Acid‐sensing ion channel 3 blockade inhibits durovascular and nitric oxide‐mediated trigeminal pain
Author(s) -
Holton Christopher M.,
Strother Lauren C.,
Dripps Isaac,
Pradhan Amynah A.,
Goadsby Peter J.,
Holland Philip R.
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14990
Subject(s) - acid sensing ion channel , migraine , cortical spreading depression , blockade , medicine , nociception , pharmacology , trigeminal ganglion , anesthesia , chronic migraine , electrophysiology , neuroscience , ion channel , receptor , psychology , sensory system
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.