Morphing morphine

How to power-up the body's own painkillers...
19 February 2019

Interview with 

Peter McNaughton, King's College London


A person in pain


Millions of people are affected by chronic pain; despite this, we're not good at treating it. But a discovery by scientists in France that's enabled them to power-up the pain-killing effect of the body's natural morphine-like chemicals, and target the effect to where in the body it's needed, means we might be about to become much better at - as the old saying goes - hitting pain where it hurts. Peter McNaughton is a pain specialist at King’s College London. He wasn't involved in the new study but he agreed to take a look at the paper for us and he explained to Chris Smith how it works...

Peter - What this group have set out to do is to find out an alternative to the opiate class of drugs: morphine heroin etc. Now these drugs are fantastic painkillers. They work really well, but they have a number of huge downsides. They cause addiction; they cause respiratory depression, which can cause people to die in their sleep. And these adverse side effects are all caused by penetration of morphine etc. into the central nervous system.

Chris - And what you're saying is it's because they get into the the brain and spinal cord - the central nervous system - that we get that downside? If we could stop that that wouldn't happen?

Peter- Exactly. And that's what they've tried to do. They've invented a - it's not really a new drug - it's a new twist on an old theme. What they've invented is a drug which doesn't enter the central nervous system, and therefore, shouldn't have all these nasty effects we talked about a moment ago.

Chris - How does it actually do that?

Peter - Well, they've done it by using what's really an old idea which came from Hans Costalitz who was working up in Aberdeen. Costalitz found that there is an endogenous opiate produced within the body. And he really discovered this just with a very simple piece of reasoning, which is that drugs of the opiate class - heroin morphine etc - are so potent that they must be latching onto a system which exists within the body already, and he isolated some peptides which are called the encephalins.

Chris - So these are compounds which are naturally present in the body and they activate the nerve pathways that morphine - when we inject that - does, and that's how they achieve their pain killing effect? The difference being that you can make those compounds yourself?

Peter - Exactly. These are the "endogenous opioids" as they're called. They have a powerful analgesic effect. You can see why this is important from an evolutionary point of view. If you're in a highly stressful situation, you're being chased by a bear or something like that, there's no point in saying "oh, ow I'll stop - the bear's biting my ankle!" - You've got to get away, otherwise you're going to die. And therefore, in stressful situations, the release of these endogenous opiates give a tremendous analgesic effect, which means effectively that you can escape by a life threatening situation.

Chris - And the group are exploiting, what, those compounds and the way in which they work in order to produce this new way of doing pain relief? 

Peter - Exactly. The encephalins are peptides, and these are compounds that are metabolised very rapidly in the body so they produce an analgesia which is very short-lasting. So from that point of view there's not much point in the injecting encephalins into people's bloodstreams; the analgesic effect will be gone in a couple of minutes. What this group have done is they've linked up encephalin with a lipid - a natural body lipid - called squalene. They found that that makes the lifetime of the encephalin very much longer. And the other advantage of squalene is many squalene groups sort of make a lipid "droplet", which is like a hedgehog: it's got the encephalins sticking out, and this produces a very long-lived form of encephalin, even longer lived than morphine.

Chris - So if you inject it, it will circulate for a long time; it can bind onto all the right nerve endings and block the transmission of pain, but it doesn't seem to get into the brain and spinal cord and cause the adverse effects of morphine?

Peter - Exactly. And in fact, one of the things they've shown, which is even more interesting, is this circulating lipid droplet, with the encephalin peptides attached, seems to be targeted specifically to areas of pain. Now it's been known that when you have local inflammation that causes pain, that makes the blood vessels more leaky, and it's at those specific spots where the blood vessels are leaky that the compound is able to leak out and have its analgesic effect.

Chris - How have they tested it to prove that it is actually as good as that?

Peter - They've attached a fluorescent compound to their encephalin-squalene drug. And they've done whole-body imaging of animals, and the drug accumulates in areas where there's a localised inflammation that's causing pain and it doesn't accumulate in other places.

Chris - And can they also prove though that, in those animals, they're not feeling pain because they've injected this?

Peter - Well, not in exactly the same animals, because the animals that are being imaged are unconscious, but parallel groups of animals they've been able to find that pain is very very much reduced by the injection of this encephalin-squalene complex.

Chris - Will it work in a human?

Peter - Well it should do. Of course, we don't know that. These are animal experiments, but I can't see any reason why it wouldn't work in a human. I just have to point out a downside of this method of getting the drug onboard to the patient that it has to be injected intravenously. And if you're treating a soldier in a battlefield situation that's something that's going to be rather difficult to do...


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