Acid-sensing ion channel 3 blockade inhibits durovascular and nitric oxide-mediated trigeminal pain.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
21
04
2019
revised:
18
12
2019
accepted:
21
12
2019
pubmed:
25
1
2020
medline:
22
6
2021
entrez:
25
1
2020
Statut:
ppublish
Résumé
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. To investigate this, we utilised validated electrophysiological and behavioural rodent preclinical models. In rats, ASIC3 blockade using APETx2 (50 or 100 μg·kg 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. 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.
Sections du résumé
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
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.
Identifiants
pubmed: 31975427
doi: 10.1111/bph.14990
pmc: PMC7205795
doi:
Substances chimiques
Acid Sensing Ion Channels
0
Nitric Oxide
31C4KY9ESH
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2478-2486Subventions
Organisme : FP7 Ideas: European Research Council
ID : 602633
Pays : International
Organisme : Wellcome Trust
ID : 104033
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802760
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001253
Pays : United Kingdom
Organisme : Medical Research Council
ID : G108/638
Pays : United Kingdom
Organisme : Migraine Trust
Pays : International
Organisme : The Dunhill Medical Trust
ID : R605/0717
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S01165X/1
Pays : United Kingdom
Organisme : NIDA NIH HHS
ID : R01 DA040688
Pays : United States
Organisme : Medical Research Council
ID : MR/P006264/1
Pays : United Kingdom
Informations de copyright
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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