Pain Mechanisms and Sensory NeuroscienceResearch PaperBehavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A
Graphical Abstract
Appearance of cleaved SNAP-25 in ipsilateral medullar dorsal horn (trigeminal nucleus caudalis) following botulinum toxin A (15 U/kg) injection into the whisker pad.
Highlights
▶Peripheral and intraganglionic BTX-A reduce formalin-induced facial pain. ▶Antinociceptive effect of BTX-A depends on axonal transport in trigeminal neurons. ▶After peripheral BTX-A application, cleaved SNAP-25 appears in medullary dorsal horn. ▶Central cleaved SNAP-25 appears with delay and at low peripheral BTX-A dose. ▶Antinociceptive effect of peripheral BTX-A is coupled with SNAP-25 cleavage in CNS.
Section snippets
Animals
Male Wistar rats (University of Zagreb School of Medicine, Croatia), weighing 300–400 g, kept on 12 h/12 h light and dark cycle, were used in all experiments. The experiments were conducted according to the European Communities Council Directive (86/609/EEC) and recommendations of the International Association for the Study of Pain (Zimmerman, 1983). All efforts were made to reduce the number of animals used and to reduce their suffering. Animal procedures were approved by the Ethical Committee
BTX-A reduces formalin-induced orofacial pain: necessity of axonal transport in sensory neurons
BTX-A had no significant antinociceptive effects during phase I of formalin-induced pain. However, peripheral BTX-A pretreatment (3.5 U/kg) significantly reduced the time of facial grooming during phase II of formalin-induced pain (measured 3 days post BTX-A injection). Injection of colchicine (5 mM) into trigeminal ganglion abolished the effect of subsequently applied BTX-A (Fig. 2).
Intraganglionic BTX-A (1 U/kg) reduced the formalin-induced face grooming 2 days after the injection (Fig. 3).
Discussion
Cleavage of SNAP-25 at neuromuscular junctions or autonomic synapses, induced by enzymatic activity of BTX-A light chain, results in blockade of acetylcholine (ACh) release. Analogous mechanism was proposed as an explanation of antinociceptive activity in peripheral sensory neurons (Cui et al., 2004, Aoki, 2005). In formalin-induced inflammatory pain, peripheral BTX-A pretreatment had no effect on the acute nociceptive pain in phase I but it reduced pain during inflammatory phase II,
Conclusion
Antinociceptive effect of BTX-A requires axonal transport through sensory neurons and it is associated with occurrence of truncated SNAP-25 in central sensory nociceptive nuclei.
Acknowledgments
This work was supported by Croatian Ministry of Science, Education and Sport, (Project No. 108-1080003-0001) and Deutscher Academischer Austauch Dienst (DAAD)—project awarded to Professors Peter Riederer, Jürgen Deckert and Zdravko Lacković. Antibody to BTX-A–cleaved SNAP-25 was a kind gift from Assist. Prof. Ornella Rossetto (University of Padua, Italy). We wish to thank Dr. Matteo Caleo (Institute of Neuroscience, Pisa, Italy) for advices regarding the immunohistochemistry protocol as well as
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