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      Current Status and Future Directions of Botulinum Neurotoxins for Targeting Pain Processing

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          Abstract

          Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics.

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          Most cited references 275

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          Nociceptors--noxious stimulus detectors.

          In order to deal effectively with danger, it is imperative to know about it. This is what nociceptors do--these primary sensory neurons are specialized to detect intense stimuli and represent, therefore, the first line of defense against any potentially threatening or damaging environmental inputs. By sensing noxious stimuli and contributing to the necessary reactions to avoid them--rapid withdrawal and the experience of an intensely unpleasant or painful sensation, nociceptors are essential for the maintenance of the body's integrity. Although nociceptive pain is clearly an adaptive alarm system, persistent pain is maladaptive, essentially an ongoing false alarm. Here, we highlight the genesis of nociceptors during development and the intrinsic properties of nociceptors that enable them to transduce, conduct, and transmit nociceptive information and also discuss how their phenotypic plasticity contributes to clinical pain.
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            Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.

             H Tsujino,  Y Dai,  T Ochi (2000)
            Activating transcription factor 3 (ATF3), a member of ATF/CREB family of transcription factors, is induced in a variety of stressed tissue. ATF3 regulates transcription by binding to DNA sites as a homodimer or heterodimer with Jun proteins. The purpose of this study was to examine the expression and regulation of ATF3 after axonal injury in neurons in dorsal root ganglia (DRG) and spinal cord. In naive rats, ATF3 was not expressed in the DRG and spinal cord. Following the cut of peripheral nerve, ATF3 was immediately induced in virtually all DRG neurons and motoneurons that were axotomized, and the time course of induction was dependent on the distance between the injury site and the cell body. Double labeling using immunohistochemistry revealed that the population of DRG neurons expressing ATF3 included those expressing c-jun, and in motoneurons ATF3 and c-jun were concurrently expressed after axotomy. In contrast to c-jun, ATF3 was not induced transsynaptically in spinal dorsal horn neurons. We conclude that ATF3 is specifically induced in sensory and motoneurons in the spinal cord following nerve injury and should be regarded as an unique neuronal marker of nerve injury in the nervous system. Copyright 2000 Academic Press.
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              Neutrophil-Derived Cytokines: Facts Beyond Expression

              Polymorphonuclear neutrophils, besides their involvement in primary defense against infections – mainly through phagocytosis, generation of toxic molecules, release of enzymes, and formation of extracellular traps – are also becoming increasingly important for their contribution to the fine regulation in development of inflammatory and immune responses. These latter functions of neutrophils occur, in part, via their de novo production and release of a large variety of cytokines, including chemotactic cytokines (chemokines). Accordingly, the improvement in technologies for molecular and functional cell analysis, along with concomitant advances in cell purification techniques, have allowed the identification of a continuously growing list of neutrophil-derived cytokines, as well as the characterization of their biological implications in vitro and/or in vivo. This short review summarizes crucial concepts regarding the modalities of expression, release, and regulation of neutrophil-derived cytokines. It also highlights examples illustrating the potential implications of neutrophil-derived cytokines according to recent observations made in humans and/or in experimental animal models.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                04 November 2015
                November 2015
                : 7
                : 11
                : 4519-4563
                Affiliations
                [1 ]Department of Bacteriology, University of Wisconsin, 6340 Microbial Sciences Building, 1550 Linden Dr., Madison, WI 53706, USA; E-Mail: sabine.pellett@ 123456wisc.edu
                [2 ]Department of Anesthesiology 0818, University of California, 214 Dickinson St., San Diego, CA 92103, USA; E-Mail: tyaksh@ 123456ucsd.edu
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: roramachandran@ 123456ucsd.edu ; Tel.: +1-619-543-3597.
                Article
                toxins-07-04519
                10.3390/toxins7114519
                4663519
                26556371
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                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/).

                Categories
                Review

                Molecular medicine

                snares, pain, botulinum neurotoxin, bont, spinal cord, primary afferent, glia, neurotransmitter

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