professor of neurology and physiology and a research scientist in the W.M. Keck Foundation Center for Integrative Neuroscience at UCSF.
While opioids such as morphine provide strong analgesic effects for many types of pain, they produce side effects such as nausea and respiratory depression. In contrast, marijuana, a type of cannabinoid drug, actually increases appetite. In the future, says Meng, it may be possible to use a lower dose of opioids if they are used in combination with a cannabinoid, producing fewer side effects and increasing the pain relieving effects.
The researchers focused their study on a region of the brain known as the rostral ventromedial medulla (RVM) which modulates pain by either increasing or decreasing the amount of pain signals that pass through the spinal cord. They tested the effects of the synthetic cannabinoid, WIN555, 212-2, on this region by measuring the time it took for rats to move their tails away from a heat source.
In the first experiment, rats that were given WIN55,212-2 kept their tails on the heat source much longer than rats that were not given the drug, indicating the drug reduced pain. However, after the researchers shut down the RVM, rats that were given WIN55,212-2 no longer demonstrated insensitivity to pain, moving their tails from the heat source as quickly as the rats who had not received the drug. The test demonstrated that the RVM was critical for producing the pain-relieving effects of cannabinoids.
Since cannabinoids also produce a loss of motor coordination, the researchers had to test the hypothesis that turning off the RVM simply reversed the motor deficits and not the analgesic effects of the cannabinoid drug. To test this possibility, they gave the rats a motor coordination test called the retard treadmill, in which the rats are placed on a rod and the time that it takes for them to fall off is measured. Rats that received WIN55, 212-2 showed a severe loss of motor coordination. However, after the RVN was shut down, a condition that reversed the analgesic effects, rats continued to show a loss of motor coordination.
"This experiment demonstrates that the rats given the cannabinoid did not leave their tails on the heat source simply because they had lost their motor coordination," said Meng. "The cannabinoid is also having an analgesic effect."
In a second set of experiments, performed in anesthetized rats, the researchers examined the effect of cannabinoids on the activity of the brain cells called neurons in the RVM. Using a method called electrophysiology, which measures the electrical impulses of neurons, the researchers were able to detect the activity of single neurons in the RVM after several different drug treatments.
The researchers determined that WIN55,212-2 produced changes in the activity of neurons in the RVM that were identical to that of morphine. However, they were also able to show that these two drugs act on the RVM in different ways. A drug that blocks the effect of morphine was unable to prevent the effect of WIN55,212-2. Likewise, a drug that blocks the effect of the WIN55,212-2 was unable to prevent the changes produced by morphine.
"These results indicate that the marijuana-like drug can reduce pain by affecting the same pain modulating neurons as morphine, but through separate mechanisms," said Meng.
Other co-authors of the UCSF study were Barton H. Manning, PhD, a postdoctoral fellow in Howard Fields lab, and William J. Martin, PhD, a postdoctoral fellow in the laboratory of Allan Basbaum, chairman of the Departmemt of Anatomy and a research scientist with the W.M. Keck Foundation Center for Integrative Neuroscience at UCSF.
The study was funded by the National Institute of Drug Abuse, the UCSF Center for the Neurobiology of Addiction and the Canadian MRC.
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