Nonsteroid Anti-Inflammatory Drugs Inhibit Both the Activity and the Inflammation-Induced Expression of Acid-Sensing Ion Channels in Nociceptors

TLDR

NSAIDs are widely used anti‑inflammatory drugs that inhibit cyclooxygenases but may also target other mechanisms; in inflammatory conditions acidosis contributes to pain via acid‑sensing ion channels (ASICs) in nociceptors, and NSAID administration reduces low‑pH‑induced pain. This study examined whether NSAIDs affect ASIC expression and function in sensory neurons, specifically assessing ASIC mRNA distribution, inflammation‑induced up‑regulation, and direct current inhibition by aspirin, diclofenac, and flurbiprofen. The results demonstrate that NSAIDs block COX activity, prevent inflammation‑induced ASIC up‑regulation, and directly inhibit ASIC currents, underscoring their dual role in pain relief.

Abstract

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 Aβ 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.