Scientists have developed new opioid pain relievers that reduce pain on a par with morphine and do not slow or stop breathing caused by overdose. According to the US Centers for Disease Control and Prevention, 91 Americans die every day from opioid overdoses — deaths caused when opiates like oxycontin, heroin and fentanyl slow and then eventually stop a person’s breathing. The research shows that a range of compounds can deliver pain-blocking potency without affecting respiration, said Laura M Bohn, Professor at The Scripps Research Institute (TSRI) in the US. The study builds on two decades of research which questioned whether the painkilling pathway, called the G protein pathway, could be unlinked from the breathing suppression pathway, called the beta-arrestin pathway. “One of the questions we had was how good we can get at separating out the pathways, and how much separation do we need to see analgesia without respiratory suppression,” said Bohn, who led the study published in the journal Cell. Researchers developed new potential drug molecules; they then tweaked their chemical structures to systematically vary the “bias” between the two pathways — G protein signalling and beta-arrestin recruitment.
They developed more than 500 compounds in the past six years, and found more than 60 that showed bias between signalling assays.The researchers then selected six compounds to represent a wide range in the degree of bias (from those that preferred barrestin recruitment to those that almost exclusively preferred G protein signalling) and determined their overall potency for inducing analgesia and respiratory suppression in mouse models. They found that the new compounds could indeed enter the brain — and all of the compounds were as potent, if not more, than morphine. The compounds that were less able to promote barrestin associations in cells were also less likely to induce respiratory suppression in mice. In contrast, the painkiller fentanyl was shown to prefer receptor-barrestin associations.