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The Journal of Neuroscience, April 15, 2009, 29(15):4981-4992; doi:10.1523/JNEUROSCI.5490-08.2009

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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

Correspondence should be addressed to J. Oliver Dolly, International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland. Email: oliver.dolly{at}dcu.ie

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 [Ca²⁺]_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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Received Nov. 13, 2008; revised Feb. 20, 2009; accepted March 3, 2009.

Correspondence should be addressed to J. Oliver Dolly, International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland. Email: oliver.dolly{at}dcu.ie

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