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      Activation of TRPV1 Mediates Calcitonin Gene-Related Peptide Release, Which Excites Trigeminal Sensory Neurons and Is Attenuated by a Retargeted Botulinum Toxin with Anti-Nociceptive Potential

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          Abstract

          Excessive release of inflammatory/pain mediators from peripheral sensory afferents renders nerve endings hyper-responsive, causing central sensitization and chronic pain. Herein, the basal release of proinflammatory calcitonin gene-related peptide (CGRP) was shown to increase the excitability of trigeminal sensory neurons in brainstem slices via CGRP1 receptors because the effect was negated by an antagonist, CGRP8–37. This excitatory action could be prevented by cleaving synaptosomal-associated protein of M r 25,000 (SNAP-25) with botulinum neurotoxin (BoNT) type A, a potent inhibitor of exocytosis. Strikingly, BoNT/A proved unable to abolish the CGRP1 receptor-mediated effect of capsaicin, a nociceptive TRPV1 stimulant, or its elevation of CGRP release from trigeminal ganglionic neurons (TGNs) in culture. Although the latter was also not susceptible to BoNT/E, apparently attributable to a paucity of its acceptors (glycosylated synaptic vesicle protein 2 A/B), this was overcome by using a recombinant chimera (EA) of BoNT/A and BoNT/E. It bound effectively to the C isoform of SV2 abundantly expressed in TGNs and cleaved SNAP-25, indicating that its /A binding domain (H C) mediated uptake of the active /E protease. The efficacy of /EA is attributable to removal of 26 C-terminal residues from SNAP-25, precluding formation of SDS-resistant SNARE complexes. In contrast, exocytosis could be evoked after deleting nine of the SNAP-25 residues with /A but only on prolonged elevation of [Ca 2+] i with capsaicin. This successful targeting of /EA to nociceptive neurons and inhibition of CGRP release in vitro and in situ highlight its potential as a new therapy for sensory dysmodulation and chronic pain.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          15 April 2009
          : 29
          : 15
          : 4981-4992
          Affiliations
          [1] 1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland,
          [2] 2Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland, and
          [3] 3Allergan Inc., Irvine, California 92612
          Author notes
          Correspondence should be addressed to J. Oliver Dolly, International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland. oliver.dolly@ 123456dcu.ie
          Article
          PMC6665337 PMC6665337 6665337 3475798
          10.1523/JNEUROSCI.5490-08.2009
          6665337
          19369567
          a418bb42-5765-49b0-ae72-799c13402076
          Copyright © 2009 Society for Neuroscience 0270-6474/09/294981-12$15.00/0
          History
          : 13 November 2008
          : 20 February 2009
          : 3 March 2009
          Categories
          Articles
          Neurobiology of Disease

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