Open AccessNS383 Selectively Inhibits Acid‐Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats
Author(s) -
Munro Gordon,
Christensen Jeppe K.,
Erichsen Helle K.,
Dyhring Tino,
Demnitz Joachim,
Dam Eva,
Ahring Philip K.
Publication year - 2016
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12487
Subject(s) - homomeric , acid sensing ion channel , neuropathic pain , pharmacology , amiloride , hyperalgesia , analgesic , chemistry , ion channel , patch clamp , sodium channel , morphine , receptor , medicine , nociception , protein subunit , biochemistry , sodium , organic chemistry , gene
Summary Aims Here, we investigate the pharmacology of NS 383, a novel small molecule inhibitor of acid‐sensing ion channels ( ASIC s). Methods ASIC inhibition by NS 383 was characterized in patch‐clamp electrophysiological studies. Analgesic properties were evaluated in four rat behavioral models of pain. Results NS 383 inhibited H + ‐activated currents recorded from rat homomeric ASIC 1a, ASIC 3, and heteromeric ASIC 1a+3 with IC 50 values ranging from 0.61 to 2.2 μ M. However, NS 383 was completely inactive at homomeric ASIC 2a. Heteromeric receptors containing AISC 2a, such as ASIC 1a+2a and ASIC 2a+3, were only partially inhibited, presumably as a result of stoichiometry‐dependent binding. NS 383 (10–60 mg/kg, i.p.), amiloride (50–200 mg/kg, i.p.), acetaminophen (100–400 mg/kg, i.p.), and morphine (3–10 mg/kg, i.p.) all dose‐dependently attenuated nocifensive behaviors in the rat formalin test, reversed pathological inflammatory hyperalgesia in complete Freund's adjuvant‐inflamed rats, and reversed mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain. However, in contrast to acetaminophen and morphine, motor function was unaffected by NS 383 at doses at least 8‐fold greater than those that were effective in pain models, whilst analgesic doses of amiloride were deemed to be toxic. Conclusions NS 383 is a potent and uniquely selective inhibitor of rat ASIC s containing 1a and/or 3 subunits. It is well tolerated and capable of reversing pathological painlike behaviors, presumably via peripheral actions, but possibly also via actions within central pain circuits.