Insight into the proteins in the brain that detect cannabis

April 30, 2019

Science Daily/University of Bristol

Researchers at the University of Bristol have made new progress in understanding how cannabinoid receptors (CB1Rs), the proteins that detect the active components of marijuana, are controlled in the brain.

The brain contains about 100 billion nerve cells that are constantly communicating with one another at specialised junctions called synapses. Nerve cells possess extensions called axons, which send signals to synapses, and dendrites, which receive information from synapses.

At the synapse, the electrical 'firing' of a nerve cell causes the release of chemicals called neurotransmitters from the presynaptic terminals of its axon. These neurotransmitters cross the synapse and pass on the signal by binding to receptors at postsynaptic sites on the dendrites of the next nerve cell.

CB1Rs help control information flow in the brain by binding molecules made in the brain called endocannabinoids, which influence brain functions such as pain, appetite, mood and memory. Unusually, endocannabinoid signalling goes in the reverse direction compared to most other neurotransmitters. The 'receiving' CB1Rs are located at presynaptic sites on axons, whereas the release sites are at postsynaptic sites on dendrites.

This reverse or 'retrograde' signalling that activates presynaptic CB1Rs 'dampens down' presynaptic release of other neurotransmitters resulting in a slowing of brain activity. Moreover, the active components of cannabis bind to CB1Rs in a similar manner to endocannabinoids, resulting in the 'mellow' sensation caused by the recreational use of cannabis.

For CB1Rs to regulate brain function properly, it is essential that they are sent to the right place on the surface of the axon. However, very little is known about exactly how this occurs. The research published today [Tuesday 30 April] in eLife investigated how this process happens.

The Bristol group showed that a specific part of the CB1R protein plays a key role in the getting CB1R into axons. The research team tracked newly made CB1Rs in nerve cells grown in a dish and found that a short region of CB1R is crucial for sending CB1R to the axon and preventing it from going to the dendrites. They also discovered that this region stabilises CB1R at the surface of the axon, making it more available to receive signals from endocannabinoids.

Jeremy Henley, Professor of Molecular Neuroscience in Bristol's School of Biochemistry, said: "In recent years there has been tremendous interest in -- and controversy about -- activation of CB1R by medical marijuana. It is becoming increasingly apparent that activation of CB1Rs could be therapeutically useful for a wide range of diseases such as chronic pain, epilepsy, or multiple sclerosis. Understanding the fundamental properties of CB1R is an important basis for future studies exploring the efficacy and optimisation of these targeted approaches."

It is hoped that this increased understanding of how CB1Rs behave in nerve cells will pave the way for future studies aimed at examining the possible medical uses of marijuana, or other drugs that target CB1Rs, in treating a wide range of disorders.

https://www.sciencedaily.com/releases/2019/04/190430103457.htm

How the brain’s own marijuana-like chemicals suppress pain

October 12, 2011

Science Daily/National University of Ireland, Galway

New findings about how the brain functions to suppress pain have been published in the journal Pain, by NUI Galway researchers. For the first time, it has been shown that the hippocampus of the brain, which is usually associated with memory, has an active role to play in suppressing pain during times of stress.

The work was carried out by researchers in Pharmacology and Therapeutics, and the Centre for Pain Research at the National Centre for Biomedical Engineering Science, NUI Galway.

In times of immense stress or fear, pain transmission and perception can be suppressed potently in humans and other animals. This important survival response can help us cope with, or escape from, potentially life-threatening situations. An increased understanding of the biological mechanisms involved in this so-called fear-induced analgesia is important from a fundamental physiological perspective and may also advance the search for new therapeutic approaches to the treatment of pain.

Dr David Finn, Co-Director of the Centre for Pain Research at NUI Galway, and study leader, says: "The body can suppress pain when under extreme stress, in part through the action of marijuana-like substances produced in the brain. What we have now identified for the first time, is that the brain's hippocampus is an important site of action of these endocannabinoids during the potent suppression of pain by fear. This research, which was funded by a grant from Science Foundation Ireland, advances our fundamental understanding of the neurobiology of pain and may facilitate the identification of new therapeutic targets for the treatment of pain and anxiety disorders."

Working with Dr Finn, first author Dr Gemma Ford was able to demonstrate that inhibition of the enzyme that breaks down one of these endogenous marijuana-like substances in the hippocampus, had the effect of enhancing stress-induced pain suppression. Further experimentation revealed that these effects were mediated by the cannabinoid CB1 receptor and were likely to be mediated by stress-induced increases in levels of endocannabinoids in the hippocampus.

https://www.sciencedaily.com/releases/2011/10/111012083619.htm

Marijuana, Genes, Medicines and Brain Scans Help Scientists Find Better Anxiety Treatments

April 22, 2008

Science Daily/University of Michigan Health System

Right now, about half of all people who take medicine for an anxiety disorder don't get much help from it. And doctors have no definitive way to predict who will, and who won't, benefit from each anti-anxiety prescription they write.

