Menu

Synthetic Botox Treats Chronic Pain in Mice

Researchers silence pain neurons in the mouse spinal cord with injections of botulinum toxins modified to bind to the neurons’ receptors.

Jul 18, 2018
Abby Olena
An image of the mouse brain area that receives information from the spinal cord. Spinal neuron axons are labeled in green and neuronal cells in red.
maria maiarù, UCL

Opioids—one of the most effective treatments for pain—come with a host of potential side effects: addiction, risk of overdose, and the development of tolerance that renders the drugs less effective over time. But in study published today (July 18) in Science Translational Medicine, researchers have used spinal injections of modified botulinum toxins to alleviate pain in mice, a strategy that may prove to be a safer alternative to opioids.

“Probably the most exciting thing is that you would be unlikely to see things like misuse” with this treatment, says Erin Young, a pain geneticist at the University of Connecticut who did not participate in the work. “Even if there is tolerance, it’s unlikely that this would be a drug of abuse,” she adds, because these conjugates are not administered systemically and because the receptor binding is not for activation, but for selectively entering the cells that are important for pain transmission.

Maria Maiarù, a postdoc at University College London and study coauthor, says that the research began with a desire to target groups of neurons that process pain in the spinal cord. Previous work had shown that botulinum toxin can block synaptic transmission in neurons by cleaving a protein necessary for the release of signals at the synapse. Researchers from the same group as Maiarù had also demonstrated in the past that modifying the portion of the toxin responsible for getting in to neurons could give it specificity for different cell types.

In this latest study, Maiarù and her colleagues linked the portion of the botulinum toxin responsible for silencing neurons with either substance P or dermorphin, molecules that bind two different receptors found on spinal neurons that carry pain signals to the brain.

When the authors injected either compound into the spinal cords of mice with inflammatory or neuropathic pain, the drugs diminished the animals’ heightened sensitivity to touch, suggesting that their pain subsided. The analgesic effects lasted for the duration of the experiment—up to 21 days after the single dose. The researchers confirmed that the treatments did not affect normal sensation—only the increased sensitivity associated with pain—and that each version made it into only the neurons it was intended for and didn’t kill the cells. They found that the dermorphin-botulinum combination, which targets the same μ-opioid receptor as morphine, was also as effective a pain reliever as morphine.

The authors “really nicely demonstrate . . . that you can target specific populations of neurons by going after the” relevant receptor, says Michael Gold, who studies the neurobiology of pain at the University of Pittsburgh and was not part of the study. One caveat is that “the substance p antagonists have not really shown any efficacy for pain in humans,” he says. “And so the implication is that this population of neurons may be important, but . . . at the end of the day, the essential question’s going to be, What is the critical population of neurons?”

Another potential issue is the common mechanism of targeting the neurons, says Young. “With opioids you see tolerance, so . . . it’s possible that because you’re binding to the same receptor in the case of the [dermorphin]-botulinum toxin that you would see changes in sensitivity to the toxin itself and that it might have reduced efficacy over time,” she says. Nonetheless, “these tools are more like using a scalpel when systemic opioids are like using a sledgehammer,” she says, adding that because the drugs are not systemic and target specific neurons, they would not have the other side effects of opioids like constipation, sedation, and mortality.

Maiarù says that future directions of the research include investigating whether the treatment works in companion dogs that experience pain related to bone cancer, which she says would be an intermediate step between the rodent research and human clinical trials. But before that, she wants to follow the mice for longer to determine how sustained the effects of the injections are. “Our preliminary data in vitro suggests that this compound can be effective for up to 100 days [following a] single injection,” Maiarù says.

Because the botulinum toxin eventually stops being effective, Young says, an important consideration is how cells fare after repeated administrations of the treatment. An extended look at these drugs could tell researchers “whether or not this would be an effective strategy for long-term pain maintenance or whether it’s really just a short-term fix,” Young adds. “You reduce suffering either way. That’s the goal.”

M. Maiarù et al., “Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice,” Science Translational Medicine, doi:10.1126/scitranslmed.aar7384, 2018.

February 2019

Big Storms Brewing

Can forests weather more major hurricanes?

Marketplace

Sponsored Product Updates

Bio-Rad Releases First FDA-Cleared Digital PCR System and Test for Monitoring Chronic Myeloid Leukemia Treatment Response
Bio-Rad Releases First FDA-Cleared Digital PCR System and Test for Monitoring Chronic Myeloid Leukemia Treatment Response
Bio-Rad Laboratories, Inc. (NYSE: BIO and BIOb), a global leader of life science research and clinical diagnostic products, today announced that its QXDx AutoDG ddPCR System, which uses Bio-Rad’s Droplet Digital PCR technology, and the QXDx BCR-ABL %IS Kit are the industry’s first digital PCR products to receive U.S. Food and Drug Administration (FDA) clearance. Used together, Bio-Rad’s system and kit can precisely and reproducibly monitor molecular response to treatment in patients with chronic myeloid leukemia (CML).
Bio-Rad Showcases New Automation Features of its ZE5 Cell Analyzer at SLAS 2019
Bio-Rad Showcases New Automation Features of its ZE5 Cell Analyzer at SLAS 2019
Bio-Rad Laboratories, Inc. (NYSE: BIO and BIOb) today showcases new automation features of its ZE5 Cell Analyzer during the Society for Laboratory Automation and Screening 2019 International Conference and Exhibition (SLAS) in Washington, D.C., February 2–6. These capabilities enable the ZE5 to be used for high-throughput flow cytometry in biomarker discovery and phenotypic screening.
Andrew Alliance and Sartorius Collaborate to Provide Software-Connected Pipettes for Life Science Research
Andrew Alliance and Sartorius Collaborate to Provide Software-Connected Pipettes for Life Science Research
Researchers to benefit from an innovative software-connected pipetting system, bringing improved reproducibility and traceability of experiments to life-science laboratories.
Corning Life Sciences to Feature 3D Cell Culture Technologies at SLAS 2019
Corning Life Sciences to Feature 3D Cell Culture Technologies at SLAS 2019
Corning Incorporated (NYSE: GLW) will showcase advanced 3D cell culture technologies and workflow solutions for spheroids, organoids, tissue models, and applications including ADME/toxicology at the Society for Laboratory Automation and Screening (SLAS) conference, Feb. 2-6 in Washington, D.C.