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ASIC3 blockade inhibits durovascular and nitric oxide-mediated trigeminal pain

Research output: Contribution to journalArticlepeer-review

Christopher Holton, Lauren Strother, Isaac Dripps, Amynah Pradhan, Peter James Goadsby, Philip Holland

Original languageEnglish
JournalBritish journal of pharmacology
Accepted/In press23 Dec 2019


King's Authors


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 nitric oxide that can trigger migraine attacks in patients, and 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 via APETx2 (i.v. 50 or 100 µgkg-1) was measured by using durovascular and nitric oxide-evoked trigeminal nociceptive responses and cortical spreading depression models. In mice, we sought to determine if periorbital mechanical sensitivity, induced by acute nitroglycerin (i.p. 10mgkg-1), was attenuated by APETx2 (i.p. 230µgkg-1), 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 nitric oxide-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 nitric oxide mediated attack triggering. This has key implications for migraine, given the major unmet need for novel therapeutic targets.

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