But a University of Michigan Medical School researcher and his team are working to bring more certainty to how doctors and patients choose anxiety treatments, by probing the connection between brain activity, genetics and medication.

K. Luan Phan, M.D., and his former University of Chicago colleagues recently reported intriguing findings from a brain imaging study in occasional, non-dependent, marijuana users in the Journal of Neuroscience.

In a placebo-controlled design, they made the findings after giving the volunteers delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana, and exposing them to photographs of emotional faces, which served as signals of social communication. The study results, which showed that THC reduces the response to threat in a brain region called the amygdala, allowed the researchers to zero in on an area of the brain that might serve as a good target for new anti-anxiety drugs.

Now, with a new clinical trial that is currently seeking participants, Phan is searching for more clues as to how anxiety treatment could be tailored to the individual patient, to give the best chance that a treatment will work for him or her.

The new study will test a generic form of the drug Zoloft (sertraline), a selective serotonin reuptake inhibitor (SSRI) approved by the U.S. Food and Drug Administration for social anxiety disorder and other anxiety disorders. Both people with social anxiety disorder and a comparison group of people without anxiety are needed for brain scanning and genetic testing.

The idea is to see whether variations in the genes for certain brain receptors and transporters are linked with variations in how a person's brain reacts to pictures of emotional faces, and variations in how they respond to the anti-anxiety drug. This information could lead to an individualized or personalized approach to medical care.

"These two studies are trying to get to the same goal: to find better treatments for anxiety disorders that affect millions of Americans and seriously interfere with their functioning," says Phan, an assistant professor of psychiatry at U-M and the VA Ann Arbor Healthcare System. "The cannabis study highlights a new avenue that we need to explore further as we try to develop novel medications, while the sertraline study will try to find out if we can tell which patients might or might not respond well, and by what mechanism, to an already existing medication known to have some efficacy in treating anxiety disorders."

Phan led the cannabis study at the University of Chicago, collaborating with Harriet deWit, Ph.D., the director of the Human Behavioral Pharmacology Laboratory in the Department of Psychiatry there. Their results are based on brain scans of 16 recreational marijuana users who agreed to undergo functional magnetic resonance imaging, or fMRI.

The researchers chose fMRI because it allows them to see in real time which areas of the brain are most active while a volunteer is performing a certain task -- for example, viewing a picture of a human face that is expressing anger or fear, or performing a decision-making exercise.

That same approach will be used in the new sertraline study, with two different scans before and after anxiety patients are prescribed the medication. The healthy volunteers in the study will also have fMRI scans, though they will not receive the drug. All study participants must between 18 and 55 years old, and those with anxiety disorders must not be taking any other medication that could be affecting the brain in order to qualify to enter the study.

The cannabis study used THC, and a placebo caplet that looked exactly like the THC caplet. The researchers found that when the marijuana users received THC, their brain's response to "threatening" faces was less than it was when they received a placebo.

The difference in response was seen in an area of the brain called the amygdala, which is a hub for the brain's ability to process signs of danger or warning, and to decide how to respond. But there were no differences between THC and placebo in the areas of the brain that process non-emotional visual signals or govern body movement -- suggesting that THC had a specific effect on a specific brain region and on a specific task of processing fear. Other researchers have shown this to be a region that's rich in a receptor called CB1, part of the brain's "cannabinoid" system.

The human brain produces compounds called endocannabinoids that act on these receptors, and are involved in anxiety and fear-learning, or the learning of which threats to be afraid of. But little has been known about the effect of THC, an exogenous cannabinoid, on the brain's own system.

For ethical reasons, the researchers did not give THC to non-marijuana users, and the study was small. But the findings in the study volunteers suggest that THC and other compounds that act on the CB1 receptors in the amygdala could be fruitful targets for new anti-anxiety medicines. Phan notes that rimonabant, a smoking-cessation and weight-loss drug not yet available in the United States for clinical use, also acts on the CB1 receptor.

Understanding how drugs such as marijuana affect the brain may also help reveal more about why people become addicted to illicit drugs or abuse certain prescription drugs, Phan notes. Some individuals may be using illicit drugs and misusing prescribed drugs to alleviate their anxiety. He hopes to investigate this issue further by studying people who have used prescription pain drugs recreationally (such as oxycodone), using new funding from the National Institutes of Health.

The THC study links three key domains of human behavior: a specific region of the brain, the function of that area, and a neurochemical agent (THC) that appears to act on them. The new sertraline study will take it one step further, by looking at genetics too. Specifically, Phan and his colleagues will look for variations ("functional polymorphisms") among several genes in individual subjects. Key among them is the gene (5-HTTLPR) that encodes the serotonin transporter protein that transports the neurotransmitter serotonin in and out of brain cells. Serotonin has long been known to be involved in depression and anxiety, and indeed most modern antidepressant and anti-anxiety drugs (such as SSRIs) work on this transporter.

https://www.sciencedaily.com/releases/2008/04/080418154959.htm