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Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain
BACKGROUND AND PURPOSE: There is a major unmet need to develop new therapies for migraine. We have previously demonstrated the therapeutic potential of the acid‐sensing ion channel (ASIC) blockade in migraine, via an ASIC1 mechanism. ASIC3 is expressed in the trigeminal ganglion and its response is...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205795/ https://www.ncbi.nlm.nih.gov/pubmed/31975427 http://dx.doi.org/10.1111/bph.14990 |
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author | Holton, Christopher M. Strother, Lauren C. Dripps, Isaac Pradhan, Amynah A. Goadsby, Peter J. Holland, Philip R. |
author_facet | Holton, Christopher M. Strother, Lauren C. Dripps, Isaac Pradhan, Amynah A. Goadsby, Peter J. Holland, Philip R. |
author_sort | Holton, Christopher M. |
collection | PubMed |
description | BACKGROUND AND PURPOSE: There is a major unmet need to develop new therapies for migraine. We have previously demonstrated the therapeutic potential of the acid‐sensing ion channel (ASIC) blockade in migraine, via an ASIC1 mechanism. ASIC3 is expressed in the trigeminal ganglion and its response is potentiated by NO that can trigger migraine attacks in patients. Thus we sought to explore the potential therapeutic effect of ASIC3 blockade in migraine. EXPERIMENTAL APPROACH: To investigate this, we utilised validated electrophysiological and behavioural rodent preclinical models. In rats, ASIC3 blockade using APETx2 (50 or 100 μg·kg(−1), i.v.) was measured by using durovascular and NO‐evoked trigeminal nociceptive responses along with cortical spreading depression models. In mice, we sought to determine if periorbital mechanical sensitivity, induced by acute nitroglycerin (10 mg·kg(−1), i.p.), was attenuated by APETx2 (230 μg·kg(−1), i.p.), as well as latent sensitisation induced by bright light stress in a chronic nitroglycerin model. KEY RESULTS: Here, we show that the ASIC3 blocker APETx2 inhibits durovascular‐evoked and NO‐induced sensitisation of trigeminal nociceptive responses in rats. In agreement, acute and chronic periorbital mechanosensitivity induced in mice by nitroglycerin and subsequent bright light stress‐evoked latent sensitivity as a model of chronic migraine are all reversed by APETx2. CONCLUSION AND IMPLICATIONS: These results support the development of specific ASIC3 or combined ASIC1/3 blockers for migraine‐related pain and point to a potential role for ASIC‐dependent NO‐mediated attack triggering. This has key implications for migraine, given the major unmet need for novel therapeutic targets. |
format | Online Article Text |
id | pubmed-7205795 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-72057952020-05-11 Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain Holton, Christopher M. Strother, Lauren C. Dripps, Isaac Pradhan, Amynah A. Goadsby, Peter J. Holland, Philip R. Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: There is a major unmet need to develop new therapies for migraine. We have previously demonstrated the therapeutic potential of the acid‐sensing ion channel (ASIC) blockade in migraine, via an ASIC1 mechanism. ASIC3 is expressed in the trigeminal ganglion and its response is potentiated by NO that can trigger migraine attacks in patients. Thus we sought to explore the potential therapeutic effect of ASIC3 blockade in migraine. EXPERIMENTAL APPROACH: To investigate this, we utilised validated electrophysiological and behavioural rodent preclinical models. In rats, ASIC3 blockade using APETx2 (50 or 100 μg·kg(−1), i.v.) was measured by using durovascular and NO‐evoked trigeminal nociceptive responses along with cortical spreading depression models. In mice, we sought to determine if periorbital mechanical sensitivity, induced by acute nitroglycerin (10 mg·kg(−1), i.p.), was attenuated by APETx2 (230 μg·kg(−1), i.p.), as well as latent sensitisation induced by bright light stress in a chronic nitroglycerin model. KEY RESULTS: Here, we show that the ASIC3 blocker APETx2 inhibits durovascular‐evoked and NO‐induced sensitisation of trigeminal nociceptive responses in rats. In agreement, acute and chronic periorbital mechanosensitivity induced in mice by nitroglycerin and subsequent bright light stress‐evoked latent sensitivity as a model of chronic migraine are all reversed by APETx2. CONCLUSION AND IMPLICATIONS: These results support the development of specific ASIC3 or combined ASIC1/3 blockers for migraine‐related pain and point to a potential role for ASIC‐dependent NO‐mediated attack triggering. This has key implications for migraine, given the major unmet need for novel therapeutic targets. John Wiley and Sons Inc. 2020-03-02 2020-06 /pmc/articles/PMC7205795/ /pubmed/31975427 http://dx.doi.org/10.1111/bph.14990 Text en © 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Papers Holton, Christopher M. Strother, Lauren C. Dripps, Isaac Pradhan, Amynah A. Goadsby, Peter J. Holland, Philip R. Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
title | Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
title_full | Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
title_fullStr | Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
title_full_unstemmed | Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
title_short | Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
title_sort | acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205795/ https://www.ncbi.nlm.nih.gov/pubmed/31975427 http://dx.doi.org/10.1111/bph.14990 |
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