Path toward non-addictive painkillers

Researchers reportedly enhance natural pain-relief chemicals without side effects

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BLOOMINGTON, Ind.—More than 97 million Americans took prescription painkillers in 2015. More than 2 million reported problems with the drugs. Drug overdoses are the leading cause of death for Americans under 50, outranking guns and car accidents and outpacing the HIV epidemic at its height. The upside is that researchers at Indiana University think they have a way to achieve pain relief without the addictive side effects behind the country’s current opioid addiction crisis.
A preclinical study led by Indiana University (IU) scientists reports in the journal Biological Psychiatry that compounds called positive allosteric modulators, or PAMs, enhance the effect of pain-relief chemicals naturally produced by the body in response to stress or injury. This study, “Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence,” supported in part by the National Institutes of Health, reinforces findings about the efficacy of these compounds first reported at the 2016 Society for Neuroscience Conference.
According to Dr. Andrea G. Hohmann, the Linda and Jack Gill Chair of Neuroscience and a professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences and study leader: “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. We see this research as an important step forward in the search for new, non-addictive methods to reduce pain.”
She added, “We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist.”
Medical researchers are increasingly studying positive allosteric modulators, because they target secondary drug receptor sites in the body. However, “orthosteric” drugs—including cannabinoids such as delta-9-tetrahydrocannabinol (THC) and opioids such as morphine—influence primary binding sites, meaning that their effects can “spill over” to other processes in the body, causing dangerous or unwanted side effects. Instead of an on/off switch, PAMs act like an amplifier of the effects of the brain’s own natural painkillers, selectively altering biological processes in the body that naturally suppress pain.
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. It 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. While the PAM compound enhanced the effects of the endocannabinoids, 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.
Pain relief was stronger and longer-lasting than drugs that block an enzyme that breaks down and metabolizes the brain’s own cannabis-like compounds. The PAM makes the natural painkillers target only the right part of the brain at the right time, instead of binding to every receptor site in the body. The PAMs showed strong advantages over the other alternative pain-relief compounds tested in the study: a synthetic cannabinoid and a metabolic inhibitor, which were likely to cause addiction or reduce effectiveness over time.
The research was conducted in mice, but endocannabinoids are released by the human body in response to inflammation or pain due to nerve injury. The compounds may be helpful in temporary pain relief after a major injury. Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence and abuse liability, the IU researchers concluded.
According to Hohmann, “These results are exciting because you don’t need a whole cocktail of other drugs to fully reverse the pathological pain in the animals. 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.”

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