Acid-sensing ion channels (ASICs): new targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs).

Non-steroid anti-inflammatory drugs (NSAIDs) are major drugs used in the treatment of inflammation and pain in a wide variety of disorders. NSAIDs constitute a diverse group of chemicals, categorized according to their chemical structures that share the same therapeutic properties. Among the main compounds are aspirin and salicylate, diclofenac and flurbiprofen. The best-known mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis secondary to their action on cyclooxygenases (COXs). However, data have been accumulating through the years indicating that NSAIDs also act on other targets to counteract pain. Their analgesic effects are not necessarily the consequence of their anti-inflammatory action. Administration of NSAIDs reduces cutaneous and corneal pain induced by acidic pH in the absence of inflammation. Tissue acidosis, which is a dominant factor in inflammation, tumors and ischemia, has an important contribution in pain and hyperalgesia. This is due to direct excitation of the nociceptive sensory neurons by protons-gated depolarizing currents. Actually, these neurons bear a major category of ion channels that are sensitive to extracellular pH changes, the acid-sensing ion channels (ASICs). ASIC channels are able to induce action potential triggering on sensory neurons after a moderate extracellular pH decrease. They undergo transcriptional induction and post-translational regulation during inflammation and thus participate in the hypersensitization of the nociceptive system in this physiopathological condition. One specific ASIC isoform is also thought to mediate cardiac ischemic pain. COX-independent direct inhibition of their activity by different NSAIDs has been shown to occur at therapeutic doses of these compounds, on native ASIC currents on sensory neurons, as well as on ASIC channels expressed in heterologous systems. Moreover, NSAIDs also prevent the large inflammation-induced increase of their expression. These two effects are thus proposed to play an important role in the analgesic effects of NSAIDs in addition to their well-known action through COXs, and particularly in case of inflammation.