Understanding the Effects of Endogenous Cannabinoids

[User]

Our bodies produce natural cannabinoids that binds to the cannabinoid receptors, CB1 and CB2, which are also targeted by ingredients in marijuana. The two known endogenous cannabinoids, AEA (N-arachidonoylethanolamine) and 2-AG (2-arachidonoylglycerol), affects our mood, appetite, pain sensation, inflammation response, and memory. Thus, they have caught the attention of the pharmaceutical industry, which is trying to find ways of regulating AEA and 2-AG activities in order to treat mood disorders, obesity, and chronic pain.

In order to effectively control AEA and 2-AG, it's essential to understand how each of them function in the body. Although it's tricky to separate their individual roles, it does help that each of them is controlled by different enzymes. The enzyme FAAH hydrolyzes AEA to decrease its levels in the nervous system and periphery, while MAGL hydrolyzes 2-AG to reduce its activity.

Scientists have found ways to selectively block FAAH in order to increase AEA levels and see what its affects are. Elevated AEA levels in animals induced activation of both the CB1 and CB2 receptors, lessening pain, inflammation, anxiety, and depression. Interestingly, the animals did not experience some key symptoms of CB1 dysregulation, such as movement disorder and hypothermia. This raises the question of whether 2-AG influences these CB1-dependent effects.



2-AG's function in live animals had been much harder to probe because there was no inhibitor that selectively and strongly inhibited MAGL. A research team led by Benjamin Cravatt of the Skaggs Institute overcame this obstacle when they discovered that JZL184 is a potent inhibitor of MAGL in vivo.

They administered JZL184 to mice and found that MAGL activity was reduced by 85 percent, thereby increasing 2-AG levels by eight-fold for at least eight hours. The elevated levels of 2-AG produced a number of CB-1 dependent behavioral effects, including pain reduction, hypothermia, and decreased motility; however, they did not develop other CB-1 effects. The mice didn't experience catalepsy (rigidity in posture and facial expressions) and they didn't display spontaneous and awkward limb movements.

The development of selectively influencing 2-AG levels opens up a new avenue for medical research. In addition to designing synthetic cannabinoids, or using the ones in marijuana, scientists can synthesize drugs to "discriminate between the activities of AEA and 2-AG in a wide range of biological systems" or inhibit both enzymes in a way that might potently mitigate pain.

By Yun Xie


Source