Neuroscientists discover previously unknown function of cannabinoid receptor

Study could improve our insights into brain diseases

May 2, 2016

Science Daily/DZNE - German Center for Neurodegenerative Diseases

In the brain, there is a delicate interplay of signaling substances and cellular activity. Scientists have now identified another key player within this ensemble. In a laboratory study they found that the 'cannabinoid type 2 receptor' influences information processing inside the hippocampus. The research results might help advance our understanding of schizophrenia and Alzheimer's, say the authors.

The cannabinoid type 2 receptor -- also called "CB2 receptor" -- is a special membrane protein. Its function is to receive chemical signals that control cellular activity. "Until now, this receptor was considered part of the immune system without function in nerve cells. However, our study shows that it also plays an important role in the signal processing of the brain," explains Professor Dietmar Schmitz, Speaker for the DZNE-Site Berlin and Director of the Neuroscience Research Center of the Charité (NWFZ/NeuroCure). Schmitz coordinated the current study, which involved Berlin colleagues and also scientists from the University of Bonn and from the "National Institute on Drug Abuse" of the US.

As the researchers demonstrated in an animal model, the CB2 receptor raises the excitation threshold of nerve cells in the hippocampus. "Operation of the brain critically depends on the fact that nerve impulses sometimes have an exciting impact on downstream cells and in other cases they have a suppressing effect," says Dr Vanessa Stempel, lead author of the current publication, who is now doing research in Cambridge, UK. "The CB2 receptor works like a set screw by which such communication processes can be adjusted."

Component of the "endocannabinoid system"

The CB2 receptor is part of the endocannabinoid system (ECS). This family of receptors and signaling substances exists in many organisms including humans. It is a biochemical control system which is involved in the regulation of numerous physiological processes. Its name refers to the fact that chemicals derived from the cannabis plant bind to receptors of the ECS. So far, there are two known types of these receptors: The CB2 receptor has no psychoactive effect. Hence, the mind-altering effects triggered by the consumption of cannabis are ascribed to the "cannabinoid type 1 receptor."

Potential therapeutic applications

The results of the current study could contribute to a better understanding of disease mechanisms and provide a starting point for novel medications. "Brain activity is disturbed in schizophrenia, depression, Alzheimer's disease and other neuropsychiatric disorders. Pharmaceuticals that bind to the CB2 receptor could possibly influence the activity of brain cells and thus become part of a therapy," Professor Schmitz concludes.

https://www.sciencedaily.com/releases/2016/05/160502111228.htm

An alternative to medical marijuana for pain?

March 4, 2015

Science Daily/Elsevier

Medical marijuana is proliferating across the country due to the ability of cannabis ingestion to treat important clinical problems such as chronic pain. However, negative side effects and the development of tolerance limit the widespread therapeutic use of Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis.

THC's side effects are produced via its actions at cannabinoid CB1 receptors in the brain. Thus, scientists theorized that an agent with similar mechanistic actions, but that activate CB2 receptors instead, may eliminate the unwanted side effects while maintaining an equivalent level of efficacy.

Dr. Andrea Hohmann and her colleagues at Indiana University tested this strategy and found that, unlike Δ9-THC, repeated dosing with the cannabinoid CB2 agonist AM1710 suppresses chemotherapy-induced pain in mice without producing tolerance, physical withdrawal, motor dysfunction, or hypothermia. Moreover, the therapeutic effects of AM1710 were preserved in mice lacking CB1 receptors but absent in mice lacking CB2 receptors.

Their findings are reported in the current issue of Biological Psychiatry.

"Our study is important because it demonstrates beyond doubt that activation of cannabinoid CB2 receptors suppresses neuropathic pain without producing signs of physical dependence (i.e., a withdrawal syndrome) or other unwanted side effects associated with activation of CB1 receptors in the brain," said Hohmann.

Their studies used animals that were treated with a chemotherapeutic agent (paclitaxel) to produce pain. When animals were given AM1710, a CB2 agonist, its pain-suppressive effects were fully preserved and its therapeutic effects were maintained even after repeated dosing.

Alternatively, and as expected, when animals were given Δ9-THC, they developed complete tolerance to the pain-suppressing effects of THC and with repeated dosing, THC was no longer effective in suppressing neuropathic pain.

When the THC-treated animals were challenged with a drug that blocks CB1 receptors in the brain, the animals showed a prominent withdrawal syndrome, indicating signs of physical dependence following removal of THC. Strikingly, this was not the case with the CB2 agonist; blocking either CB1 or CB2 receptors produced no signs of withdrawal in animals treated chronically with the CB2 agonist.

Hohmann added, "We think our data suggests that CB2 receptors are an important target for suppressing chronic pain without unwanted side effects (e.g. psychoactivity, addiction)."

"It is important to know whether the benefits of cannabis ingestion for pain could be attributed in large part to the stimulation of CB2 receptors," commented Dr. John Krystal, Editor of Biological Psychiatry. "CB2 agonists, in theory, would present less risk regarding addiction and intoxication than the ingestion of cannabis or THC."

More work will be necessary before CB2 receptor agonists could be prescribed for use in humans, but for now, these data support the therapeutic potential of CB2 agonists for managing pain without the adverse effects associated with cannabis.

https://www.sciencedaily.com/releases/2015/03/150304075336.htm