Chronic pain is very difficult to treat. A recent experiment in mice showed that a synthetic botulinum toxin can silence the neurons that transmit pain signals to the brain, suggesting that it could be used as a chronic pain treatment.
Chronic pain can significantly decrease one’s quality of life. It is especially common among the elderly. For example, as many as 60% of British adults over the age of 75 suffer from this condition. Opioids, such as codeine or morphine, can effectively relieve this pain. However, they can cause serious side effects, including constipation, drowsiness and – with long-term use – addiction. There may be some non-drug methods of chronic pain treatment, such as tai chi, that help decrease chronic pain, but there is still a need for new, more effective, pain-killing drugs.
Botulinum toxin (sometimes referred to as the brand name Botox) prevents neurons from working properly. Neurons are an important type of cell that conveys signals back and forth between the brain, the spinal cord, and other parts of the body. Blocking neuron function can result in paralysis and death, but the careful use of low doses of botulinum toxin has several cosmetic and medical applications. One medical advantage of botulinum toxin is that remains active for a long period of time. This means that frequent injections are not necessary.
Recent studies have hinted that botulinum toxin could be used to specifically prevent neurons from transmitting pain signals, without harming the neuron’s other roles. For example, injecting botulinum toxin can reduce nerve pain and decrease the frequency of migraines. A group of British and Canadian researchers has recently tested the ability of new, synthetic, forms of botulinum toxin to decrease pain in mice. They published their results in the journal Science Translational Medicine.
Creating a synthetic botulinum toxin that targets pain-signalling neurons
The researchers wanted their botulinum toxin compound to only be absorbed by the neurons that are involved in sending pain signals to the brain. To do this, they made a synthetic compound that consisted of the active part of botulinum toxin bound to special protein fragments that are only recognized by the neurons involved in pain signalling. These include the neurons that are normally affected by opiates. This means that only these neurons should be affected by the synthetic compound.
Preventing pain in mice
The researchers used two different models of chronic, low-intensity, pain in mice. To produce inflammatory pain, they injected a pro-inflammatory compound into the ankle or hind paw of the mice. To produce neuropathic pain (i.e., nerve pain), they surgically damaged some peripheral nerves in the mice. A few days afterward, they injected the synthetic botulinum toxin compound directly into the spinal cord.
Over the next several days, they measured pain sensitivity by poking the affected paw with a thin nylon wire and seeing how long it took for the mouse to react. As expected, mice with inflammatory pain or nerve pain were much more sensitive. However, the synthetic botulinum toxin decreased pain sensitivity within a few days after it was injected. This effect remained for the rest of the experiment, which was up to three weeks. It was effective for both inflammatory pain and nerve pain.
The synthetic botulinum toxin had no effect on walking or running speed or balance. It also had no effect on pain sensitivity in normal mice that were not experiencing chronic pain.
Just as effective as morphine, but longer lasting
The researchers also compared the pain-relieving action of the synthetic toxin to morphine, an opiate drug. Morphine injections were just as effective as the synthetic toxin at decreasing the pain sensitivity of mice. However, morphine wore off within an hour, whereas the synthetic toxin remained active for much longer.
They also tried giving morphine injections to the mice that had already received the synthetic toxin. The morphine didn’t have any additional effect on pain sensitivity in these mice. This indicates that the synthetic toxin was completely mimicking the effects of morphine.
Only the targeted neurons were affected
The researchers euthanized the mice after the experiment and used a high-powered microscope to examine neurons in their spinal cords. They confirmed that the synthetic botulinum toxin was only active in the targeted pain-signalling neurons, with other neurons being unaffected. None of the affected neurons were killed; only their ability to signal pain was affected.
A promising method of pain relief that needs to be tested in humans
This study was done on mice, and it is, therefore, necessary to test the synthetic botulinum toxin compounds for safety and effectiveness in humans. Unfortunately, many previous attempts at moving therapies for pain from the animal laboratory to the human clinic have been unsuccessful. This could be because the biology of pain is different between animals and humans. It is also possible that behavioural tests in animals do not correspond to the human experience of pain.
Another potential difficulty is the use of spinal injections to administer the synthetic toxin. Spinal injections are sometimes used in hospitals, but the suitability of this approach could depend on how frequently the injections are needed.
Despite these potential issues, the researchers concluded that this synthetic botulinum toxin compound is a new and promising method for pain relief as a chronic pain treatment. They showed that a single injection was able to provide long-lasting relief from pain, without measurable side effects. If it works in human patients, this could greatly improve the lives of the many people who suffer from chronic pain.
Written by Bryan Hughes, PhD
- Maiarù, M., Leese, C., Certo, M., Echeverria-Altuna, I., Mangione, A. S., Arsenault, J., Davletov, B. & Hunt, S. P. Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice. Science Translational Medicine10 (2018)
- Fayaz, A., Croft, P., Langford, R. M., Donaldson, L. J. & Jones, G. T. Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies. BMJ Open6 (2016) http://dx.doi.org/10.1136/bmjopen-2015-010364