Hitting pain where it hurts

Up to one in five people suffers from some form of chronic pain, and these sorts of conditions are notoriously hard to treat. Now scientists in London have made a breakthrough: they’ve used a component of the nerve-deactivating chemical “botox” - this is called botulinum toxin - and linked it like two Lego bricks to a molecule of something that looks like the pain killer morphine. Injected into the spinal cord of mice, the construct docks with the pain nerve signals that are normally sensitive to opioid painkillers, which then take the botulinum toxin inside, where it selectively shuts down the transmission of just pain signals in that part of the spine for up to 3 months. Chris Smith spoke to UCL’s Maria Maiaru discovered how to do it.

Maria - Pain is a huge global health problem and seriously affects quality of life. Opioid drugs at the moment are considered to be the gold standard for pain relief, but there is little evidence that long term use is effective in the treatment of chronic pain. Moreover, the body blocks tolerance to repeated drug treatment which necessitates a higher dose to achieve pain relief. The body will also develop dependence and addiction. For all these reasons we need more safe and effective drugs to treat chronic pain.

Chris - How have you tried to go about doing this then, because people have been trying to invent better painkillers ever since Bayer invented aspirin a hundred years ago.

Maria - We started from work that was published about 20 years ago. In the spinal cord we have the specific neuronal population that send these painful messages, if you want, to the brain. So these people selectively killed this neuron in the spinal cord and provided pain relief.

The same approach didn’t translate into the clinic for human use because doctors are reluctant to use drugs that will kill your cells and your neurons. So to overcome this issue, we used the neurotoxin properties of the botulinum toxin to specifically silence, but not kill, neurons in the spinal cord.

Chris - So you can temporarily sort of knock out the nerve cells in the same way as a person who doesn’t want wrinkles can inject a bit of botox which temporarily paralyses the conversation between the nerve and the muscles and the wrinkle irons out. You’re saying go into the spinal cord and use botox in the same way to temporarily interrupt the chemical conversation between the pain nerves, so that the person still has their nerve intact but they can’t feel anything?

Maria - Exactly. We did this by using a lego system to link the botulinum toxin to a specific molecule; in this case it’s an opioid called morphine to target neurons in the spinal cord that express a specific receptor used by morphine. So the compound can go inside the neurons and then silence the neuron without killing them.

Chris - Right. So what we have here is you’re linking something that looks a bit like morphine with the component of the botulinum toxin so that it will bind onto the cells that would normally hear the morphine signal and this will carry the toxin to just the cells that need to be deactivated?

Maria - Exactly. What the botulinum does is it just stops for a period the release of the neurotransmitter, so the pain signalling that the neuron in the spinal cord is receiving is not travelling up to the brain. So you don’t feel the pain anymore, because the neuron that was responsible for the transmission of this information is now silent.

Chris - How do you get the construct of the morphine-like chemical with the toxin-like chemical into the nerves that need it in the first place?

Maria - We inject a tiny amount of the compound intrathecally into the spinal cord of our animal models.

Chris - What sorts of pain states or pain syndromes have you investigated to see how good this is?

Maria - We used two different preclinical models of chronic pain: a model of inflammatory pain, and the model of neuropathic pain. And we found that a single injection of our compound reduces the pain hypersensitivity for up to one month, and to the same extent as morphine.

Chris - So in other words a person who, assuming you translate this successfully to human patients, a person who had one of your injections wouldn’t need another one for a month?

Maria - Exactly. By waiting we did some experiments in-vitro, so on cell culture and, in fact they last for at least 100 days, so up to three months.

Chris - But do you not end up with a patch of the body which, albeit temporarily, does not have any ability to feel pain? So, is there a possibility you could use this on somebody, they get a numb patch of skin that they could then injure quite severely because they’re not aware that they’re burning that bit of their skin, for example?

Maria - I’m glad you asked because the pain relief that we achieve is not completely. These mice are still able to discriminate what is an acute stimulation. We do not achieve a 100 percent of pain relief.