A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome : PAIN

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A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome

Cardoso, Fernanda C.a; Castro, Joelb,c; Grundy, Lukeb,c; Schober, Gudrunb,c; Garcia-Caraballo, Soniab,c; Zhao, Tianjiaoa; Herzig, Volkera,d; King, Glenn F.a; Brierley, Stuart M.b,c; Lewis, Richard J.a,*

Author Information

aCentre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia

bVisceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, South Australia, Australia

cHopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia

dSchool of Science and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia

*Corresponding author. Address. Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia. Tel.: +61 7 3346 2984; fax: +61 7 3346 210. E-mail address: [email protected] (R.J. Lewis).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

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PAIN 162(2):p 569-581, February 2021. | DOI: 10.1097/j.pain.0000000000002041

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.

© 2020 International Association for the Study of Pain

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