Scientists identify connection between dopamine and behavior related to pain and fear

New research illuminates crucial links between avoidance behavior and key brain chemicals

April 19, 2018

Science Daily/University of Maryland School of Medicine

Scientists at the University of Maryland School of Medicine have for the first time found direct causal links between the neurotransmitter dopamine and avoidance -- behavior related to pain and fear.

Researchers have long known that dopamine plays a key role in driving behavior related to pleasurable goals, such as food, sex and social interaction. In general, increasing dopamine boosts the drive toward these stimuli. But dopamine's role in allowing organisms to avoid negative events has remained mysterious.

The new study establishes for the first time that dopamine is central in causing behavior related to the avoidance of specific threats. The work was published today in the journal Current Biology.

"This study really advances what we know about how dopamine affects aversively motivated behaviors," said Joseph F. Cheer PhD, a professor in the UMSOM Department of Anatomy & Neurobiology and the study's corresponding author. "In the past, we thought of dopamine as a neurotransmitter involved in actions associated with the pursuit of rewards. With this new information we can delve into how dopamine affects so many more kinds of motivated behavior."

To better understand the role that dopamine plays in this process, Dr. Cheer and his colleagues, including principal author Jennifer Wenzel, PhD, a fellow in Dr. Cheer's laboratory, studied rats, focusing on a particular brain area, the nucleus accumbens. This brain region plays a crucial role in linking the need or desire for a given reward -- food, sex, etc. -- with the motor response to actually obtain that reward.

To study the animals under natural conditions, they used optogenetics, a relatively new technique in which specific groups of neurons can be controlled by exposure to light. In this case, Dr. Cheer's group used a blue laser to stimulate genetically modified rats whose dopamine neurons could be controlled to send out more or less dopamine. In this way, they were able to see how dopamine levels affected the animals' behavior. The principal advantage of this approach: he could control dopamine levels even as the animals moved freely in their environment.

The researchers subjected the animals to small electric shocks, but also taught the animals how to escape the shocks by pressing a small lever. Using optogenetics, they controlled the amount of dopamine released by neurons in the nucleus accumbens. Animals with high levels of dopamine in this brain region learned to avoid a shock more quickly and more often than animals that had a lower level of dopamine in this region.

Dr. Cheer says that this indicates that dopamine causally drives animals to avoid unpleasant or painful situations and stimuli. The results greatly expand the role that dopamine plays in driving behavior.

The researchers also examined the role that endocannabinoids play in this process. Endocannabinoids, brain chemicals that resemble the active ingredients in marijuana, play key roles in many brain processes. Here, Dr. Cheer and his colleagues found that endocannabinoids essentially open the gate that allows the dopamine neurons to fire. When the researchers reduced the level of endocannabinoids, the animals were much less likely to move to avoid shocks.

Dr. Cheer argues that the research sheds light on brain disorders such as post-traumatic stress disorder and depression. In depression, patients feel unable to avoid a sense of helplessness in the face of problems, and tend to ruminate rather than act to improve their situation. In PTSD, patients are unable to avoid an overwhelming sense of fear and anxiety in the face of seemingly low-stress situations. Both disorders, he says, may involve abnormally low levels of dopamine, and may be seen on some level as a failure of the avoidance system.

In both depression and PTSD, doctors already sometimes treat patients with medicine to increase dopamine and there are now clinical trials testing use of endocannabinoid drugs to treat these conditions. Dr. Cheer suggests that this approach may need to be used more often, and should certainly be studied in more detail.

https://www.sciencedaily.com/releases/2018/04/180419131108.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

Endocannabinoids, Closely Related to Active Ingredients in Cannabis Plant, Can Promote Pain

https://www.sciencedaily.com/images/2009/09/090911212404_1_540x360.jpg

September 14, 2009

Science Daily/ETH Zurich

The endocannabinoids occurring naturally in the human body are closely related to the active ingredients of the cannabis plant. Cannabis has been used for thousands of years, for example to treat chronic pain. However, the fact that the endocannabinoids produced by the body itself can also be involved in the origin of pain is the astonishing result of studies by a Zurich research team.

The first mention of cannabis as a medicinal plant was in the Chinese book of medicinal plants “Shennong bencao jing”, which is almost 5000 years old. The Chinese emperor Shennong is said to have recommended cannabis resin as a remedy for various illnesses. After the use of its active ingredients for thousands of years to alleviate chronic pain, a study by the research group led by Hanns Ulrich Zeilhofer, Professor at the Institute of Pharmaceutical Sciences at ETH Zurich and the Institute of Pharmacology and Toxicology at the University of Zurich now shows that the endocannabinoids produced by the body itself can lead to pain sensitisation in certain types of pain. Their study was recently published in the scientific journal Science.

