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Activation of TRPV1 Mediates Calcitonin Gene-Related Peptide Release, Which Excites Trigeminal Sensory Neurons and Is Attenuated

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Activation of TRPV1 Mediates Calcitonin Gene-Related Peptide Release, Which Excites Trigeminal Sensory Neurons and Is Attenuated The Journal of Neuroscience, April 15, 2009 • 29(15):4981–4992 • 4981 Neurobiology of Disease 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 Jianghui Meng,1 Saak V. Ovsepian,1 Jiafu Wang,1 Mark Pickering,2 Astrid Sasse,1 K. Roger Aoki,3 Gary W. Lawrence,1 and J. Oliver Dolly1 1International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland, 2Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland, and 3Allergan Inc., Irvine, California 92612 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 Mr 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 (HC) 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 2ϩ residues with /A but only on prolonged elevation of [Ca ]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. Introduction velopment of chronic neuroinflammation with associated sus- Management of chronic pain poses a major challenge for modern tained pain (Black, 2002). Such a mechanism appears to underlie healthcare, because sufferers represent ϳ20% of the adult popu- the hyper-reactivity of meningeal nociceptors in migraines at- lation (Breivik et al., 2006). The creation, referral, and sensation tributable to a disproportionate release of calcitonin gene-related of pain entail complicated and highly sophisticated processes peptide (CGRP) from the trigemino-cerebrovascular system. (Scholz and Woolf, 2007). The trigeminal nerve (Vth) innervates CGRP is the most abundant pain mediator in trigeminal ganglionic nociceptor-rich intracranial structures and transfers signals from neurons (TGNs), a major sensory relay center (Gulbenkian et al., the periphery through the afferents to the second-order sensory 2001; Durham et al., 2004). CGRP stimulates extravasation of in- neurons in the trigeminal nucleus caudalis (TNC). From there, flammatory mediators that cause intracranial hypersensitivity and the information is propagated to the ventroposterior thalamic throbbing migraine headache (Burstein et al., 2000; Bolay et al., nucleus and then cerebral cortex, in which ultimately the percep- 2002). Moreover, acute migraine headaches can often be alleviated tion of pain occurs (Roper and Brown, 2005). Under certain by CGRP receptor antagonists (e.g., BIBN4096) or serotonin ago- pathological conditions, the excessive release of certain neuro- nists (e.g., triptans), which lower CGRP release (Ferrari et al., 2001; modulators can cause sensitization of nociceptors, leading to de- Olesen et al., 2004); the reduction in pain is accompanied by nor- malization of CGRP levels in cranial venous outflow (Goadsby et al., Received Nov. 13, 2008; revised Feb. 20, 2009; accepted March 3, 2009. 1990; Goadsby and Edvinsson, 1993). Accordingly, intravenous in- This work was supported in part by a Research Professorship Award from Science Foundation Ireland (SFI) (to fusion of CGRP produces a migraine-like headache in susceptible J.O.D) and a Programme for Research in Third Level Institutions Cycle 4 grant from the Irish Higher Education Authorityfor“Target-driventherapeuticsandtheranostics.”Dr.KeithMurphy(UniversityCollegeDublin)isthanked volunteers (Olesen and Lipton, 2004). A pressing need for therapeu- for facilitating the Ca 2ϩ fluorescence measurements, supported by SFI Grant 03/IN3/B403C. We thank Rita Warde tics to treat chronic pain (Scholz and Woolf, 2007) is highlighted by for her preparation of this manuscript. the relatively short half-lives and numerous adverse side effects of Correspondence should be addressed to J. Oliver Dolly, International Centre for Neurotherapeutics, Dublin City pain killers commonly used in clinical practice (nonspecific analge- University, Glasnevin, Dublin 9, Ireland. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.5490-08.2009 sics/opioids and nonsteroidal anti-inflammatory drugs) (Ballantyne Copyright © 2009 Society for Neuroscience 0270-6474/09/294981-12$15.00/0 and Mao, 2003; Doods et al., 2007). 