The findings have implications for both drug development and basic science
ERepeatedly boosting brain levels of one natural painkiller soon shuts down the brain cell receptors that respond to it, so that the painkilling effect is lost, according to a surprising new study led by Scripps Research Institute and Virginia Commonwealth University scientists. The study has important implications for drug development.
The natural painkiller, 2-AG, is one of the two major "endocannabinoid" neurotransmitters. The other, anandamide, can be kept at high levels in the brain without losing its therapeutic effects, and researchers had hoped that the same would be true for 2-AG.
"One implication is that maximally elevating 2-AG levels in the brain might not provide a straightforward path to new pain drugs," says Benjamin F. Cravatt III, PhD, professor and chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Biology at Scripps Research in La Jolla, California, who led the study with Aron Lichtman, PhD, a professor of pharmacology and toxicology at Virginia Commonwealth University in Richmond, Virginia. "But we remain optimistic that more modest elevations in 2-AG could produce sustained pain relief. Perhaps more importantly, on a basic science level, we've been able to tease apart a key difference between the two major endocannabinoid signaling pathways, since one can maximally elevate anandamide without observing tolerance."
The report appears in the August 22, 2010 issue of Nature Neuroscience.
A Better Chill Pill
Like the opioid system, the endocannabinoid system was discovered as a result of humans identifying a plant - in this case marijuana (cannabis sativa) - that artificially boosts its activity. Marijuana's main active ingredient, THC, typically reduces pain and anxiety. Researchers have sought to develop drugs that reproduce such therapeutic effects while leaving out THC's unwanted side effects - which include memory impairment, locomotor dysfunction, and possibly addiction.
Cannabinoid research received a boost in 1990 with the description of the main cannabinoid receptor in the brain, CB1, and a few years later with the discoveries of the body's own (endo-) cannabinoids, anandamide and 2-AG, which exert most of their effects by binding to CB1. Cannabinoid receptors are now known to be widely distributed in the brain, and when activated by anandamide or 2-AG, tend to calm the activity of the neurons where they reside. However, researchers so far have been unable to develop artificial cannabinoids that bind to CB1 without producing unwelcome THC-like side effects.
An alternative strategy has been to boost levels of the body's own cannabinoids by inhibiting the enzymes that normally break them down. And so far this has worked for anandamide. Inhibitors of its breakdown enzyme, fatty acid amide hydrolase (FAAH), have been shown to boost anandamide levels and reduce pain and inflammation without adverse side effects in animal tests and early clinical trials.
A similar strategy for boosting 2-AG may be promising, too, especially since 2-AG levels in the brain are naturally higher than anandamide's. Two years ago, the Cravatt and Lichtman laboratories jointly reported the development of an inhibitor of 2-AG's breakdown enzyme, monoacylglycerol lipase (MAGL). When administered to mice, it boosted their brain levels of 2-AG on average by a factor of eight, and produced a pain-killing effect comparable to that of FAAH inhibitors.
Diminishing Returns
Now the two labs report that 2-AG's pain-killing effect disappears after six days of treatment. "When you continually stimulate the endocannabinoid system by maximally raising 2-AG levels, you effectively desensitize the system," says Cravatt.