Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors.
Nonsteroid anti-inflammatory drugs (NSAIDs) are major drugs against inflammation and pain. They are well known inhibitors of cyclooxygenases (COXs). However, many studies indicate that they may also act on other targets. Acidosis is observed in inflammatory conditions such as chronic joint inflammation, in tumors and after ischemia, and greatly contributes to pain and hyperalgesia. Administration of NSAIDs reduces low-pH-induced pain. The acid sensitivity of nociceptors is associated with activation of H(+)-gated ion channels. Several of these, cloned recently, correspond to the acid-sensing ion channels (ASICs) and others to the vanilloid receptor family. This paper shows (1) that ASIC mRNAs are present in many small sensory neurons along with substance P and isolectin B4 and that, in case of inflammation, ASIC1a appears in some larger Abeta fibers, (2) that NSAIDs prevent the large increase of ASIC expression in sensory neurons induced by inflammation, and (3) that NSAIDs such as aspirin, diclofenac, and flurbiprofen directly inhibit ASIC currents on sensory neurons and when cloned ASICs are heterologously expressed. These results suggest that the combined capacity to block COXs and inhibit both inflammation-induced expression and activity of ASICs present in nociceptors is an important factor in the action of NSAIDs against pain.
Voilley
N
N
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité, Mixte de Recherche 6097, Sophia Antipolis, 06560 Valbonne, France.
de Weille
J
J
Mamet
J
J
Lazdunski
M
M
D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D019556:COS Cells; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006930:Hyperalgesia / Q000209:etiology; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D010146:Pain / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D014162:Transfection
C568266:ASIC1 protein, human; C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D000143:Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D037102:Lectins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013373:Substance P