Hypersensitivity: when touch is too much

01 May 2018

Interview with 

Dr Paul Heppenstall, European Molecular Biology Laboratory, Rome

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Physical touch is important for our development. But what feels like a gentle touch for some people can be very painful for others. Allodynia or hypersensitivity is debilitating - even individual hairs brushing against the skin can be enough to cause considerable pain. So what can be done about it? Well news is out of a potential light treatment that has shown promise in alleviating this hypersensitivity in mice. Georgia spoke to Paul Heppenstall from the European Molecular Biology Laboratory in Rome. Paul started off by explaining that hypersensitivity can come about as a symptom of what’s called neuropathic pain...

Paul - Neuropathic pain is a pain caused by injury to the nervous system that can come from a trauma, from an accident or from a metabolic disease such as diabetes or from chemotherapy, for example. This actually affects a large number of people; about 7-8% of people have some form of neuropathic pain. It has lots of different symptoms: an ongoing constant pain, hypersensitivity to touch, and also hypersensitivity to cold. These pains are chronic and they go on for a long time, often for a lifetime.

Georgia - Do we know why people are sensitive to touch? What were the theories?

Paul - There are two possibilities: one the pain sensing neurons become more sensitive so that they can then detect light touch; the other possibility is the gentle touch sensing neurons somehow change their connectivity in the brain or in the spinal cord and then these provoke pain instead of pleasure. This argument’s been going on for quite a while and this is what we tried to tackle.

Georgia - Is there anything we can currently do about this?

Paul - At the moment it’s very difficult to treat so most of the traditional ways of treating pain, for example opioids and morphine don’t really work with this type of pain. Antiepileptics are sometimes used for this; in these cases they are also not particularly effective. About one in three people report some improvement in their pain when they take one of these drugs and, of course, these have got quite horrible side effects as well.

Georgia - Right. So what have you been doing to investigate this?

Paul - We started off by identifying a type of neuron that is responsible for detecting the gentlest of touches. We’ve then gone on to show that this same type of neuron is responsible for this mechanical hypersensitivity in neuropathic pain. Further, we’ve devised a method where we can shut off this neuron in neuropathic pain, switch it off and stop the mechanical hypersensitivity in this condition.

Georgia - Right. How did you go about doing that then?

Paul - By trying to find molecular markers for these different populations of neurons in the skin. Then from these we made transgenic mice, which allowed us to manipulate these neurons, either by switching them on or by switching them off. Once we can do this, we can look at the behaviour of the mouse and see what happens to the behaviour when we turn on or turn off these neurons.

Georgia - Now we know which neurons are responsible for this is there anything we can do about it?

Paul - Yes. The next step is to be able to turn these neurons off by using pharmacological means rather than having to use transgenic animals to do this. This is what we’ve tried to do, we’ve developed methods whereby we can inject a chemical into the skin, shine light onto this chemical and then switch off these neurons and switch off the mechanical hypersensitivity.

Georgia - That sounds fantastic. But how does that actually work?

Paul - We found a naturally occurring molecule which binds only to these neurons when you put it into the skin. We’ve then taken this molecule - it’s a protein, and we’ve engineered it, and attached onto it a so-called photosensitizer. If you shine light onto a photosensitizer, it then releases free radicals and zaps everything within about ten nanometres of it. So we can load this onto the back of our protein, put it into the skin; it attaches to the neurons. We can then shine light onto the skin and it will clip off the ends of these neurons in the skin, cause them to retract and so that they no longer sense the forces which are acting upon the skin.

Georgia - Could you see a reduction of pain in the animal when you did this?

Paul - We saw a very strong reduction: the animals basically returned to normal and this lasted for about three weeks after a single treatment.

Georgia - Right. So by depriving a mouse of this kind of touch sensation, you’re equally removing this chronic and terrible pain that comes with it?

Paul - Exactly, yeah. I think that that is the trade off. The beauty of it is though is that you can target this to a very small area by shining the light only on the area where you have the pain. So you would still have your normal touch sensitivity elsewhere throughout the body but you would lose that pain in the area which is painful.

Georgia - Okay. So what has your work revealed to us about this then?

Paul - Firstly, it’s identified the neurons which were responsible for that. We’ve now got a handle on these neurons and we can try and find out how it is that they work. Secondly, this method of removing their endings by shining light onto them might be generalised for many other different types of sensory disorder, such as for controlling itch or for controlling other different types of pain.

Georgia - How feasible to you think this will be logistics wise, and price wise, and just scientifically to scale up to human use?

Paul - It’s very early stage. For us, the encouraging this is that it works and we’ve never seen anything work quite so well. We’ve now got to do a lot of safety tests on this approach. We need to know whether it causes inflammation in itself. Maybe it also causes pain in itself for a while. We need to be able to scale up and produce the chemical. It’s a protein that we’re producing and, of course, this is a challenge to make at reasonable levels. But with these results in mind, we think that it is worth it and that’s the way we’re progressing.

Georgia - Would you say then the debate has been put to bed by this research?

Paul - We’ve shown that if we remove the neurons, then mice don’t get neuropathic pain but also, if we activate the neurons, then they do get neuropathic pain. So I think these both is gain of function as we say, and loss of function experiments, so I think they really confirm that.

Comments

Many suffer severe neuropathic skin pain as an after effect of shingles. The prospect of selective ablation of the neural pathways causing this debilitating pain provides a measure of hope although it's clear that this research is in its very early stages.

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