Centipede venom may hold key to future of analgesics

After years of research and billions of dollars in funding scientists have found what could potentially be the biggest step forward in management of pain since the discovery of the numbing properties of opium as far back as the Neolithic age. Did they finally synthesize a new chemical? Or generate an antibody therapy? No, the potential key to treatment of pain was with the humble centipede all along.

A painful disorder 

For a long while scientists thought they had pain pretty much nailed down. It’s a protective mechanism by which the body is notified of potential damage to tissues and said tissue can be removed quick-sharpish accordingly. A classic example of this was described as early as 1664 French philosopher and all round thinker Rene Descartes in this diagram. Neat huh? Well unfortunately as always it’s a tad more complicated, more recent research has shown that in some cases we still feel quite severe pain well after any potential danger has been averted. This rather pesky sensation is known as ‘chronic pain’ and recent figures show it affects as many as a third of the population at a US annual economic cost of ~$600 billion (Melnikova 2010), that’s more than cancer, heart disease and diabetes combined! I bet you’re listening now.

 

Treating pain

So hold on here, how can this disorder be so common? We’ve got loads of different painkillers for almost every type of pain you can think of. Paracetamol, ibruprofen, aspirin, codine, the list goes on. Well in actual fact we’re not doing so good at treating this thing after all, at present there are numerous different types of painkiller on the market and no matter how many of them we use and in what combination 3 out of 4 patients still receive inadequate drug therapy for their condition (Melnikova 2010). The shortfalls don’t stop there either, current medications are notorious for severe side effects from gastrointestinal bleeding to respiratory depression. So the reason scientists are getting excited about this one is that these centipedes might hold a new analgesic (‘painkiller’ to you and me) that could treat chronic pain without any of the nasty side effects above. But what’s special about this one? How can they be so sure they’ve                                                                                   got something exciting here? Well it all starts with a young boy in                                                                                 Northern Pakistan…

The genetic marvel 

The 10-year old street performer unsurprisingly caught the attention of a number of the leaders in the field of nociception (the transmission of pain in the body) when he was observed walking on hot coals and placing knives through his arms with complete indifference to pain (Cox et al. 2006).

Sadly this enthralling life was bought to an end rather abruptly when the boy, on his 14th birthday, jumped from the roof of a house with fatal consequences.

His life however was not in vain, the scientists began thorough research into how someone could have perfect command of touch and feel but have no knowledge of the sensation of pain. They looked into a number of ‘closely intra-related’ families where similar cases had been reported and found all 6 individuals they studied had no idea what pain felt like. They even noted that the older individuals knew what a person in pain looked like, this included rolling around on the floor after a particularly vicious football tackle!

So why should we care? Well considering the close familial link between the individuals studied, the researchers had a look at the genes of those affected and came across a quite startling discovery. They all had a mutation in a gene (SCN9A) coding for a specific ion channel, Nav1.7. This is a specific subtype of a voltage gated ion channel that, upon opening by a specific change in the electrical potential across the membrane in which it sits, allows passage of positively charged sodium ions (Na+). What this means in terms of pain is that without the influx of positive ions something called an ‘action potential’ cannot occur and the pain neurons can’t be activated thus they don’t send the signal up to our brains.

This research made BIG waves in the scientific community, if you haven’t made the link already what the scientists had found was a specific ion channel that functions only to transmit pain and leaves all other senses and normal bodily functions intact. If we can find a drug to specifically block this ion channel we may well have the greatest ever painkiller and a perfect treatment to the chronic pain I mentioned earlier.

 

The perfect painkiller?

Sounds great right? Well there’s a few reasons this wonder drug isn’t on the market just yet and that’s because it turned out it’s not so easy to specifically block Nav1.7 without also blocking other closely related receptors. Pharmaceutical companies had extreme difficulty achieving selectivity over channels such as Nav1.4, Nav1.5 and Nav1.6 which are heavily involved in cardiac and skeletal muscle contraction, I bet you can see where the issue there is! Even when it looked like they had something selective they were scuppered by an effect where the drug was cleared from the body before it could have any real effects (Theile & Cummins 2011).

A multi-legged saviour? 

After synthesizing and testing countless compounds it wasn’t looking great; researchers in the field needed a new angle for tackling this tricky ion channel. However in a paper published in Proceedings of the National Academy of Sciences (PNAS) last week a group of scientists reckon they may well have found the answer in the venom of the Scolopendra subspinipes mutilans (or Chinese red-headed centipede) (Yang et al. 2013).

