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
Natural chemical helps brain adapt to stress
March 29, 2017
Science Daily/Vanderbilt University Medical Center
A natural signaling molecule that activates cannabinoid receptors in the brain plays a critical role in stress-resilience -- the ability to adapt to repeated and acute exposures to traumatic stress, according to researchers at Vanderbilt University Medical Center.
The findings in a mouse model could have broad implications for the potential treatment and prevention of mood and anxiety disorders, including major depression and post-traumatic stress disorder (PTSD), they reported in the journal Nature Communications.
"The study suggests that deficiencies in natural cannabinoids could result in a predisposition to developing PTSD and depression," said Sachin Patel, M.D., Ph.D., director of the Division of Addiction Psychiatry at Vanderbilt University School of Medicine and the paper's corresponding author.
"Boosting this signaling system could represent a new treatment approach for these stress-linked disorders," he said.
Patel, the James G. Blakemore Professor of Psychiatry, received a Presidential Early Career Award for Scientists and Engineers last year for his pioneering studies of the endocannabinoid family of signaling molecules that activate the CB1 and CB2 cannabinoid receptors in the brain.
Tetrahydrocannabinol (THC), the active compound in marijuana, binds the CB1 receptor, which may explain why relief of tension and anxiety is the most common reason cited by people who use marijuana chronically.
Patel and his colleagues previously have found CB1 receptors in the amygdala, a key emotional hub in the brain involved in regulating anxiety and the fight-or-flight response. They also showed in animal models that anxiety increases when the CB1 receptor is blocked by a drug or its gene is deleted.
More recently they reported anxiety-like and depressive behaviors in genetically modified mice that had an impaired ability to produce 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid. When the supply of 2-AG was increased by blocking an enzyme that normally breaks it down, the behaviors were reversed.
In the current study, the researchers tested the effects of increasing or depleting the supply of 2-AG in the amygdala in two populations of mice: one previously determined to be susceptible to the adverse consequences of acute stress, and the other which exhibited stress-resilience.
Augmenting the 2-AG supply increased the proportion of stress-resilient mice overall and promoted resilience in mice that were previously susceptible to stress, whereas depleting 2-AG rendered previously stress-resilient mice susceptible to developing anxiety-like behaviors after exposure to acute stress.
Taken together, these results suggest that 2-AG signaling through the CB1 receptor in the amygdala promotes resilience to the adverse effects of acute traumatic stress exposure, and support previous findings in animal models and humans suggesting that 2-AG deficiency could contribute to development of stress-related psychiatric disorders.
Marijuana use is highly cited by patients with PTSD as a way to control symptoms. Similarly, the Vanderbilt researchers found that THC promoted stress-resilience in previously susceptible mice.
However, marijuana use in psychiatric disorders has obvious drawbacks including possible addiction and cognitive side effects, among others. The Vanderbilt study suggests that increasing production of natural cannabinoids may be an alternative strategy to harness the therapeutic potential of this signaling system.
If further research finds that some people with stress-related mood and anxiety disorders have low levels of 2-AG, replenishing the supply of this endocannabinoid could represent a novel treatment approach and might enable some of them to stop using marijuana, the researchers concluded.
https://www.sciencedaily.com/releases/2017/03/170329140945.htm
Exercise can increase levels of hunger-promoting endocannabinoids even if you are sleep-deprived
September 26, 2016
Science Daily/Uppsala Universitet
A research group at Uppsala University has investigated how levels of endocannabinoids -- which target the same receptors as cannabis -- are affected by short sleep duration, and whether acute exercise can modulate this effect.
Chronic lack of sleep has been linked to an increased risk of overweight and obesity and previous studies have demonstrated that healthy participants who are sleep deprived eat more, make unfavorable food choices and crave more high-calorie foods. Now, a research group at Uppsala University has investigated how levels of endocannabinoids -- which target the same receptors as cannabis -- are affected by short sleep duration, and whether acute exercise can modulate this effect.
'Previous studies have shown alterations in the levels of some hunger hormones after sleep loss, but the results have been mixed and hormones that drive hedonic food intake have been less investigated. Furthermore, whereas exercise has many beneficial effects, whether exercise can modulate the effects of sleep loss on various hormonal pathways is currently unknown,' says lead author of the new study Jonathan Cedernaes, M.D., Ph.D, at Uppsala University.
In the new study, published in the journal Psychoneuroendocrinology, the researchers invited healthy normal-weight participants to a sleep laboratory on two separate occasions, to be studied after three consecutive nights of normal sleep, and after three nights of only sleeping four hours each night. Meals and activity patterns were kept standardized while participants were in the lab, and blood was drawn repeatedly to assess endocannabinoid levels in blood. This was also done on the last day both before and after a short bout of intensive exercise.
The researchers found that the levels of 2-arachidonoylglycerol -- the most abundant endocannabinoid in the brain -- was about 80 percent higher after the nights of short sleep compared with after the normal sleep session. When the participants exercised, the levels of 2AG still went up almost by half, regardless of whether participants had been allowed to sleep for three normal nights, or to only sleep four hours each night.
'As previously shown by us and others, sleep loss increased subjective hunger compared with the well-rested state. Given the role of endocannabinoids for promoting hunger and hedonic eating, this could offer an explanation as to why. Meanwhile, we instead saw lower stress ratings after exercise in the sleep deprivation condition, which could also possibly be attributed to the observed endocannabinoid levels following our exercise intervention,' says senior author associate professor Christian Benedict.
'It is noteworthy that when sleep-deprived, the participants saw the same amount of increase in endocannabinoid levels following the acute exercise. Endocannabinoids are thought to confer both the "runner's high" as well as at least some of the neuroprotective effects of exercise. Therefore, this may suggest that even under conditions of chronic sleep loss, exercise may exert similar centrally active, and possibly neuroprotective, properties as under conditions of sufficient sleep. This is an important area for future research as we and others have found that short sleep duration by itself may be harmful to the brain, and in the long run increase the risk of e.g. Alzheimer's disease', says Jonathan Cedernaes.
https://www.sciencedaily.com/releases/2016/09/160926105542.htm