title: Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons.
abstract: Unlike most classical analgesics, botulinum toxin type A (BoNT/A) does not alter acute nociceptive thresholds, and shows selectivity primarily for allodynic and hyperalgesic responses in certain pain conditions. We hypothesized that this phenomenon might be explained by characterizing the sensory neurons targeted by BoNT/A in the central nervous system after its axonal transport. BoNT/A's central antinociceptive activity following its application into the rat whisker pad was examined in trigeminal nucleus caudalis (TNC) and higher-level nociceptive brain areas using BoNT/A-cleaved synaptosomal-associated protein 25 (SNAP-25) and c-Fos immunohistochemistry. Occurrence of cleaved SNAP-25 in TNC was examined after nonselective ganglion ablation with formalin or selective denervation of capsaicin-sensitive (vanilloid receptor-1 or TRPV1-expressing) neurons, and in relation to different cellular and neuronal markers. Regional c-Fos activation and effect of TRPV1-expressing afferent denervation on toxin's antinociceptive action were studied in formalin-induced orofacial pain. BoNT/A-cleaved SNAP-25 was observed in TNC, but not in higher-level nociceptive nuclei. Cleaved SNAP-25 in TNC disappeared after formalin-induced trigeminal ganglion ablation or capsaicin-induced sensory denervation. Occurrence of cleaved SNAP-25 in TNC and BoNT/A antinociceptive activity in formalin-induced orofacial pain were prevented by denervation with capsaicin. Cleaved SNAP-25 localization demonstrated toxin's presynaptic activity in TRPV1-expressing neurons. BoNT/A reduced the c-Fos activation in TNC, locus coeruleus, and periaqueductal gray. Present experiments suggest that BoNT/A alters the nociceptive transmission at the central synapse of primary afferents. Targeting of TRPV1-expressing neurons might be associated with observed selectivity of BoNT/A action only in certain types of pain.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Department of Pharmacology and Croatian Brain Research Institute, University of Zagreb School of Medicine, Zagreb 10000, Croatia Department of Biomedical Sciences, University of Padua, Padua 35121, Italy.
authors.forename: Ivica
authors.initials: I
authors.lastname: Matak
authors.forename: Ornella
authors.initials: O
authors.lastname: Rossetto
authors.forename: Zdravko
authors.initials: Z
authors.lastname: Lacković
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology* / Q000627:therapeutic use; D002211:Capsaicin / Q000494:pharmacology*; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D050825:Synaptosomal-Associated Protein 25; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D019274:Botulinum Toxins, Type A; D002211:Capsaicin
keywords: Axonal transport; Botulinum toxin type A; Central afferent terminals; Pain; TRPV1-expressing neurons; Trigeminal nucleus caudalis