Acid-Sensing Ion Channels (ASICs): New Targets for the Analgesic Effects of Non-Steroid Anti-Inflammatory Drugs (NSAIDs)

Abstract

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.

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…For decades, the entity or receptor that detects pH o changes surrounding neurons and its signal transduction pathway remained elusive. The recent finding that a fall of pH o activates a distinct class of cation channels, the acid-sensing ion channels (ASICs), in peripheral sensory neurons and in the neurons of the central nervous system, dramatically changed the view of acid signaling and offered new pharmacological targets for neurological diseases [7][8][9][10][11][12].…”

Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels

“…In sensory neurons, ASICs are implicated in nociception (Krishtal and Pidoplichko, 1981;Bevan and Yeats, 1991;Benson et al, 1999;McCleskey and Gold, 1999;Yiangou et al, 2001;Chen et al, 2002;Ugawa et al, 2002;Krishtal, 2003;Sluka et al, 2003;Voilley, 2004), mechanosensation (Corey and Garcia-Anoveros, 1996; Price et al, 2000Price et al, , 2001; Garcia-Anoveros et al, 2001), and taste transduction (Lindemann, 1996;Lin et al, 2002;Ugawa, 2003;Ugawa et al, 2003). In central neurons, ASICs are involved in synaptic plasticity, learning-memory (Wemmie et al, 2002), and fear conditioning , and in the pathology of neurological conditions such as seizures and brain ischemia (Biagini et al, 2001;Johnson et al, 2001).…”

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“…The acetic acid induced writhing response is a sensitive procedure to evaluate peripherally acting analgesics. The response is thought to be mediated by peritoneal mast cells 21 , acid sensing ion channels (Vogel and Vogel, 1997) and the prostaglandin pathways 22 . Preliminary phytochemical screening showed the presence of tanin, alkaloid and glycoside in the plant extract.…”