Nav: Home

Novel botulinum toxin compound relieves chronic pain

July 18, 2018

A modified form of botulinum toxin gives long-lasting pain relief in mice without adverse effects and, in time, could replace opioid drugs as a safe and effective way of treating chronic pain, according to research by UCL, the University of Sheffield and the Hospital for Sick Children, Toronto.

For the study, published today in Science Translational Medicine and funded by the Medical Research Council, scientists deconstructed the botulinum molecule and reassembled it with an opioid called dermorphin to make Derm-BOT - a compound which successfully targets and silences pain signals from neurons in the spinal cords of mice.

Key neurons in the spinal cord are targets for pain management as they directly 'sense' pain and send this information to the brain.

"Injected into the spine, Derm-BOT relieves chronic pain - such as that caused by nerve damage - and avoids the adverse events of tolerance and addiction often associated with repeated opioid drug use," explained co-corresponding author, Professor Steve Hunt (UCL Cell & Developmental Biology).

"It doesn't affect muscles like the botulinum toxin used to reduce wrinkles but it does block nerve pain for up to four months without affecting normal pain responses. It really could revolutionise how chronic pain is treated if we can translate it into clinic, removing the need for daily opioid intake."

Chronic pain of 'moderate to severe' intensity is widespread affecting 7.8 million people in the UK and 19% of adult Europeans. It is a serious social and medical problem which negatively impacts quality of life.

Opioids like morphine and fentanyl are considered to be the gold standard for pain relief but there is little evidence that their long-term use is effective in treating chronic pain. This is because the body builds up a tolerance to repeated drug use which over the long term. Paradoxically opioids can also increase the body's sensitivity to pain.

In the UK, 5% of the population are on opioids with 80% reporting negative side effects.

Opioid medications can also activate brain reward regions, causing addiction. Over 2 million individuals in the US have 'opioid use disorder' with most starting with prescribed opioid painkillers and opioid overdose is now the second leading cause of death in the US.

Previous studies in rats and companion dogs show that precise injections of tiny amounts of toxic substances, such as 'substance P-saporin', into the spine kill neurons responsible for crippling, chronic pain. This approach relies on an analogue of ricin which is difficult to manufacture to clinical standards and clinicians are resistant to irreversibly kill nerve cells.

In contrast, Derm-BOT is safe to manufacture, is non-toxic and does not kill neurons.

"We needed to find the best pain targeting molecular parts to direct the botulinum silencing 'warhead' to the pain-controlling system in the spine. For this, we developed a molecular Lego system which allows us to link the botulinum 'warhead' to a navigation molecule, in this case, the strong opioid called dermorphin, allowing the creation of widely desired long-lasting pain killers without the side effects of opioids," said co-corresponding author Professor Bazbek Davletov from the Department of Biomedical Science at the University of Sheffield.

Dermorphin targets and binds to opioid receptors on the surface of neurons which allows the Derm-BOT compound to enter the cells where the botulinum 'warhead' then reversibly inhibits the release of neurotransmitter, silencing the cells essential for sending pain signals to the brain.

Over a five year period, 200 mice were used to simulate the early stages of human inflammatory and neuropathic pain and were treated with a single injection of either Derm-BOT, SP-BOT (a substance P-modified botulinum molecule) or morphine. The behaviour of the mice was monitored to track their pain-response and the locations and binding properties of the botulinum compounds were investigated.

"Both SP-BOT and Derm-BOT have a long-lasting effect in both inflammatory and neuropathic pain model, successfully silencing neurons without cell death. We were impressed to see that one tiny injection was enough to stop chronic pain caused by inflammation and nerve damage for at least a month.

"Furthermore, a single injection of Derm-BOT reduced mechanical hypersensitivity to the same extent as morphine. We hope to take our investigations forward with the aim of translating this into the clinic," concluded lead author, Dr Maria Maiarù (UCL Cell & Developmental Biology).
-end-


University College London

Related Neurons Articles:

New tool to identify and control neurons
One of the big challenges in the Neuroscience field is to understand how connections and communications trigger our behavior.
Neurons that regenerate, neurons that die
In a new study published in Neuron, investigators report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others.
How neurons use crowdsourcing to make decisions
When many individual neurons collect data, how do they reach a unanimous decision?
Neurons can learn temporal patterns
Individual neurons can learn not only single responses to a particular signal, but also a series of reactions at precisely timed intervals.
A turbo engine for tracing neurons
Putting a turbo engine into an old car gives it an entirely new life -- suddenly it can go further, faster.
Brain neurons help keep track of time
Turning the theory of how the human brain perceives time on its head, a novel analysis in mice reveals that dopamine neuron activity plays a key role in judgment of time, slowing down the internal clock.
During infancy, neurons are still finding their places
Researchers have identified a large population of previously unrecognized young neurons that migrate in the human brain during the first few months of life, contributing to the expansion of the frontal lobe, a region important for social behavior and executive function.
How many types of neurons are there in the brain?
For decades, scientists have struggled to develop a comprehensive census of cell types in the brain.
Molecular body guards for neurons
In the brain, patterns of neural activity are perfectly balanced.
Engineering researchers use laser to 'weld' neurons
University of Alberta researchers have developed a method of connecting neurons, using ultrashort laser pulses -- a breakthrough technique that opens the door to new medical research and treatment opportunities.

Related Neurons Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Climate Crisis
There's no greater threat to humanity than climate change. What can we do to stop the worst consequences? This hour, TED speakers explore how we can save our planet and whether we can do it in time. Guests include climate activist Greta Thunberg, chemical engineer Jennifer Wilcox, research scientist Sean Davis, food innovator Bruce Friedrich, and psychologist Per Espen Stoknes.
Now Playing: Science for the People

#527 Honey I CRISPR'd the Kids
This week we're coming to you from Awesome Con in Washington, D.C. There, host Bethany Brookshire led a panel of three amazing guests to talk about the promise and perils of CRISPR, and what happens now that CRISPR babies have (maybe?) been born. Featuring science writer Tina Saey, molecular biologist Anne Simon, and bioethicist Alan Regenberg. A Nobel Prize winner argues banning CRISPR babies won’t work Geneticists push for a 5-year global ban on gene-edited babies A CRISPR spin-off causes unintended typos in DNA News of the first gene-edited babies ignited a firestorm The researcher who created CRISPR twins defends...