Botulinum toxin’s pain relief: not through sodium channels

Botulinum toxin type A (BoNT/A), also known as Botox, is widely used in cosmetic dermatology, prized for its ability to temporarily relax facial muscles and give the skin a smoother, more youthful appearance. But beyond its use in cosmetics, BoNT/A also treats various medical conditions including chronic migraines, cervical dystonia, strabismus, hyperhidrosis, and neuropathic pain.

Despite its frequent off-label use as a third-line therapy for neuropathic pain, the mechanisms by which BoNT/A exerts its analgesic effects are not well understood. Previous research suggested that BoNT/A might work by blocking voltage-gated sodium channels (Nav), which are critical for pain perception.

However, a recent study provides strong evidence that BoNT/A’s analgesic effects in neuropathic pain do not involve sodium channel inhibition.

The research utilized various methods, including high-throughput automated patch clamp (SyncroPatch 384), multielectrode array (MEA) recordings, and iPSC-derived sensory neurons to study the toxin’s effects in both normal and neuropathic conditions.

Experiments were conducted on various sodium channel isoforms (Nav1.7 and Nav1.3), endogenous Navs in the neuronal cell line ND7/23, and on iPSC-derived neurons from a patient with a hereditary neuropathic pain syndrome (inherited erythromelalgia) carrying the Nav1.7/p.Q875E mutation.

The findings indicate that BoNT/A and its catalytic light chain, LC/A, had limited effects on sodium channel function and did not alter spontaneous activity in iPSC-derived sensory neurons, regardless of whether they were from a healthy control or a patient carrying the mutation.

These results challenge earlier assumptions about BoNT/A’s mechanism of action being linked to sodium channel blockage.

The study highlights the need for further research to understand the mechanisms through which BoNT/A provides pain relief. While the toxin’s known effects on muscle relaxation through inhibition of acetylcholine release at the neuromuscular junction are well-documented, its impact in the context of neuropathic pain appears to be independent of direct action on sodium channels. Other pathways, such as the inhibition of pain mediators, reduction in local inflammation, or reduced expression of TRPV1, might contribute to the analgesic effects.

In conclusion, this comprehensive study suggests that the analgesic properties of BoNT/A in neuropathic pain are likely due to mechanisms other than the blockage of sodium channels, calling for a reevaluation of existing hypotheses and encouraging the exploration of alternative pathways to optimize the use of BoNT/A in pain treatment.

Find the original article here: https://www.sciencedirect.com/science/article/pii/S0028390824001369

Learn more about the SyncroPatch 384 here: https://www.nanion.de/products/syncropatch-384/