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dc.contributor.authorCastro, Joel
dc.contributor.authorHarrington, Ann Chrystine
dc.contributor.authorGarcia-Caraballo, Sonia
dc.contributor.authorMaddern, Jessica
dc.contributor.authorGrundy, Luke
dc.contributor.authorZhang, Jingming
dc.contributor.authorPage, Guy
dc.contributor.authorMiller, Paul E
dc.contributor.authorCraik, David J
dc.contributor.authorAdams, David J
dc.contributor.authorBrierley, Stuart M
dc.date.accessioned2017-06-09T03:38:11Z
dc.date.available2017-06-09T03:38:11Z
dc.date.issued2016-02-17
dc.identifier.citationCastro J, Harrington AM, Garcia-Caraballo S, et al α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors Gut 2017;66:1083-1094.en
dc.identifier.issn1468-3288
dc.identifier.urihttp://hdl.handle.net/2328/37282
dc.descriptionThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/en
dc.description.abstractObjective α-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown. Design We determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitative-reverse-transcription-PCR, single-cell-reverse-transcription-PCR and immunohistochemistry determined γ-aminobutyric acid receptor B (GABABR) and voltage-gated calcium channel (CaV2.2, CaV2.3) expression in human and mouse DRG neurons. Results Vc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABABR did not. Human DRG neurons expressed GABABR and its downstream effector channels CaV2.2 and CaV2.3. Mouse colonic DRG neurons exhibited high GABABR, CaV2.2 and CaV2.3 expression, with upregulation of the CaV2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABABR antagonist prevented Vc1.1-induced inhibition, whereas blocking both CaV2.2 and CaV2.3 caused inhibition comparable with Vc1.1 alone. Conclusions Vc1.1-mediated activation of GABABR is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABABR on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.en
dc.language.isoen
dc.publisherBMJ Publishing Groupen
dc.relationhttp://purl.org/au-research/grants/nhmrc/1049928en
dc.rightsPublished by the BMJ Publishing Group Limited.en
dc.subjectα-Conotoxin Vc1.1en
dc.subjectdisulfide-bonded peptideen
dc.subjectvenomen
dc.subjectmarine cone snailen
dc.subjectneuropathic pain,en
dc.subjectchronic visceral pain (CVP)en
dc.titleα-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptorsen
dc.typeArticleen
dc.relation.grantnumberNHMRC/1049928en
dc.identifier.doihttps://doi.org/10.1136/gutjnl-2015-310971en
dc.rights.holderThe authorsen
local.contributor.authorOrcidLookupBrierley, Stuart M: https://orcid.org/0000-0002-2527-2905en_US
local.contributor.authorOrcidLookupHarrington, Ann Chrystine: https://orcid.org/0000-0002-5074-2606en_US


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