Botulinum toxin A targets pain hypersensitivity

Botulinum toxin A targets pain hypersensitivity

Botulinum toxin type A (BoNT/A), an enzyme produced by Clostridium botulinum, owes its potency to its exquisite ability to invade neurons and to block the vesicular release of neurotransmitters

By cleaving a peptide bond on a synaptic protein called synaptosomal-associated protein 25 (SNAP-25), BoNT/A prevents the synaptic vesicles from fusing with presynaptic plasma membrane.

BoNT/A is an approved chronic migraine drug, and a treatment option for certain chronic pain disorders that are more difficult to treat with conventional analgesics, like different types of neuropathies, low-back pain, arthritis, etc. The biggest advantage of BoNT/A use is that, due to the long-term survival of toxin’s enzymatic part within neurons, the clinical effects may last for 3-6 months after a single peripheral application. Another important benefit of BoNT/A in chronic pain states accompanied by hypersensitivity, is its ability to normalize the thresholds to non-nociceptive and nociceptive stimuli.

The question of why BoNT/A targets the pain hypersensitivity, and not the normal sensitivity to evoked stimuli has not been addressed in detail up to now. In a recent study we examined if the BoNT/A action on pain may be selective for a certain neuronal population. We found that the likely candidates were capsaicin (chili pepper pungent substance)-sensitive sensory neurons, or more specifically, their central terminals in CNS.

Growing evidence suggests that these dorsal horn terminals, that express the capsaicin receptor (also known as vanilloid-1 receptor or TRPV1), are important mediators of chronic pain and hyperalgesia

in order to prevent different types of pain, BoNT/A must be centrally transported by axonal traffic within sensory neurons

peripherally administered BoNT/A may modulate the nociceptive transmission of glutamate and other neurotransmitters associated with capsaicin-sensitive neurons at the first sensory synapse in the CNS. Theoretically, since TRPV1 translocation to plasma membrane is also mediated by SNAP-25, BoNT/A might block the TRPV1 receptor-mediated nociceptive transmission at central afferent terminals

BoNT/A and opioid agonist morphine have synergistic effects on inflammatory and neuropathic pain, and BoNT/A prevents morphine-induced tolerance (8). We are still unsure of the mechanisms that underpin these observations. Theoretically, they might be linked to possible changes in dorsal horn synaptic plasticity, which is considered a key player involved in chronic pain development.

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