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Type: Journal article
Title: A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome
Author: Cardoso, F.C.
Castro, J.
Grundy, L.
Schober, G.
Garcia-Caraballo, S.
Zhao, T.
Herzig, V.
King, G.F.
Brierley, S.M.
Lewis, R.J.
Citation: Pain, 2020; 162(2):569-581
Publisher: International Association for the Study of Pain
Issue Date: 2020
ISSN: 0304-3959
Statement of
Fernanda C. Cardoso, Joel Castro, Luke Grundy, Sonia Garcia-Caraballo, Tianjiao Zhao, Volker Herzig … et al.
Abstract: Chronic pain is a serious debilitating condition that affects ∼20% of the world's population. Currently available drugs fail to produce effective pain relief in many patients and have dose-limiting side effects. Several voltage-gated sodium (NaV) and calcium (CaV) channels are implicated in the etiology of chronic pain, particularly NaV1.1, NaV1.3, NaV1.7-NaV1.9, CaV2.2, and CaV3.2. Numerous NaV and CaV modulators have been described, but with few exceptions, they display poor potency and/or selectivity for pain-related channel subtypes. Here, we report the discovery and characterization of 2 novel tarantula-venom peptides (Tap1a and Tap2a) isolated from Theraphosa apophysis venom that modulate the activity of both NaV and CaV3 channels. Tap1a and Tap2a inhibited on-target NaV and CaV3 channels at nanomolar to micromolar concentrations and displayed moderate off-target selectivity for NaV1.6 and weak affinity for NaV1.4 and NaV1.5. The most potent inhibitor, Tap1a, nearly ablated neuronal mechanosensitivity in afferent fibers innervating the colon and the bladder, with in vivo intracolonic administration reversing colonic mechanical hypersensitivity in a mouse model of irritable bowel syndrome. These findings suggest that targeting a specific combination of NaV and CaV3 subtypes provides a novel route for treatment of chronic visceral pain.
Keywords: Animals
Irritable Bowel Syndrome
Calcium Channels
Spider Venoms
Pharmaceutical Preparations
Chronic Pain
Visceral Pain
NAV1.7 Voltage-Gated Sodium Channel
Rights: © 2020 International Association for the Study of Pain.
DOI: 10.1097/j.pain.0000000000002041
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