4982 • J. Neurosci., April 15, 2009 • 29(15):4981–4992 Meng et al. • Blockade of CGRP Release by a Chimeric Toxin Prevents Excitation of Sensory Neurons A promising therapeutic candidate has been unveiled by clin- kg) and perfused transcardially with 150 ml of PBS, pH 7.2, followed by a ical research showing a decrease in the frequency, duration, and fixative [150 ml 4% paraformaldehyde (PFA) in PBS]. The brainstem was intensity of migraine after administration of botulinum toxin A dissected, kept in 4% PFA overnight, and cryoprotected by 24 h (4°C) ␮ complex (BOTOX) (Binder et al., 2000). BOTOX offers the ad- incubation in 30% sucrose; coronal sections (50 m) were cut on a vantages of having a much longer action and greater potency in cryostat and collected free floating in PBS. After rinsing, the slices were placed in 4% horse serum (1 h) before permeabilization with 0.2% Triton blocking the release of transmitters and inflammatory/pain me- X-100 for 2 min. Rabbit antibodies to CGRP (1:2000) in 0.02% Triton diators via cleavage of SNAP-25, a 206-residue SNARE protein X-100 containing PBS were applied for 24 h before the samples were essential for neuroexocytosis (de Paiva et al., 1993). However, rinsed and incubated with cyanine 3-conjugated anti-rabbit secondary additional investigations are required to find a molecular basis antibody (1:500). The intensity of fluorescence staining was monitored for its beneficial effects in some migraineurs (Silberstein et al., every 2 h; after reaching a desirable intensity, slices were extensively 2000; Mauskop, 2002), which are not consistently observed (for washed with PBS, dried, and fixed with Vectashield. Microscopic images review, see Naumann et al., 2008). This raises the related and perti- were recorded as indicated above. ϩ ϩ nent question of why botulinum neurotoxin type A (BoNT/A) fails Measurements of Ca2 dynamics and 45Ca2 uptake into TGNs. Cov- to block CGRP release from TGNs evoked by a nociceptive C-fiber erslips containing TGNs were loaded with 3 ␮M Fluo-4 AM in basal stimulant, capsaicin, despite inhibiting this exocytosis when trig- release HEPES buffer saline [BR-HBS (in mM): 22.5 HEPES, pH 7.4, 3.5 ϩ KCl, 1 MgCl , 2.5 CaCl , 3.3 glucose, and 0.1% bovine serum albumin gered by K or bradykinin (Meng et al., 2007). 2 2 (BSA)] (Meng et al., 2007) at room temperature for 20 min and mounted It is shown herein that, in contrast to BoNT/A and /E, a novel on a custom-built low-volume (350 ␮l) chamber attached to an Axios- chimera (EA) of /A and /E serotypes inhibits CGRP release from kop 2 FS MOT/LSM Pascal confocal microscope (Zeiss). An argon laser TGNs and eliminates the excitatory effects of this peptide in was used to excite the fluorophore at 488 nm. Serial images of fluorescent brainstem sensory neurons evoked by capsaicin, which activates signals were grabbed every 10 s, whereas the superfusate was switched the transient receptor potential vanilloid receptor type 1 after ϳ2 min from BR-HBS to stimulation buffer containing either 60 ϩ (TRPV1). CGRP exocytosis elicited by this TRPV1 agonist was mM K or 1 ␮M capsaicin. The intensity of fluorescence at 505–530 nm found to require residues 180–197 of SNAP-25 but not the nine ( f) was analyzed offline on a cell-by-cell basis and expressed relative to Ϯ C-terminal amino acids removed by BoNT/A. Effective inhibi- the baseline fluorescence ( f0) measured for each cell in BR-HBS. Mean tion of this release by /EA seems to arise from a combination of SEM was plotted against time; n values are given in the figure legends. For assessment of Ca 2ϩ uptake, TGNs were incubated with 24 ␮Ci/ml binding to the sensory neurons via synaptic vesicle protein (SV2) 45 2ϩ Ca in BR-HBS containing 0.1% ethanol, l ␮M capsaicin, or 60 mM C isoform and the resultant internalized /E protease preventing ϩ K at room temperature for the times indicated in the figures before the formation of stable SNARE complexes. Such unique and mul- stopping the incubation by six washes in 1 ml of BR-HBS. The cells were tiple properties of EA indicate its anti-nociceptive potential with solubilized in 200 ␮l of 0.1% SDS and counted in Beckman Coulter CP implications for chronic pain therapy. scintillation spectrometer. Ca 2ϩ uptake was calculated from a standard curve of known amounts of 45Ca 2ϩ against counts per minute. Materials and Methods Expression and purification of recombinant proteins and glutathione Materials. Suppliers of cell culture materials and the various antibodies S-transferase pull-down assay.
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