Breakthrough study identified chemical that can improve pain treatments

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Washington, November 24 : New and highly effective treatments for chronic pain may soon be available, thanks to researchers at the Scripps Research Institute who have identified a compound which can inhibit one of the enzymes that break down the pain-killing effect of marijuana.

Marijuana kills pain by activating a set of proteins known as cannabinoid receptors, which can also regulate appetite, inflammation, and memory.

The body also naturally activates components of the cannabinoid system, namely N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), which are broken down by the enzymes called fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively.

While a number of compounds are being studied for their effectiveness in breaking down FAAH, no group had been able to develop a chemical that inhibits MAGL specifically.

"The tools-selective and efficacious MAGL inhibitors-just weren't there, " says Jonathan Long, a graduate student of the Scripps Research Kellogg School of Science and Technology who is a member of the Cravatt lab, and a first author of the new paper.

He, however, adds that his team at the lab have finally identified a MAGL-specific inhibitor.

Long attributes this breakthrough to Activity-Based Protein Profiling, a unique chemical technique the group devised.

During the study, the researchers developed about 200 compounds and found that one was a highly effective block for MAGL. They named the compound JZL184, named after Long's initials and the order in the series of potential inhibitors tested.

Long says that JZL184 was found to effectively block only MAGL among more than 40 related brain enzymes, opening the door for the first definitive study of 2-AG's activity.

The researchers have found that MAGL inhibition using JZL184, and the resulting increase in 2-AG concentration, not only reduced pain in mice, but also induced other effects associated with the cannabinoid receptors, namely hypothermia and decreased movement.

"This really does suggest a sort of segregation of labor, if you will. That, I think, is a truly unique result," says Cravatt of the differential effects of elevating AEA versus 2-AG as part of the overall function of the cannabinoid system.

Treatments based on inhibiting FAAH have already shown great promise for controlling pain, and the researchers are of the opinion that manipulating MAGL levels may prove to be a boon for treatment development, especially if 2-AG's other effects, such as hypothermia, can be managed.

"There are so many different types of pain that it's possible some types could be more effectively treated with one treatment than another," Cravatt says.

ANI

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