title: Electrophysiological characterization of activation state-dependent Ca(v)2 channel antagonist TROX-1 in spinal nerve injured rats.
abstract: Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.
authors.affiliation: University College London, Gower Street, Department of Neuroscience, Physiology and Pharmacology, London WC1E 6BT, UK. Electronic address: ryan.patel.10@ucl.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rutten
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Valdor
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schiene
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wigge
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schunk
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Damann
authors.affiliation: Grünenthal GmbH, Global Preclinical Research, 52078 Aachen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Christoph
authors.affiliation: University College London, Gower Street, Department of Neuroscience, Physiology and Pharmacology, London WC1E 6BT, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000096:Acetone / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000473:pathology*; D006930:Hyperalgesia / Q000503:physiopathology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013127:Spinal Nerves / Q000473:pathology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: C551468:5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one; D002121:Calcium Channel Blockers; D007211:Indoles; D014230:Triazoles; D020960:omega-Conotoxins; D000096:Acetone; C078452:ziconotide
keywords: Ca(v)2.2; N-type calcium channel; dorsal horn; dorsal root ganglia; electrophysiology; spinal nerve ligation
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