They isolated a specific peptide in the venom of these creatures (denoted μ-SLPTX- Ssm6a) and found not only that it blocked Nav1.7 function but that it also had only a weak effect on Nav1.1, Nav1.2 and Nav1.6 and no effect at all on Nav1.3, Nav1.4, Nav1.5 and Nav1.8. What’s more is that they also found Ssm6a was able to inhibit pain behaviour in mice (upon injection of formalin, an agent that will cause mild pain, the mice lick their paws). Another exciting point is that they also tested morphine (known for a centuries as one of, if not the best analgesic around) on this model and found that it wasn’t as good. Their newly discovered compound was better than morphine!

But there’s always a but. Although the selectivity profile is far improved on the drugs we had before Ssm6a still blocks Nav1.6, something that is going to need to be addressed if we’re going to see a drug based on it in the market anytime soon. Also we have no idea how this peptide will fare in the human body, will we see a similar effect with the clearance rate as was found with previous compounds. Another point to note is that animal models for pain aren’t all that reliable (Mogil 2009) so I’m not too sure the opioids will be knocked off their perch unless a fair bit more research is done.

Reflection

Despite the setbacks this is nonetheless a really important piece of research and yet another reminder that no matter how advanced we get as a species we can still be beaten by the hundreds of millions of years of evolution centipedes have behind them. Check out Evolution vs Man for more on how we can be thankful to Mother Nature or for more on how we have used the tools of nature for drug discovery have a read of A (very) brief history of therapeutics.

If Ssm6a does hold the key to the perfect analgesic it will be a real eye-opener as to how much we think we know and how much we do know about our own bodies. Especially seeing as the two best painkillers we’ll have will have come from a poppy and a centipede.

 

References

COX, J.J. et al. 2006. An SCN9A channelopathy causes congenital inability to experience pain. Nature [online]. 444(7121),pp.894–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17167479 [Accessed September 30, 2013].

MELNIKOVA, I. 2010. Pain market. Nature reviews. Drug discovery [online]. 9(8),pp.589–90. Available from: http://dx.doi.org/10.1038/nrd3226 [Accessed October 15, 2013].

MOGIL, J.S. 2009. Animal models of pain: progress and challenges. Nature reviews. Neuroscience [online]. 10(4),pp.283–94. Available from: http://dx.doi.org/10.1038/nrn2606 [Accessed September 21, 2013].

THEILE, J.W. and T.R. CUMMINS 2011. Recent developments regarding voltage-gated sodium channel blockers for the treatment of inherited and acquired neuropathic pain syndromes. Frontiers in pharmacology [online]. 2,p.54. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3185237&tool=pmcentrez&rendertype=abstract [Accessed September 20, 2013].

YANG, S. et al. 2013. Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models. Proceedings of the National Academy of Sciences [online],pp.2–7. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1306285110 [Accessed October 1, 2013].

 

Written by Mike Daniels

Mike Daniels

I’m currently studying for a PhD in neuroinflammation at the the University of Manchester, UK. My work is based mainly on the role of a huge protein complex called the inflammasome in diseases such as Alzheimer’s, stroke and haemorrhagic fever.
When I’m not in the lab I’m usually found up a mountain or out in the countryside somewhere and am always on the lookout for any new science outreach ideas!

4 thoughts on “Centipede venom may hold key to future of analgesics

    • That is a good point, I think they found this peptide isn’t similar to any currently known one but I don’t think they have done much in terms of structure/binding. We should be looking into this Laura! Need your HDX skills!

  1. Very interresting,

    Recently been reading about similar stuff, from spider venom and that grashopper mouse.
    Seems to all work somewhat the same, targeting these channels, maybe they can combine all these methods and work it out :)

    Anyway, whats never mentioned in these articles, no matter how long/short they are, are the future theoretical usages. If we get a perfect painkiller this way, that takes almost all pain away, and no side effects, is it likely it can be used during and after surgery? Much more awake operations and noone will feel pain or puke or get constipated. Is that a possible scenario from what we know today, seeing how these will work (if they work all issues out)?

    Many thanks for some feedback on this, if anyone has a hint,
    /Seb

    • Hi Seb,

      You make a really good point! The majority of these studies are based around chronic pain such as neuropathic pain, I had never really considered substitution of anaesthetics with these drugs. Post-operative pain is also a really big issue and one which could certainly benefit from these kinds of drugs.
      The overall point you make is a classic issue with this kind of research, the boundary between truly pathological pain and (the non-useful kind) and physiological pain we need. For instance there have been candidate painkillers which have failed clinical trials for osteoarthritic knee pain because they led to a worsening of the condition due to overuse of the joint. In other words the drug worked fine but the pain the patients felt was there for a reason, to protect a damaged joint.

      This is a real issue and one that a selfish person like me often overlooks as I’m so focussed on the cool research, it’s important to focus on the true end gains. As for the grasshopper mouse and spider venom that looks really interesting! I have been off the ball recently and need to read up.

      Thanks for your comment and I hope was of some use!

      Mike

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