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, 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."
Keith McKeown | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction