Pre-clinical study suggests path toward non-addictive painkillers
Researchers use a compound with a novel mechanism to treat pain in mice without tolerance or physical dependence
Science Daily/October 25, 2017
Indiana University
A pre-clinical study led by Indiana University scientists reports a promising step forward in the search for pain relief methods without the addictive side effects behind the country's current opioid addiction crisis.
The research, which appears in the journal Biological Psychiatry, finds that the use of compounds called positive allosteric modulators, or PAMs, enhances the effect of pain-relief chemicals naturally produced by the body in response to stress or injury. This study also significantly strengthens preliminary evidence about the effectiveness of these compounds first reported at the 2016 Society for Neuroscience Conference in San Diego, California.
"Our study shows that a PAM enhances the effects of these pain-killing chemicals without producing tolerance or decreased effectiveness over time, both of which contribute to addiction in people who use opioid-based pain medications," said Andrea G. Hohmann, a Linda and Jack Gill Chair of Neuroscience and professor in the IU Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences, who led the study. "We see this research as an important step forward in the search for new, non-addictive methods to reduce pain."
Over 97 million Americans took prescription painkillers in 2015, with over 2 million reporting problems with the drugs. Drug overdoses are the No. 1 cause of death for Americans under 50, outranking guns and car accidents and outpacing the HIV epidemic at its peak.
Medical researchers are increasingly studying positive allosteric modulators because they target secondary drug receptor sites in the body. By contrast, "orthosteric" drugs -- including cannabinoids such as delta-9-tetrahydrocannabinol (THC) and opioids such as morphine -- influence primary binding sites, which means their effects may "spill over" to other processes in the body, causing dangerous or unwanted side effects. Rather than acting as an on/off switch, PAMs act like an amplifier, enhancing only the effects of the brain's own natural painkillers, thereby selectively altering biological processes in the body that naturally suppress pain.
The PAM used in the IU-led study worked by amplifying two brain compounds -- anandamide and 2-arachidonoylglycerol -- commonly called "endocannabinoids" because they act upon the CB1 receptor in the brain that responds to THC, the major psychoactive ingredient in cannabis.
Although the PAM compound enhanced the effects of the endocannabinoids the study found that it did not cause unwanted side effects associated with cannabis -- such as impaired motor functions or lowered body temperature -- because its effect is highly targeted in the brain. The pain relief was also stronger and longer-lasting than drugs that block an enzyme that breaks down and metabolizes the brain's own cannabis-like compounds. The PAM alone causes the natural painkillers to target only the right part of the brain at the right time, as opposed to drugs that bind to every receptor site throughout the body.
The PAMs also presented strong advantages over the other alternative pain-relief compounds tested in the study: a synthetic cannabinoid and a metabolic inhibitor. The analysis' results suggested these other compounds' remained likely to produce addiction or diminish in effectiveness over time.
While the IU-led research was conducted in mice, Hohmann said it's been shown that endocannabinoids are also released by the human body in response to inflammation or pain due to nerve injury. The compounds may also play a role in the temporary pain relief that occurs after a major injury.
"These results are exciting because you don't need a whole cocktail of other drugs to fully reverse the pathological pain in the animals," Hohmann said. "We also don't see unwanted signs of physical dependence or tolerance found with delta-9-tetrahydrocannabinol or opioid-based drugs. If these effects could be replicated in people, it would be a major step forward in the search for new, non-addictive forms of pain relief."
The PAM used in the study was GAT211, a molecule designed and synthesized by Ganesh Thakur at Northeastern University, who is a co-author on the study. The lead author on the study was Richard A. Slivicki, a graduate student in Hohmann's lab in the IU Program in Neuroscience and Department of Psychological and Brain Sciences. Additional authors on the study are Zhili Xu, an IU research fellow; Ken Mackie, IU professor and director of the Gill Center; Pushkar M. Kulkarni at Northeastern University; and Roger G. Pertwee at the University of Aberdeen, Scotland.
This study was supported in part by the National Institutes of Health.
https://www.sciencedaily.com/releases/2017/10/171025105038.htm
Muted stress response linked to long-term cannabis use
July 31, 2017
Science Daily/Washington State University
A new study by Washington State University psychology researchers reveals a dampened physiological response to stress in chronic cannabis users.
Using a nationally recognized procedure designed to provoke elevated levels of stress, Carrie Cuttler, clinical assistant professor of psychology, Ryan McLaughlin, assistant professor of integrative physiology and neuroscience, and colleagues in the WSU Department of Psychology examined levels of the stress hormone cortisol in both chronic cannabis users and non-users.
"To the best of our knowledge, this is the first study to examine the effects of acute stress on salivary cortisol levels in chronic cannabis users compared to non-users," Cuttler said. "While we are not at a point where we are comfortable saying whether this muted stress response is a good thing or a bad thing, our work is an important first step in investigating potential therapeutic benefits of cannabis at a time when its use is spreading faster than ever before."
The WSU researchers found virtually no difference in the salivary cortisol levels of two groups of heavy cannabis users confronted with either a psychologically and physiologically stressful situation or a non-stressful one.
In contrast, cortisol levels among non-users of cannabis who experienced the same simulated stressful situation were found to be much greater than the cortisol level of non-users in the no-stress scenario.
The findings are consistent with a growing body of literature that indicates chronic cannabis use is associated with dulled adrenal and emotional reactivity. The study was published recently in the journal Psychopharmacology.
The stress test
Research participants self-identified as either a chronic cannabis consumer, with daily or nearly daily use for the previous year, or as a non-user who had consumed cannabis 10 or fewer times in their life and not at all within the previous year. Forty daily cannabis users and 42 non-users participated in the study. All were required to abstain from consuming cannabis on the day of testing.
Upon arrival at the lab, participants provided a saliva sample and were asked to rate their current level of stress. The chronic cannabis users and non-users were randomly assigned to experience either the high-stress or no-stress version of the Maastricht Acute Stress Test. Known by its acronym MAST, it is a commonly used procedure for stress-related research which combines elements of physical, psychosocial and unpredictable types of stress.
The no-stress version was simple: participants placed one hand in lukewarm water for 45-90 seconds and then were asked to count from 1 to 25.
The high-stress version upped the stakes significantly. Participants placed their hand in ice cold water for 45-90 seconds. They were then asked to count backwards from 2043 by 17 and were given negative verbal feedback when they made a mistake. On top of this, subjects were monitored by a web camera and the video feed was displayed on a screen directly in front of the participants so they couldn't help but see themselves.
Immediately following the stress manipulation, all participants once again provided a saliva sample and were asked to rate their current level of stress. Before departing the testing facility, participants also provided a urine sample so researchers could corroborate self-reported use with bodily THC levels.
Interpreting the results
Cuttler and her colleagues' work suggests cannabis may have benefits in conferring resilience to stress, particularly in individuals who already have heightened emotional reactivity to stressful situations.
However, the researchers emphasized the release of cortisol typically serves an adaptive purpose, allowing an individual to mobilize energy stores and respond appropriately to threats in the environment.
"Thus, an inability to mount a proper hormonal response to stress could also have detrimental effects that could potentially be harmful to the individual," Cuttler said. "Research on cannabis is really just now ramping up because of legalization and our work going forward will play an important role in investigating both the short-term benefits and potential long-term consequences of chronic cannabis use."
Next steps in the research will include investigating various factors, such as the presence of residual THC, which may be influencing the muted stress response in cannabis users.
https://www.sciencedaily.com/releases/2017/07/170731090828.htm
Why does prenatal alcohol exposure increase the likelihood of addiction?
July 7, 2017
Science Daily/University at Buffalo
One of the many negative consequences when fetuses are exposed to alcohol in the womb is an increased risk for drug addiction later in life. Neuroscientists in the University at Buffalo Research Institute on Addictions are discovering why.
Through a research grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH), Senior Research Scientist Roh-Yu Shen, PhD, is studying how prenatal alcohol exposure alters the reward system in the brain and how this change continues through adulthood.
The key appears to lie with endocannibinoids, cannabis-like chemicals that are produced by the brain itself.
"By understanding the role endocannibinoids play in increasing the brain's susceptibility to addiction, we can start developing drug therapies or other interventions to combat that effect and, perhaps, other negative consequences of prenatal alcohol exposure," Shen says.
Prenatal alcohol exposure is the leading preventable cause of birth defects and neurodevelopmental abnormalities in the United States. Fetal Alcohol Spectrum Disorders (FASD) cause cognitive and behavioral problems. In addition to increased vulnerability of alcohol and other substance use disorders, FASD can lead to other mental health issues including Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety and problems with impulse control.
"After the prenatal brain is exposed to alcohol, the endocannibinoids have a different effect on certain dopamine neurons which are involved in addicted behaviors than when brain is not exposed to alcohol," Shen says. "The end result is that the dopamine neurons in the brain become more sensitive to a drug of abuse's effect. So, later in life, a person needs much less drug use to become addicted."
Specifically, in the ventral tegmental area (VTA) of the brain, endocannibinoids play a significant role in weakening the excitatory synapses onto dopamine neurons. The VTA is the part of the brain implicated in addiction, attention and reward processes. However, in a brain prenatally exposed to alcohol, the effect of the endocannabinoids is reduced due to a decreased function of endocannabinoid receptors. As a result, the excitatory synapses lose the ability to be weakened and continue to strengthen, which Shen believes is a critical brain mechanism for increased addiction risk.
https://www.sciencedaily.com/releases/2017/07/170707211125.htm
New approach to combatting anxiety states, pain and inflammation
June 6, 2017
Science Daily/University of Bern
Endogenous cannabinoids (endocannabinoids) play an important role in the brain and immune system. Bern researchers from the National Centre of Competence in Research (NCCR) "TransCure" have now found a new way to influence the endocannabinoid system. Anti-inflammatory, analgesic as well as anxiolytic effects could be achieved in an animal model.
Endocannabinoids are substances similar to fatty acids which are produced by the body. They activate specific cannabinoid receptors and among other things can exert anti-inflammatory or analgesic effects. Cannabis or tetrahydrocannabinol (THC) exhibit similar therapeutic effects in clinical use, but they are fraught with adverse effects. In contrast, endogenous cannabinoids are only produced in the cells when the body needs them, and therefore cannot be overdosed. The endocannabinoid system is considered promising as it uncovers new therapeutic options, for instance for disorders of the nervous system. For years, the research team led by Jürg Gertsch from the Institute of Biochemistry and Molecular Medicine at the University of Bern has been exploring the possibility to selectively activate endocannabinoids in the brain in order to treat neuropsychiatric disorders -- for example, anxiety states -- within the scope of the NCCR "TransCure" financed by the Swiss National Science Foundation (SNSF).
In cooperation with an international research team, the Bern research group led by Gertsch has now succeeded in blocking the transport route or endocannabinoids in the brain of mice for the first time by means of innovative inhibitors. This led to positive effects on the stress behaviour and immune system of mice. Anti-inflammatory, analgesic as well as anxiolytic effects have been observed. Although for several years it has been assumed that there is an endocannabinoid transport system in nerve cells and immune cells, this could now be shown for the first time. "I am convinced that in addition to the administration of exogenous cannabinoids, the endocannabinoid system will be specifically activated for therapeutic purposes in the future," says Gertsch. The study was published in the journal "Proceedings of the National Academy of Sciences (PNAS)."
Endocannabinoid Transport blocked
In cooperation with chemists from the Swiss Federal Institute of Technology/ETH Zurich (research group led by Prof. Karl-Heinz Altmann) and the industry, hundreds of endocannabinoid transport inhibitors were synthesised in order to develop ideal pharmacological properties. The researchers were inspired for these inhibitors by a natural substance from the purple coneflower (Echinacea purpurea), a medicinal plant which is frequently utilised for colds and partially has an effect on the endocannabinoid system. The newly developed inhibitors block the uptake of endocannabinoids through the membrane of cells. As a result, cannabinoid receptors on nerve and immune cells are activated, which leads to a "brake" in the brain and in the immune system upon stress and in inflammatory disorders, restoring the physiological equilibrium.
New perspectives for new medicines
Andrea Chicca, lead author of the study from the group led by Prof. Gertsch, is confident that the molecular mechanism of endocannabinoid transporter can be elucidated in the coming years: "Then nothing stands in the way for the development of new medicines." Thanks to the new findings from the study, already now substances can be made which differ from previous drugs as they specifically activate the endogenous cannabinoids in the brain. The researchers see great potential in the field of stress-related disorders, because endocannabinoids regulate important stress hormones and restore the equilibrium in the brain.
https://www.sciencedaily.com/releases/2017/06/170606090806.htm