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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.
Pain. 2020 Aug 17 [Online ahead of print]PAIN

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.

Authors+Show Affiliations

Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia.Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, South Australia, Australia. Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia.Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, South Australia, Australia. Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia.Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, South Australia, Australia. Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia.Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, South Australia, Australia. Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia.Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia.Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia. School of Science and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia.Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia.Visceral Pain Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, South Australia, Australia. Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia, Australia.Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32826759

Citation

Cardoso, Fernanda C., et al. "A Spider-venom Peptide With Multitarget Activity On Sodium and Calcium Channels Alleviates Chronic Visceral Pain in a Model of Irritable Bowel Syndrome." Pain, 2020.
Cardoso FC, Castro J, Grundy L, et al. A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome. Pain. 2020.
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. (2020). A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome. Pain. https://doi.org/10.1097/j.pain.0000000000002041
Cardoso FC, et al. A Spider-venom Peptide With Multitarget Activity On Sodium and Calcium Channels Alleviates Chronic Visceral Pain in a Model of Irritable Bowel Syndrome. Pain. 2020 Aug 17; PubMed PMID: 32826759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome. AU - Cardoso,Fernanda C, AU - Castro,Joel, AU - Grundy,Luke, AU - Schober,Gudrun, AU - Garcia-Caraballo,Sonia, AU - Zhao,Tianjiao, AU - Herzig,Volker, AU - King,Glenn F, AU - Brierley,Stuart M, AU - Lewis,Richard J, Y1 - 2020/08/17/ PY - 2020/8/23/pubmed PY - 2020/8/23/medline PY - 2020/8/23/entrez JF - Pain JO - Pain N2 - 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. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/32826759/A_spider_venom_peptide_with_multitarget_activity_on_sodium_and_calcium_channels_alleviates_chronic_visceral_pain_in_a_model_of_irritable_bowel_syndrome_ L2 - https://doi.org/10.1097/j.pain.0000000000002041 DB - PRIME DP - Unbound Medicine ER -