Short-circuit in the spinal cord

Pain and touch are conducted to the brain through the spinal cord via two different systems. This enables the brain to distinguish between pain and simple touch. However, because the two systems are interconnected via nerve fibres in the spinal cord, simple touches can also be perceived as pain, for example as a result of a “short circuit”. Such faulty circuits can occur if inhibitory chemical messengers (neurotransmitters) in the spinal cord are absent or blocked. Zeilhofer says, “This happens in various illnesses and can even be triggered by intense pain stimuli themselves.”

The body’s own endocannabinoids play a considerable part in the biochemical processes taking place in this, as the study by Zeilhofer and his team shows. In particular, the release of endocannabinoids in the spinal cord seems to be responsible for the fact that, after an initial pain stimulus, pain sensitivity spreads beyond the area originally stimulated. Even slight touch in this area is then perceived as painful. The endocannabinoids thus cause a “short circuit” between the touch signals and pain.

The scientists tested the theory that endocannabinoids released in the spinal cord during intense pain stimuli are responsible for this short-circuit. It actually became apparent that activating the endocannabinoid receptors on isolated spinal cord reduced the release of pain-inhibiting neurotransmitters. Animals that had developed the expected oversensitivity to slight touching after a pain stimulus behaved normally again after their cannabinoid receptors in the spinal cord were blocked.

Endocannabinoid inhibitors relieve pain

The fact that these processes also occur in humans was shown by experiments on healthy volunteers carried out in the Anaesthesiology Department at the University of Erlangen. Pain receptors in the volunteers’ skin were locally stimulated with an electric current, after which the size of the area hypersensitive to pain was determined. In the next step, half of the volunteers received a placebo for ten days, while the others were given Rimonabant, a substance that blocks certain cannabinoid receptors. The experiment was then repeated. Zeilhofer says, “The painful area formed in the test subjects whose endocannabinoid receptors had been blocked was about fifty percent smaller than in those who had taken the placebo.”

Helpful to the pharmaceutical industry

However, further experiments also showed that other forms of pain, e.g. those occurring as a result of nerve injuries, developed normally in mice that lacked endocannabinoid receptors. The endocannabinoids seem to play no major pain promoting role in this case. Zeilhofer says, “In the next step we want to find out which pain patients might possibly benefit from blocking the cannabinoid receptors. At any rate our findings should be of great interest to drug companies who are working with this pain model to develop new analgesics.”

https://www.sciencedaily.com/releases/2009/09/090911212404.htm

Discovery of Mechanism that Processes 'THC' Type Brain Compound May Lead to New Medicines for Pain, Addiction

March 31, 2009

Science Daily/Stony Brook University Medical Center

Dale Deutsch, Ph.D., Professor of Biochemistry and Cell Biology at Stony Brook University and colleagues discovered a new molecular mechanism for the processing of endocannabinoids, brain compounds similar to THC, the active ingredient in marijuana, and essential in physiological processes such as pain, appetite, and memory.

Reported online this week in the Proceedings of the National Academy of Sciences (PNAS), the finding could pave the way for new medicines for pain, addiction, appetite control and other disorders.

Dr. Deutsch and colleagues in the Departments of Biochemistry and Cell Biology (Martin Kaczocha) and Neurobiology and Behavior (Sherrye Glaser, Ph.D.) are the first to successfully identify two known fatty acid binding proteins (FABPs) that carry the endocannabinoid anandamide (AEA), a neurotransmitter, from the cell membrane to interior of the cell where it is destroyed. This identification enabled the research team to inhibit FABPs in various laboratory experiments and thereby reduce AEA breakdown inside cells. In their study, “Identification of intracellular carriers for the endocannabinoid anandamide,” the researchers report that they decreased the breakdown of AEA in some instances by approximately 50 percent.

“Inhibiting FABPs could potentially raise the levels of AEA in the brain’s synapses,” says Dr. Deutsch. “Naturally occurring AEA levels have been shown to curb pain without the negative side effects, such as motor coordination problems, from molecules like THC. Therefore, it makes sense to target AEA for therapeutic purposes.”

He emphasizes that their groundbreaking discovery of the role of FABPs in transporting this class of neurotransmitters may prove to be a crucial step in developing novel drug targets for endocannabinoids by way of inhibiting FABPs. In support of the research, The State University of New York (SUNY) Stony Brook Office of Technology Licensing and Industry Relations (OTLIR) has filed U.S. Patent applications comprising the discovery.

