LONDON When someone smokes a joint containing cannabis, active compounds called cannabinoids enter the bloodstream and eventually interact with a receptor on nerve cells called the central cannabinoid receptor, or CB1. Studies in mice now suggest that blocking the CB1 receptor can ameliorate the effects of withdrawing opiate drugs raising the prospect that cannabinoids could provide a treatment for the shaking, sweating and other symptoms in people coming cold turkey off opiate drugs such as heroin.
Marc Parmentier, associate professor at the Free University of Brussels, in Belgium, and colleagues from Paris and Cagliari, Italy, decided to investigate the role of the CB1 receptor by developing knockout mice which lacked the gene for this molecule. They reported their results in last week¿s issue of Science, in a paper titled ¿Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice.¿
Parmentier told BioWorld International: ¿One of the limitations on the use of opiate drugs is that people become dependent on them. But if it were possible to block this side effect, opiates would have a more general use in the treatment of pain. Our results suggest that it may be possible to do this by blocking the CB1 receptor.¿
The CB1 receptor is just one of many G-protein-coupled receptors being studied by Parmentier¿s group. ¿We cloned human CB1 as an orphan receptor we knew its structure, but not its function and studied its pharmacology several years ago,¿ he said. ¿At that time, there were no antagonists, so we decided to go for a knockout model.¿
After testing the knockout mice pharmacologically to check that there were no binding sites for cannabinoid ligands in the brain, Parmentier and his colleagues went on to test certain characteristics of the genetically modified animals. After examining their behavior in novel environments, they concluded that the ability of the knockout mice to adapt to new environments could be mildly impaired, perhaps because of changes in short-term memory or attention, or both.
They also carried out several tests to compare the ability of wild-type mice to withstand painful stimuli with that of the knockout mice. The results of these tests were similar in the two groups, and the researchers concluded that the CB1 receptor is not crucial to the control of pain. They suggest other systems might compensate for its absence.
When wild-type mice are given the cannabinoid delta9-tetrahydrocannabinol (delta9-THC), they normally show an increased tolerance to painful stimuli. However, the knockout mice lacking CB1 did not respond in this way.
Knockout Mice Less Dependent On Morphine
In addition, both knockout and wild-type mice were put in a situation where they could obtain WIN55,212-2, a cannabinoid agonist. While the wild-type mice self-administered the drug, the knockout mice did not. Parmentier and his colleagues write in Science that the results of these tests ¿demonstrate that the main pharmacological responses to delta9-THC, as well as the addictive properties of cannabinoids, are indeed mediated mostly, if not exclusively, by the CB1 receptor.¿
But the most surprising results came from an experiment which looked at the interaction between opiate drugs and cannabinoids. Parmentier told BioWorld International: ¿We found that the knockout mice had less dependence on morphine. Morphine has an analgesic effect on these mice, but their dependence on morphine administration and the withdrawal syndrome when chronic treatment with morphine is stopped was greatly reduced. This was a really unexpected finding.¿
This demonstrated, Parmentier added, that there is a link between opiate receptors and the CB1 receptor in the development of dependence.
This discovery could have practical implications, he suggested. ¿One possible outcome might be to inhibit the development of dependence on morphine, for example, by giving an antagonist of the CB1 receptor, without impairing the analgesic effect of the morphine.¿
Could the finding be useful to recreational users of these drugs, or those addicted to them? ¿We need to have more studies dedicated to this aspect before it will become possible even to speculate on this,¿ Parmentier said. Next, he plans to study other features of the knockout mice, such as the role played by the CB1 receptor in the regulation of the immune system. n