Botulinum toxin B in the sensory afferent: Transmitter release, spinal activation, and pain behavior

Abstract

We addressed the hypothesis that intraplantar Botulinum toxin B (rimabotulinumtoxin B: BoNT-B) has an early local effect upon peripheral afferent terminal releasing function and over time will be transported to the central terminals of the primary afferent. Once in the terminals it will cleave synaptic protein, block spinal afferent transmitter release and thereby prevent spinal nociceptive excitation and behavior. In mice, C57Bl/6 males, intraplantar BoNT-B (1U), given unilaterally into the hind paw had no effect upon survival or motor function but ipsilaterally decreased: i) intraplantar formalin evoked flinching; ii) intraplantar capsaicin evoked plasma extravasation in the hindpaw measured by Evans blue in the paw; iii) intraplantar formalin evoked dorsal horn SP release (NK1 receptor internalization); iv) intraplantar formalin evoked dorsal horn neuronal activation (cFos); v) ipsilateral DRG VAMP; vi) ipsilateral SP release otherwise evoked bilaterally by intrathecal capsaicin; vii) ipsilateral activation of cFos otherwise evoked bilaterally by intrathecal substance P. These results indicate that BoNT-B after unilateral intraplantar delivery is taken up by the peripheral terminal, is locally active (blocking plasma extravasation), is transported to the ipsilateral DRG to cleave VAMP and is acting presynaptically to block release from the spinal peptidergic terminal. The observations following intrathecal SP offer evidence for a possible transsynaptic effect of intraplantar BoNT. These results provide robust evidence that peripheral BoNT-B can alter peripheral and central terminal release from a nociceptor and attenuate downstream nociceptive processing via a presynaptic effect, with further evidence suggesting a possible postsynaptic effect.

Botulinum toxin A, brain and pain

“…Most recent study suggested that BoNT/B, applied at high peripheral dose, may also be axonally transported in mouse sensory neurons. Marino et al (2014) reported reduction of VAMP/synaptobrevin immunoreactivity in dorsal root ganglia after BoNT/B intraplantar injection in mice, suggesting BoNT/B enzymatic activity in the ganglia. In addition, the authors showed reduced neurokinin 1 receptor internalization evoked by intraplantar formalin or intrathecal capsaicin, and suggested that BoNT/B may reduce spinal substance P presynaptic release (Marino et al, 2014).…”

Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons

“…Thus, BoNT/A might prevent glutamate as well as other co-transmitters' release from a distinct set of nerve endings [19,21]. Recently, it was proposed that BoNT serotype B reduces spinal substance P release from TRPV1-expressing neurons in mice [38]. -BoNT/A and suppression of TRPV1-expressing neurons (evoked by denervation of TRPV1-expressing neurons, or TRPV1 antagonists) do not affect acute mechanical thresholds [4,5,14,15,32,43,44,59].…”

Einsatz intra- bzw. subkutaner Botulinumtoxine bei Post-Zoster-Neuralgie

“…Eine Beobachtung ist, dass durch BoNT die Freisetzung unterschiedlicher Entzün-dungsmediatoren (Substanz P, Glutamat, "calcitonin gene-related peptide" [CG-PR]) verringert bzw. verhindert wird [14,27,28,30,31,54]. Außerdem hemmt es die für die Aktivierung des proinflammatorischen Zytokins Interleukin(IL)-1 wichtigen G-Proteine [33] sowie die Prostaglandinsynthase COX-2 (Cyclooxygenase-2; [9]).…”