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 inflamm ation and pain. They are well known inhibitors of cyclooxygenases (COXs). H owever, many studies indicate that they may also act on other targets. Acid osis is observed in inflammatory conditions such as chronic joint inflammat ion, in tumors and after ischemia, and greatly contributes to pain and hype ralgesia. Administration of NSAIDs reduces low-pH-induced pain. The acid se nsitivity of nociceptors is associated with activation of H+-gated ion chan nels. Several of these, cloned recently, correspond to the acid-sensing ion channels (ASICs) and others to the vanilloid receptor family. This paper s hows (1) that ASIC mRNAs are present in many small sensory neurons along wi th substance P and isolectin B4 and that, in case of inflammation, ASIC1a a ppears in some larger A beta fibers, (2) that NSAIDs prevent the large incr ease 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 a nd inhibit both inflammation-induced expression and activity of ASICs prese nt in nociceptors is an important factor in the action of NSAIDs against pa in.