Injections of botulinum conjugate relieves chronic pain in mice

The Botox injections that smooth wrinkles rely on the ability of botulinum toxins from the bacterium Clostridium botulinum to block communication between cells. In the cosmetic treatment, these toxins stop nerve cells from telling muscles to contract. Now, scientists have modified the molecules to prevent nerves from sending pain signals.

Researchers led by University of Sheffield’s Bazbek Davletov and University College London’s Stephen P. Hunt report two botulinum conjugates that relieved chronic pain in mice for three weeks (Sci. Transl. Med. 2018, DOI: 10.1126/scitranslmed.aar7384). The conjugates, delivered by a single injection into the spine, showed no side effects in the animals and could be a promising, nonaddictive alternative to opioids for treating pain, Bazbek says.

The conjugates consist of two molecules stitched together with proteins. One end is a truncated botulinum toxin that silences pain-processing nerves by cleaving SNAP25, a protein that helps release neurotransmitters. The other end is a molecule that directs the conjugate to specific receptors on the nerve cells. This molecule is either substance P, which binds to neurokinin-1 receptors, or a peptide called dermorphin, which binds to mu opioid receptors.

Patrick W. Mantyh at the University of Arizona says the team’s conjugate design is “elegant and very clever.” Mantyh’s lab developed a similar conjugate for treating pain that used the protein saporin instead of botulinum as the payload. The saporin-based conjugate alleviated pain from bone cancer in dogs, but it also killed spinal neurons. The main advantage of the new conjugates, Mantyh says, is that botulinum inactivates neurons without killing them.

Eventually neurons degrade the botulinum molecules and SNAP25 proteins get replenished. But this process takes several months, Bazbek says, which means the conjugate could silence pain signals for four to five months after an injection. The team is working to produce their conjugate at clinical standards for human trials and is currently seeking partners to fund these investigations.