Opioids, like sledgehammers, are powerful but blunt tools. When they are used to flatten pain, opioids may give other things a pounding, too. The problem is conventional opioids act on inflamed or damaged tissues as well as healthy tissues. Consequently, while opioids may relieve pain, they may also cause serious side effects, such as drowsiness, nausea, constipation, and dependency—and in some cases, respiratory arrest.
In hopes of finding a way to craft finer painkilling tools, scientists based at Charité-Universitätsmedizin Berlin scrutinized different ways opioids can interact with opioid receptors. These scientists, led by Prof. Dr. Christoph Stein, were on the lookout for “disease-specific” opioid receptor-ligand conformations. That is, the scientists plan was to exploit pathological (rather than physiological) conformation dynamics in the design of new opioids, and thereby create drugs that would target damaged or inflamed tissues yet bypass healthy tissues.
“By analyzing drug–opioid receptor interactions in damaged tissues, as opposed to healthy tissues, we were hoping to provide useful information for the design of new painkillers without harmful side effects,” said Prof. Dr. Stein.
Prof. Dr. Stein’s team was aware that previous strategies in drug development had focused on central opioid receptors in noninjured environments, even though many painful syndromes (such as arthritis, neuropathy, and surgery) are driven by peripheral sensory neurons and are typically accompanied by inflammation with tissue acidosis. Ultimately, the team decided that this alternative mechanism of action—the binding and activation of peripheral opioid receptors—could be preferentially exploited by a new class of opioids. The key was the occurrence of acid conditions.
By following through on this idea, the scientists designed a new opioid that, unlike clinically used opioids, best activates the receptors in acidified tissues. When the new opioid was evaluated in a rat model of inflammatory pain, it exerted strong pain relief essentially without the side effects of standard opioids.
Details appeared March 3 in the journal Science, in an article entitled, “A Nontoxic Pain Killer Designed by Modeling of Pathological Receptor Conformations.” The article describes how the scientists used computer modeling to analyze morphine-like molecules and their interactions with opioid receptors. In particular, computer modeling was used to simulate an increased concentration of protons, thereby mimicking the acidic conditions found in inflamed tissues.
“By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation,” wrote the article’s authors. “Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide–binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3′,5′-monophosphate inhibition in vitro.”
The authors observed that their novel opioid produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential. These results, the authors suggested, mean that treating postoperative and chronic inflammatory pain should now be possible without causing side effects. Doing so would substantially improve patient quality of life.
“In contrast to conventional opioids, our NFEPP-prototype appears to only bind to, and activate, opioid receptors in an acidic environment,” explained the study's first authors, Dr. Viola Spahn and Dr. Giovanna Del Vecchio. “This means it produces pain relief only in injured tissues, and without causing respiratory depression, drowsiness, the risk of dependency, or constipation.”
“We were able to show that the protonation of drugs is a key requirement for the activation of opioid receptors,” the authors concluded. Their findings, which may also apply to other types of pain, may even find application in other areas of receptor research. Thereby, the benefits of improved drug efficacy and tolerability are not limited to painkillers, but may include other drugs as well.