The OTLIR manages all intellectual property matters for the SUNY Research Foundation. In actively marketing this unlicensed technology created by Dr. Deutsch, the Stony Brook OTLIR welcomes commercial entities interested in partnering with the University. The licensing agent for the project is Adam DeRosa of the OTLIR.

The breakdown of AEA requires two factors. First, there needs to be a mechanism for transporting AEA to the location where it is inactivated because AEA is a fatty compound and thus unable to move inside the watery cellular environment. Second, the cell must express an enzyme called FAAH, which controls the breakdown and inactivation of AEA. In the laboratory, the researchers coaxed a nonneuronal cell type (COS-7) to express FAAH. These FAAH-expressing COS-7 cells were able to break down AED efficiently, indicating that the intracellular AEA transport mechanism was already present and operation in these cells. The researchers identified these carriers as two separate FABPs.

Dr. Deutsch believes that because a transporter for the AEA class of neurotrasmitters had never been discovered until the Stony Brook findings, continued research may explain many unanswered questions about AEA. Future research may uncover more knowledge about AEA transport, as well as the entire role these neurotransmitters play in pain, inflammation, appetite control, addiction, and perhaps other physiological processes related to many human disorders.

The research was funded by the National Institute on Drug Abuse, part of the National Institutes of Health.

https://www.sciencedaily.com/releases/2009/03/090325190342.htm

Weeding Out the Highs of Medical Marijuana

July 15, 2008

Science Daily/University of Manchester

Research exploring new ways of exploiting the full medicinal uses of cannabis while avoiding unwanted side-effects will be presented to pharmacologists on July 15 by scientists attending the Federation of European Pharmacological Societies Congress, EPHAR 2008.

Cannabis is a source of compounds known as cannabinoids, one of which, THC -- the main chemical responsible for the 'high' -- has long been licensed as a medicine for suppressing nausea produced by chemotherapy and for stimulating appetite, for instance, in AIDS patients.

More recently, the cannabis-based medicine Sativex was licensed both for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. Sativex contains approximately equal amounts of THC and the non-psychoactive plant cannabinoid, cannabidiol.

"THC works by targeting molecules in our bodies called cannabinoid receptors" said Roger Pertwee, Professor of Neuropharmacology at the University of Aberdeen, who is co-chairing the cannabis symposium.

"So some current research is focused on designing drugs that only target cannabinoid receptors in the part of the body relevant to the disease in question and not the receptors in the central nervous system involved in the unwanted effects of cannabis."

A further approach to avoiding the psychoactivity caused by THC involves harnessing the body's own cannabis, called 'endocannabinoids'.

"We don't have cannabinoid receptors just in case we come into contact with plant-derived chemicals that activate them but rather because we have our own molecules that do this," said Christopher Fowler, Professor of Pharmacology at Umea University, in Sweden, and co-chair of the meeting.

"The neat thing about endocannabinoids is that they are often produced only when we need them, such as when our bodies are damaged in some way; pain, for example, leads to a release of endocannabinoids in a region of the brain that is involved with pain control.

"The problem with this natural protective 'endocannabinoid system' is that it is too short-lived to be of great benefit -- enzymes in our bodies quickly breakdown or metabolise the endocannabinoids negating their effect. It's a bit like a bathtub without a plug -- the water is turned on but rapidly disappears down the plughole. This suggests an immediate target: block the plughole and the water will stay longer.

"Since the release of endocannabinoids is local, levels in other parts of the brain, stay low. This approach is under intense investigation and programmes for the development of new drugs targeting pain and possibly other disorders such as anxiety and depression are currently underway."

Speakers will report on promising studies that show improved strategies for targeting the endocannabinoid system, not only for pain relief, but also for treating other conditions, including stroke, liver diseases and, ironically, nicotine addiction and obesity.

Thus, as the conference will hear, there are some disorders in which endocannabinoid release appears to be detrimental to our health, one example being obesity, which can be treated with Acomplia*, a licensed synthetic medicine that acts by blocking cannabinoid receptors.

Professor Pertwee added: "THC in cannabis is of course well known for its ability to induce 'the munchies' and, as mentioned, is used in clinics to boost appetite. But my research group has discovered that another constituent of cannabis, THCV, acts in a similar way to Acomplia, blocking one of the cannabinoid receptors, so providing an alternative -- and potentially better -- treatment route in the fight against obesity.

"The conference will hear about some of the possible advantages THVC has over current obesity treatments, as well as data on the potential of cannabinoids to treat other conditions, including neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's disease."

*Acomplia has been a licensed medicine for obesity in the UK and Europe for about two years and was accepted by the National Institute for Clinical Excellence (NICE) on June 28, 2008.

https://www.sciencedaily.com/releases/2008/07/080714192555.htm