Recent histochemical and physiological evidences for central effects of Botulinum toxin type A. what we know and what we don’t know?

Zdravko Lackovic1, Ivica Matak1, Lidija Bach-Rojecky2, Boris Filipovic1. 1University of Zagreb School of Medicine, Department of Pharmacology, Zagreb 10000, Croatia, 2University of Zagreb School of Pharmacy and Biochemistry, Department of Pharmacology, Zagreb 10000, Croatia

Light chain of botulinum toxin type-A (BTX) enzymatically cleaves SNAP-25, a protein involved in neurotransmitter vesicle release. Association of this effect with acetylcholine release in the neuromuscular junction is a textbook knowledge. However, in series of experiments we and other authors demonstrated that BTX reduces also pain perception, presumably inhibiting release of neurotransmitters other than acetylcholine (details will be presented at this symposia by Lidija Bach-Rojecky). BTX does not reduce mechanically or thermally induced acute superficial nociceptive pain but it reduces allodynia and pain supersensitivity in carrageenan, capsaicin and in second phase of formalin-induced pain. BTX reduces also a neuropathic pain induced by nerve ligature, diabetes or cytostatic paclitaxel. Up to now its action in visceral pain is shown only in few models like capsaicin-induced prostate pain. The effect on deep somatic pain was investigated in formalin-induced knee joint pain. BTX reduces also bilateral pain pain induced by repeated i.m. injection of acidic saline, which is considered to be centrally mediated. Interestingly BTX reduces neuropathic and formalin induced orofacial pain but also accompanying dural extravasation (Filipovic at al PlosOne 2012;7(1):e29803). Our preliminary experiments demonstrate the same effect in temporomandibular joint pain. In several pain models we demonstrated that antinociceptive effect of peripherally applied BTX is axonal transport dependent. After peripheral BTX injection in trigeminal area, using antibody against truncated BTX, recently we found immunohistochemical evidence of enzymatic activity of BTX in ipsilateral trigeminal sensory nuclei Neuroscience. 2011;186:201-7). Our additional experiments excluded the possibility that peripheral sensory nerve endings significantly contribute to antinociceptive effect of BTX. In comparison to several classical analgesics, BTX reduced only second phase of pain induced by subcutaneous injection of formalin. In general it seems that BTX does not produce general pain insensitivity but reduces allodynia an pain supersensitivity. In other words BTX appears more like drug that normalizes the perception of pain then like classical analgesic. Potentially the greatest benefit of BTX might be its long lasting effect.. Discovery that BTX normalizes the perception of pain and that it’s action on pain is exclusively or dominantly a central effect raises many new questions: how is possible that it acts primarily on allodynia and hyperalgesia and not on “normal” nociception? Is that associated only with some neurotransmitters, or only with some types of nerves, or only with some types of ion channels? Is BTX associated with central synaptic remodeling like in neuromuscular junction? In conclusion we must admit that after these new discoveries we understand less than we previously (wrongly) believed. Supported by Croatian Ministry of Science, Education and Sport and Deutscher Academischer Austauch Dienst.