Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

Opioids are some of the most effective and most problematic drugs in the entire pharmacopeia. For severe, intractable pain we really have nothing to match them, despite decades of searching for alternatives. The history of research for new pain medications itself calls for pain medication, because it is a tapestry of expensive late-stage clinical failures. All sorts of receptors, enzymes, ion channels and other targets have been proposed as pain targets (on the basis of perfectly reasonable biological hypotheses) and many of these appear to work in when targeted in animal models. But when you go into human trials, they collapse. It’s been apparent for decades that there are severe problems in the translational medicine of new analgesics, but we still haven’t been able to fix the problem, and such programs continue to evaporate in the clinic.

Perhaps drugs targeting the opioid receptors can be fixed? Decoupling pain relief from addiction will be extremely difficult (likely impossible?) as long as you’re hitting the opioid receptors themselves, thus the long search for other pain targets. But for some years now it’s been thought that opioid drugs themselves could possibly be made less dangerous. There are all sorts of side effects to hitting one of the main subtypes, the mu receptor, with the neuromuscular problems high on the list. It’s that respiratory depression that generally kills people in the case of an overdose, and pain patients also experience severe constipation due to the effects on intestinal smooth muscle.

And that takes us into the wilds of G-protein coupled receptor (GPCR) signaling. For at least ten years now, it’s been a popular hypothesis that the mu-opioid receptor might be splitting its effects via two different signaling pathways – the “standard” G-protein second-messenger one and the beta-arrestin pathway. That’s thought to be involved in receptor desensitization, among many other things, and there are a number of examples of differential signaling (and differentiation of side effects) depending on arrestin binding. There’s some evidence that you might be able to get analgesia without development of opioid tolerance and without smooth muscle effects if you could find ligands that activated the G-protein pathway and not the beta-arrestin one, and naturally enough there’s been a lot of work devoted to that idea. Compounds trying to put this idea to the test have recently made it far into clinical trials, but results have not been encouraging.

Comes now the cold water. A new paper demonstrates that in mice that have had their key beta-arrestin-2 protein completely knocked out that morphine and other opioid ligands still produce respiratory depression (and constipation, for that matter). This ties in with another recent paper (from some of the same authors) that looked at a series of mutant proteins that biased the mu-opioid receptor towards G-protein signaling and away from arrestin pathways, and that one showed that the heightened sensitivity to analgesia part might well be real, but that respiratory depression was still showing up and might even be worse.

So why hasn’t this experiment been run before? Well, that’s the thing: it has. In fact, the 2005 paper that really called attention to the possible therapeutic split in mu-opioid signaling was a demonstration in beta-arrestin-2 knockout mice (!) This latest paper, in fact, is a consortium across research teams in Germany, the UK, and Australia to re-examine this whole hypothesis due to all the conflicting results. They used the same knockout rodent line as in the 2005 work, but their results flatly contradict the earlier study, and they have no explanation for why this should be (although there’s a possibility that the earlier paper’s knockout animal strains were not sufficiently characterized). The paper also mentions a recent conference presentation from yet another group that has failed to reproduce the results as well. So I would put my money down on the idea that there’s something off with the 2005 work, and with the whole idea of being able to manipulate opioid effects via G-protein versus arrestin signaling.

Back, once again, to the damned drawing board. And back, once again, to the realization that we don’t understand receptor signaling anywhere as much as we need to, or as we sometimes might think we do. . .