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
New way to boost potency of natural pain relief chemical in body
November 21, 2011
Science Daily/University of California - Irvine
UC Irvine and Italian researchers have discovered a new means of enhancing the effects of anandamide -- a natural, marijuana-like chemical in the body that provides pain relief.
Led by Daniele Piomelli, UCI's Louise Turner Arnold Chair in the Neurosciences, the team identified an "escort" protein in brain cells that transports anandamide to sites within the cell where enzymes break it down. They found that blocking this protein -- called FLAT -- increases anandamide's potency.
Previous work by the researchers indicates that compounds boosting anandamide's natural abilities could form the basis of pain medications that don't produce sedation, addiction or other central nervous system side effects common with existing painkillers, such as opiates.
"These findings raise hope that the analgesic properties of marijuana can be harnessed for new, safe drugs," said Piomelli, a professor of pharmacology. "Specific drug compounds we are creating that amplify the actions of natural, marijuana-like chemicals are showing great promise."
For the study, which appears in the Nov. 20 online version of Nature Neuroscience, he and his colleagues used computational methods to understand how FLAT binds with anandamide and escorts it to cell sites to be degraded by fatty acid amide hydrolase (FAAH) enzymes.
Anandamide has been dubbed "the bliss molecule" for its similarities to the active ingredient in marijuana. A neurotransmitter that's part of the body's endocannabinoid system, it's been shown in studies by Piomelli and others to play analgesic, antianxiety and antidepressant roles. It's also important in regulating food consumption. Blocking FAAH activity enhances several effects of anandamide without generating the "high" seen with marijuana.
Piomelli and his collaborators speculate that inhibiting FLAT (FAAH-like anandamide transporters) might be particularly useful in controlling certain forms of pain -- that caused by damage to the central nervous system, for example -- and curbing addiction to such drugs as nicotine and cocaine.
Researchers from UCI, Italy's University of Parma and University of Bologna, and the Italian Institute of Technology participated in the study, which was supported by grants from the U.S. National Institute on Drug Abuse, the U.S. National Institute on Alcohol Abuse & Alcoholism, and the U.S. National Institute of General Medical Sciences.
https://www.sciencedaily.com/releases/2011/11/111121142501.htm
Compound boosts marijuana-like chemical in the body to relieve pain at injury site
September 21, 2010
Science Daily/University of California -- Irvine
American and Italian researchers have found that a novel drug allows anandamide -- a marijuana-like chemical in the body -- to effectively control pain at the site of an injury.
Led by Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at UC Irvine, the study suggests that such compounds could form the basis of pain medications that don't produce sedation, addiction or other central nervous system side effects common with existing painkillers, such as opiates.
"These findings raise hope that the analgesic properties of marijuana can be harnessed to curb pain," Piomelli said. "Marijuana itself is sometimes used in clinical settings for pain relief but causes many unwanted effects. However, specific drugs that amplify the actions of natural, marijuana-like chemicals are showing great promise."
For the study, which appears in the Sept. 19 online version of Nature Neuroscience, rats and mice were given a drug created by Piomelli and colleagues at the Italian universities of Urbino and Parma. The researchers discovered that the compound, URB937, did not enter the central nervous system but simply boosted the levels of anandamide in peripheral tissues. Still, it produced a profound analgesic effect for both acute and chronic pain. This was surprising, since anandamide had been thought to only work in the brain.
The synthetic drug inhibits FAAH, an enzyme in the body that breaks down anandamide, dubbed "the bliss molecule" for its similarities to the active ingredient in marijuana. A neurotransmitter that's part of the endocannabinoid system, anandamide has been shown in studies by Piomelli and others to play analgesic, antianxiety and antidepressant roles. It's also important in regulating food consumption. Blocking FAAH activity enhances the effects of anandamide without generating the "high" seen with marijuana.
Piomelli and his team are now collaborating with drug discovery specialists at the Italian Institute of Technology, in Genoa, to develop the new compound -- which is protected by a patent application -- into a clinically useful medication.
Researchers from UCI, the University of Georgia, the University of Naples, the University of Parma, the University of Urbino and the Italian Institute of Technology participated in the study, which was supported by the National Institute on Drug Abuse and the Italian Ministry of Public Education.
https://www.sciencedaily.com/releases/2010/09/100920131140.htm