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      Botulinum Toxin as a Pain Killer: Players and Actions in Antinociception

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          Abstract

          Botulinum neurotoxins (BoNTs) have been widely used to treat a variety of clinical ailments associated with pain. The inhibitory action of BoNTs on synaptic vesicle fusion blocks the releases of various pain-modulating neurotransmitters, including glutamate, substance P (SP), and calcitonin gene-related peptide (CGRP), as well as the addition of pain-sensing transmembrane receptors such as transient receptor potential (TRP) to neuronal plasma membrane. In addition, growing evidence suggests that the analgesic and anti-inflammatory effects of BoNTs are mediated through various molecular pathways. Recent studies have revealed that the detailed structural bases of BoNTs interact with their cellular receptors and SNAREs. In this review, we discuss the molecular and cellular mechanisms related to the efficacy of BoNTs in alleviating human pain and insights on engineering the toxins to extend therapeutic interventions related to nociception.

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          The vanilloid receptor: a molecular gateway to the pain pathway.

          M. J. Caterina, D Julius (2001)
          The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation of heat-evoked pain.
          Article 0 comments Cited 267 times – based on 0 reviews     Review now
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            Neurotoxins affecting neuroexocytosis.

            G Schiavo, M Matteoli, C Montecucco (2000)
            Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.
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              SV2 is the protein receptor for botulinum neurotoxin A.

              Min Dong, Felix Yeh, William Tepp … (2006)
              How the widely used botulinum neurotoxin A (BoNT/A) recognizes and enters neurons is poorly understood. We found that BoNT/A enters neurons by binding to the synaptic vesicle protein SV2 (isoforms A, B, and C). Fragments of SV2 that harbor the toxin interaction domain inhibited BoNT/A from binding to neurons. BoNT/A binding to SV2A and SV2B knockout hippocampal neurons was abolished and was restored by expressing SV2A, SV2B, or SV2C. Reduction of SV2 expression in PC12 and Neuro-2a cells also inhibited entry of BoNT/A, which could be restored by expressing SV2 isoforms. Finally, mice that lacked an SV2 isoform (SV2B) displayed reduced sensitivity to BoNT/A. Thus, SV2 acts as the protein receptor for BoNT/A.
              Article 0 comments Cited 171 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Bahman Jabbari: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Toxins (Basel)
                Journal ID (iso-abbrev): Toxins (Basel)
                Journal ID (publisher-id): toxins
                Title: Toxins
                Publisher: MDPI
                ISSN (Electronic): 2072-6651
                Publication date (Electronic): 30 June 2015
                Publication date Collection: July 2015
                Volume: 7
                Issue: 7
                Pages: 2435-2453
                Affiliations
                [1 ]Department of Life Science, School of Natural Science, Hanyang University, Seoul 133-791, Korea; E-Mail: wizardbook@ 123456hanmail.net
                [2 ]BK21 PLUS Life Science for BioDefense Research (BDR) Team, Hanyang University, Seoul 133-791, Korea
                [3 ]The Research Institute for Natural Science, Hanyang University, Seoul 133-791, Korea
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Authors to whom correspondence should be addressed; E-Mails: sunkyungl@ 123456hanyang.ac.kr (S.-K.L.); joohong@ 123456hanyang.ac.kr (J.A.); Tel.: +82-2-2220-4955 (S.-K.L.); +82-2-2220-4484 (J.A.); Fax: +82-2-2220-3495 (S.-K.L. & J.A.).
                Article
                Publisher ID: toxins-07-02435
                DOI: 10.3390/toxins7072435
                PMC ID: 4516922
                PubMed ID: 26134255
                SO-VID: a963d7b8-8fc0-47ec-8e45-dced8def56fd
                Copyright © © 2015 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 31 May 2015
                Date accepted : 23 June 2015
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Keywords: botulinum neurotoxin,pain,nociception,neurotransmitter,neuropeptide,trp
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: botulinum neurotoxin, pain, nociception, neurotransmitter, neuropeptide, trp

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