Sunday, August 30, 2009

Marijuana-inspired Painkiller? New Chemical Pathway Discovered

Marijuana can be an effective painkiller, but social issues and unhealthy smoke inhalation complicate its use. As a result, researchers have focused great attention on understanding the biochemical system involved so they might manipulate it by other means. Toward that end, scientists have definitively identified a chemical pathway that, in mice, imitates marijuana's painkilling effect. The work could enable the development of new pain treatments.

Marijuana kills pain by activating a set of proteins known as cannabinoid receptors, which can also regulate appetite, inflammation, and memory. The body also has chemicals known as endocannabinoids that naturally activate these same receptors, namely N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG).

These natural components of the cannabinoid system remain the focus of intense efforts to develop new treatments not only for chronic pain, but also for obesity, anxiety, and depression. However, until the new paper (citation below) specific methods to study 2-AG signaling have been lacking.

AEA's activity has been well understood for years. In past research, Cravatt and his team identified an enzyme called fatty acid amide hydrolase, or FAAH, that breaks down AEA, effectively reducing its pain killing activity. A number of compounds are now in clinical development that target and breakdown FAAH, allowing AEA to build up, reducing pain. However, FAAH does not control 2-AG metabolism in vivo, and therefore, the potential biological functions and therapeutic potential of this second endocannabinoid have remained largely unknown.

Teasing out 2-AG's specific impacts have proven challenging. Comparable to FAAH, an enzyme called monoacylglycerol lipase (MAGL) breaks down 2-AG. But, despite numerous attempts, 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.

But now, a MAGL-specific inhibitor is finally available, thanks to the lab's new work. Key to this success was Activity-Based Protein Profiling, a unique chemical technique the group devised and has used fruitfully in other inhibitor hunts. This system enables the rapid engineering and testing of chemical compounds against many members of enzyme families, in hope of finding effective and selective inhibitors.

For this project, the group developed about 200 compounds and found that one was a highly effective block for MAGL. The scientists dubbed the compound JZL184, named after Long's initials and the order in the series of potential inhibitors tested. JZL184 effectively blocks only MAGL among more than 40 related brain enzymes, which opened the door for the first definitive study of 2-AG's activity.

A New View of 2-AG

Unlike increased AEA, which causes only reduced pain sensation, the team 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," says Cravatt of the differential effects of elevating AEA versus 2-AG as part of the overall function of the cannabinoid system. "That, I think, is a truly unique result."

While treatments based on inhibiting FAAH show great promise for controlling pain, manipulating MAGL levels could also 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," Cravatt says, "that it's possible some types could be more effectively treated with one treatment than another."

This research was supported by the National Institutes of Health, the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute, and the Skaggs Institute for Chemical Biology.

Journal reference:

1. Long et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nature Chemical Biology, Online November 24, 2008; DOI: 10.1038/nchembio.129

Adapted from materials provided by Scripps Research Institute, via EurekAlert!, a service of AAAS.

Marijuana-inspired Painkiller? New Chemical Pathway Discovered

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3 comments:

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There are many persuasive arguments on why America should legalize marijuana, and the reasons are sound, but the fact that many millions of Americans have used pot has not translated into real political pressure on the people who can change the laws. One of the problems inhibiting legalization is that people that smoke a glass pipe are not considered serious or mature. It is This stigma that scares many pot users to hide that they smoke pot. Therefore the Reality of who smokes pot and how much the smoke is very different than it seems. The last three presidents were admitted pot users and by my Understanding the same is probably true of the first three presidents as well. Marijuana Legislation is very serious and has everything with how we define what it means to be American. What credence do we as Americans give the rights of the individual to the pursuit of happiness as well as a right to privacy? In the end it is up to us to be public about our choices and to Voice our opinions to the ones that ultimately decide what the rules are. Every hand written Letter that makes it to a representative is considered to be the voice of a thousand people who did not take the time to write. Send an email, send a letter make a phone call and get counted.
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Anonymous said...

Smoke more bongs

Dean Shaw said...

In my personal opinion the law against a naturally growen plant is a fucking joke to this country and i spit on the flag i got caught with 3 grams and now have to stand trial for possesion i don't rob shops i don't do other drugs and worse this law makes the government look hypocritical i mean cigerettes kill more australians yet they sell them and it like marajuana we have our choice to buy it worse they waste tax payers money locking those up for possessing it or selling it wich is a joke i am disgusted to call myself australian and untill that day they legalize it i wipe my ass with the australian flag for shame on you if amsterdam can legalize it why can't we