Abstract
In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25), the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw’s nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC). We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients’ quality of life.
Highlights
Botulinum neurotoxin type A (BoNT/A) is currently used to treat numerous medical conditions, including musculoskeletal disorders, dystonia, and pain
Behavioral Effect of BoNT/A on Neuropathic Pain The unilateral ligature of the sciatic nerve, as that performed in constriction injury (CCI) model of neuropathic pain, induces mechanical allodynia in the hindpaw ipsilateral to the ligature
We demonstrated that peripherally injected BoNT/A may affect neuropathic pain at the central level by an indirect and through a direct action by means of axonal retrograde transport
Summary
Botulinum neurotoxin type A (BoNT/A) is currently used to treat numerous medical conditions, including musculoskeletal disorders, dystonia, and pain. Among the other botulinum neurotoxins, BoNT/A cleaves the 25 kDa synaptosomal-associated protein (SNAP-25), which is anchored to the cell membrane, by removing 9 aminoacid residues at the Cterminus [6]. This cleavage results in a formation of a nonfunctional SNARE complex thereby blocking the synaptic transmission [7,8]
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