Meng J, Wang J, Lawrence G et al.Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci 120:2864-2874

International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.
Journal of Cell Science (Impact Factor: 5.43). 08/2007; 120(Pt 16):2864-74. DOI: 10.1242/jcs.012211
Source: PubMed


Calcitonin-gene-related peptide (CGRP), a potent vasodilator that mediates inflammatory pain, is elevated in migraine; nevertheless, little is known about its release from sensory neurons. In this study, CGRP was found to occur in the majority of neurons from rat trigeminal ganglia, together with the three exocytotic SNAREs [SNAP25, syntaxin 1 and the synaptobrevin (Sbr, also known as VAMP) isoforms] and synaptotagmin. Ca(2+)-dependent CGRP release was evoked with K(+)-depolarisation and, to lower levels, by capsaicin or bradykinin from neurons that contain the vanilloid receptor 1 and/or bradykinin receptor 2. Botulinum neurotoxin (BoNT) type A cleaved SNAP25 and inhibited release triggered by K(+) > bradykinin > capsaicin. Unlike BoNT type D, BoNT type B did not affect exocytosis, even though the neurons possess its receptor and Sbr II and Sbr III got proteolysed (I is resistant in rat) but, in mouse neurons, it additionally cleaved Sbr I and blocked transmitter release. Sbr I and II were found in CGRP-containing vesicles, and each was shown to separately form a SNARE complex. These new findings, together with punctate staining of Sbr I and CGRP in neurites, implicate isoform Sbr I in exocytosis from large dense-core vesicles together with SNAP25 (also, probably, syntaxin 1 because BoNT type C1 caused partial cleavage and inhibition); this differs from Sbr-II-dependent release of transmitters from small synaptic vesicles. Such use of particular Sbr isoform(s) by different neurons raises the functional implications for other cells previously unrecognised.

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    • "The BoNT‐A treatment regime reduced itch and pain sensibility in response to challenge with histamine and AITC, respectively. In both cases neurogenic flare was reduced, consistently with the hypothesis that BoNT‐A reduces neurogenic inflammation and in agreement with previous studies.6 We also found that BoNT‐A selectively reduced the subject's sensitivity to noxious mechanical stimuli, but there was no change in response to low‐threshold mechanical stimuli or to thermal stimuli. "
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    ABSTRACT: The mechanisms underlying the analgesic effects of BoNT-A are not well understood. We have tested the hypothesis that BoNT-A can block nociceptor transduction. Intra-dermal administration of BoNT-A to healthy volunteers produced a marked and specific decrease in noxious mechanical pain sensitivity whilst sensitivity to low-threshold mechanical and thermal stimuli was unchanged. BoNT-A did not affect cutaneous innervation. In cultured rodent primary sensory neurons, BoNT-A decreased the proportion of neurons expressing slowly adapting mechano-gated currents linked to mechanical pain transduction. Inhibition of mechanotransduction provides a novel locus of action of BoNT-A, further understanding of which may extend its use as an analgesic agent. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 04/2014; 75(4). DOI:10.1002/ana.24122 · 9.98 Impact Factor
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    • "The mechanism involved is the inhibition of acetylcholine exocytosis through cleavage of synaptosome-associated protein (SNAP)-25, one of the SNRE proteins. A growing amount of evidence reveals that BTX-A also inhibits the release of selected neuropeptide transmitters such as SP and CGRP from trigeminal nerve ends and primary sensory neurons (27, 37) and from autonomic and enteric nervous terminals (28, 38). The exact mechanism of BTX-A-mediated inhibition of SP and CGRP release is unknown. "
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    ABSTRACT: Botulinum toxin type A (BTX-A) has been reported to be effective for the therapy for migraine. The purpose of this study was to investigate the effect of BTX-A on the immunoreactive levels of calcitonin gene-related peptide (CGRP) and substance P (SP) in the jugular plasma and medulla oblongata of migraine in rats induced by nitroglycerin (NTG), and then to evaluate and compare the effectiveness of fixed (muscle)-sites and acupoint-sites injection of BTX-A for migraine therapy of patients in a randomly controlled trial extending over four months. Rats with NTG-induced migraine were subcutaneously injected with vehicle or BTX-A (5 U/kg or 10 U/kg bodyweight). CGRP- and SP-like immunoreactivity (CGRP-LI and SP-LI) were determined by radioimmunoassay. In clinical trials, sixty patients respectively received BTX-A (2.5 U each site, 25 U per patient) at fixed-sites (group F, n = 30) including occipitofrontalis, corrugator supercili, temporalis and trapezius or at acupoint-sites (group A, n = 30) including EX-HN3, EX-HN5, GV20, GB8, GB20 and BL10. Local BTX-A injection suppressed NTG-induced CGRP-LI and SP-LI levels in jugular plasma and oblongata. BTX-A injection for both groups with migraine significantly reduced the attack frequency, intensity, duration and associated symptoms. The efficacy of BTX-A for migraine in group A (93% improvement) was more significant than that in group F (83% improvement) (P < 0.01). The evidence that BTX-A decreases NTG-induced CGRP-LI and SP-LI levels in trigeminovascular system suggests that BTX-A attenuates migraine by suppression of neuropeptide release. BTX-A injections for migraine at acupoint-sites and fixed-sites are effective. Acupoint-sites BTX-A administration shows more efficacy for migraine than fixed-sites application.
    10/2013; 15(10):e7704. DOI:10.5812/ircmj.7704
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    • "In another RCT, IA botulinum toxin had efficacy similar to IA corticosteroid [32]. Botulinum toxin is known to inhibit substance P and calcitonin-gene related protein [33-36], the main mediators of neurogenic inflammation, a phenomenon of vasodilatation, protein extravasation, and stimulation of inflammatory cells induced by antidromic stimulation of primary afferent fiber [37]. "
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    ABSTRACT: Osteoarthritis (OA), the most common type of arthritis in the world, is associated with suffering due to pain, productivity loss, decreased mobility and quality of life. Systemic therapies available for OA are mostly symptom modifying and have potential gastrointestinal, renal, hepatic, and cardiac side effects. BMC Musculoskeletal Disorders recently published a study showing evidence of reparative effects demonstrated by homing of intra-articularly injected autologous bone marrow stem cells in damaged cartilage in an animal model of OA, along with clinical and radiographic benefit. This finding adds to the growing literature showing the potential benefit of intra-articular (IA) bone marrow stem cells. Other emerging potential IA therapies include IL-1 receptor antagonists, conditioned autologous serum, botulinum toxin, and bone morphogenetic protein-7. For each of these therapies, trial data in humans have been published, but more studies are needed to establish that they are safe and effective. Several additional promising new OA treatments are on the horizon, but challenges remain to finding safe and effective local and systemic therapies for OA. Please see related article:
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