Fig. 1

The neurobiological mechanisms of the effect of botulinum neurotoxin (BonT) on pain according to animal models [16] and the anatomical levels where they may take place. Panel a shows a normal axon and the role of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, here represented by a chain, for allowing the fusion between the synaptic vescicles (red circles) containing a neurotransmitter (black dots) and the axonal membrane resulting in the neurotransmitter release. Panel b shows the effect of the BoNT, represented by scissors that cleave the SNARE complex and impede vescicle fusion and neurotransmitter release. Panel c shows peripheral sensitization after tissue injury, which results in the release of a number of inflammatory mediators (e.g., histamine, bradykinin, prostaglandins, interleukins, adenosine, and nerve growth factors) that, in turn, induce the expression of transient receptor potential (TRP) channels and cause sensitization of the peripheral nociceptor. BoNT may cleave the SNARE complex, block fusion of the vescicles (blue circles) containing TRP channels (white dots) and reduce peripheral nociceptor sensitization. This mechanism may contribute to the effect of BoNT on nociceptive pain and peripheral neuropathic pain (NP). Panel d shows retrograde axonal transport of BoNT to the dorsal horn of the spinal cord where it can block the release of pain-modulating neurotransmitters, such as glutamate, substance P, and calcitonin gene-related peptide (CGRP). This mechanism may reduce central sensitization phenomena and spinal NP