Opioids are a mainstay of pain therapy. But their addictive and sometimes life-threatening side effects have fueled researchers’ search for better medicines. Now, several groups of researchers have worked together to identify a drug that eases pain in mice, without the side effects common to opioids.
Using computer simulations, lead authors Aashish Manglik, Henry Lin, Dipendra Aryal and colleagues tested how three million commercially available molecules interacted with the mu-opioid receptor, a protein critical for the pain relief provided by opioids. Ultimately, the researchers converged on one promising candidate, which after some tweaks to its molecular structure, they dubbed PZM21. When given to mice, PZM21 dulled pain as well as morphine. But unlike the classic opioid, it did not slow breathing (respiratory depression), nor did it seem to be rewarding, suggesting less potential for addiction.
Michael Bruchas, Washington University, St. Louis, US, who was not involved in the study, says the discovery is timely. “If there’s any example of a rationally designed drug that people have been waiting for, it’s something for the mu-opioid receptor that doesn’t have these other side effects.”
The study was published online August 17 in the journal Nature.
From millions to one
Mu-opioid receptors lie on the surface of neurons, where they bind to opioids made and released within the body, in addition to those taken to manage pain. When activated, these receptors trigger a number of chemical cascades inside the cells.
In 1999, Laura Bohn and colleagues reported that mice genetically engineered to lack a key player in one cascade, called beta-arrestin, were quite unlike their normal counterparts. In response to morphine, these mice showed more pain relief. And, as revealed in 2005, they were also less susceptible to respiratory depression and constipation, the latter being another typical side effect of opioids.
Those findings, along with others, planted the seed of an idea. By developing a drug that avoids beta-arrestin, researchers could perhaps tip the balance of effects toward pain relief and away from unwanted consequences. This became all the more feasible when, in 2012, researchers figured out the molecular structures of the different opioid receptors (there are four main subtypes), including the mu-opioid receptor.
“After the structures were solved, we realized that it would be possible to discover new and potentially useful drug-like molecules,” says Bryan Roth, one of the co-senior authors of the study and who helped uncover the structures of two of the major subtypes of opioid receptors.
In the new study, Roth and colleagues used the structure of the mu-opioid receptor to virtually screen millions of small molecules. For each, they modeled the myriad of ways they could interact with the receptor. Of those compounds that stood out, they decided to pursue PZM21, which activated one cascade, involving a protein known as a G protein, but not beta-arrestin, in isolated cells. Morphine, on the other hand, activated both.
Given these findings, “the potential was that, at least in theory, PZM21 would be effective for suppressing pain sensations but might not have the side effects associated with morphine,” says Roth.
Fewer side effects
As predicted, PZM21 injected under the skin in mice reduced pain-related behaviors, compared to injections of saline used as control experiments, likely by acting on neural circuits within the brain. And, its effect plateaued earlier and lasted longer than that of morphine. Yet, PZM21 seemed safer. It did not slow breathing, and produced less constipation. Moreover, mice did not prefer to spend their time in an area where they received PZM21. That suggests it may not be rewarding, and thus, not addictive.
Bruchas, however, says that to better assess the addiction potential of PZM21, researchers should test if animals will take the drug themselves, rather than have the experimenters give it to them. “In a self-administration study, where the animals have control of how much they take, what does their behavior look like?”
PZM21 is but one of several drugs that could fulfill the role of a safer opioid. The pharmaceutical company Trevena has developed one, called TRV130, that’s now in phase 3 clinical trials. Its effects resemble those of PZM21. And, at the end of August, an independent group of researchers published findings on another drug, tested in monkeys, that also provided pain relief without a handful of opioid side effects.
As for PZM21, there’s a long road ahead before it can be considered effective and safe for people. For example, there’s still the question of tolerance: whether PZM21 will suppress pain as strongly after a first dose, which Roth intends to answer in future studies.
“The prediction would be that animals show less tolerance to PZM21, because beta-arrestin is one of the main factors involved in tolerance, but we need to do the experiments.” –Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.