Inhibition of acid‐sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain

• DOI: 10.1111/bph.14089
• Publication Date: 2017-11-14T07:06:37Z
• Authors: Jia Yu Peppermint...; Natalie J Saez; Ben Cristofori‐Ar...; Raveendra Anangi; Glenn F King; Maree T Smith; Lachlan D Rash
• Keywords: Male; 0301 basic medicine; 571; venom; Rats, Sprague-Dawley; Xenopus laevis; 03 medical and health sciences; Cnidarian Venoms; Animals; Hypoglycemic Agents; Freund's complete adjuvant; inflammatory pain; Pain Measurement; Inflammation; APETx2; peptide; diminazene; Rats; rats; Acid Sensing Ion Channels; Disease Models, Animal; 3004 Pharmacology; Acid Sensing Ion Channel Blockers; Hyperalgesia; Acid-sensing ion channel; Chronic Pain; Diminazene; mechanism of action

Background and PurposeAcid‐sensing ion channels (ASICs) are primary acid sensors in mammals, with the ASIC1b and ASIC3 subtypes being involved in peripheral nociception. The antiprotozoal drug diminazene is a moderately potent ASIC inhibitor, but its analgesic activity has not been assessed.Experimental ApproachWe determined the ASIC subtype selectivity of diminazene and the mechanism by which it inhibits ASICs using voltage‐clamp electrophysiology of Xenopus oocytes expressing ASICs 1–3. Its peripheral analgesic activity was then assessed relative to APETx2, an ASIC3 inhibitor, and morphine, in a Freund's complete adjuvant (FCA)‐induced rat model of inflammatory pain.Key ResultsDiminazene inhibited homomeric rat ASICs with IC50 values of ~200–800 nM, via an open channel and subtype‐dependent mechanism. In rats with FCA‐induced inflammatory pain in one hindpaw, diminazene and APETx2 evoked more potent peripheral antihyperalgesia than morphine, but the effect was partial for APETx2. APETx2 potentiated rat ASIC1b at concentrations 30‐fold to 100‐fold higher than the concentration inhibiting ASIC3, which may have implications for its use in in vivo experiments.Conclusions and ImplicationsDiminazene and APETx2 are moderately potent ASIC inhibitors, both inducing peripheral antihyperalgesia in a rat model of chronic inflammatory pain. APETx2 has a more complex ASIC pharmacology, which must be considered when it is used as a supposedly selective ASIC3 inhibitor in vivo. Our use of outbred rats revealed responders and non‐responders when ASIC inhibition was used to alleviate inflammatory pain, which is aligned with the concept of number‐needed‐to‐treat in human clinical studies.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc