Mohammed, Z., Kaloyanova, K. and Nassar, M.A. (2020) An unbiased and efficient assessment of excitability of sensory neurons for analgesic drug discovery. PAIN, 161 (5). pp. 1100-1108. ISSN 0304-3959
Abstract
Alleviating chronic pain is challenging, due to lack of drugs that effectively inhibit nociceptors without off target effects on motor or central neurons. Dorsal root ganglia (DRG) contain nociceptive and non-nociceptive neurons. Drug screening on cultured DRG neurons, rather than cell lines, allows the identification of drugs most potent on nociceptors with no effects on non-nociceptors (as a proxy for unwanted side effects on CNS and motor neurons). However, screening using DRG neurons is currently a low-throughput process and there is a need for assays to speed this process for analgesic drug discovery. We previously showed that veratridine elicits distinct response profiles in sensory neurons. Here we show evidence that a veratridine-based calcium assay allows an unbiased and efficient assessment of a drug effect on nociceptors (targeted neurons) and non-nociceptors (non-targeted neurons). We confirmed the link between the oscillatory profile and nociceptors; and the slow-decay profile and non-nociceptors using three transgenic mouse lines of known pain phenotypes. We used the assay to show that blockers for Nav1.7 and Nav1.8 channels, which are validated targets for analgesics, affect non-nociceptors at concentrations needed to effectively inhibit nociceptors. However, a combination of low doses of both blockers had an additive effect on nociceptors without a significant effect on non-nociceptors, indicating that the assay can also be used to screen for combinations of existing or novel drugs for the greatest selective inhibition of nociceptors.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 International Association for the Study of Pain. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CC BY-NC-ND), https://creativecommons.org/licenses/by-nc-nd/4.0/, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
Keywords: | Calcium imaging; veratridine; voltage gated channel blockers; mouse knockout; nociceptors; mouse DRG; capsicin |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 17 Jan 2020 11:39 |
Last Modified: | 21 Oct 2021 10:53 |
Status: | Published |
Publisher: | Ovid Technologies (Wolters Kluwer Health) |
Refereed: | Yes |
Identification Number: | 10.1097/j.pain.0000000000001802 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:155755 |
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