Insights into the effects of diclofenac and other non-steroidal anti-inflammatory agents on ion channels

Abstract

Objectives Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain. Most effects of NSAIDs are attributed to the inhibition of cyclooxygenases (COX). However, many NSAIDs may have other effects not related to COX, including the modulation of various ion channels. The clinical implications of the effects on channels are not fully understood. This review outlines the effects of NSAIDs, with special attention to diclofenac, on ion channels and highlights the possible underlying mechanisms. Key findings NSAIDs have effects on channels such as inhibition, activation or changes in expression patterns. The channels affected include voltage-gated Na + , Ca 2+ , or K + channels, ligand-gated K + channels, transient receptor potential and other cation channels as well as chloride channels in several types of cells. The mechanisms of drug actions not related to COX inhibition may involve drug-channel interactions, interference with the generation of second messengers, changes in channel expression, or synergistic/antagonist interactions with other channel modulators. Summary The effects on ion channels may account for novel therapeutic actions of NSAIDs or for adverse effects. Among the NSAIDs, diclofenac may serve as a template for developing new channel modulators and as a tool for investigating the actions of other drugs.

Inhibition of Kv channel expression by NSAIDs depolarizes membrane potential and inhibits cell migration by disrupting calpain signaling

“…[39]). Specifically, NSAIDs with ulcerogenic potential (indomethacin and NS-398), but not non-ulcerogenic NSAIDs (SC-560), decrease total and surface expression of K v 1.4 and surface expression of K v 1.6 in IEC-6 cell monolayers, and it was suggested that this loss of expression inhibited cell migration and caused depolarization of E m [18].…”

pH-dependent inhibition of tetrodotoxin-resistant Na+ channels by diclofenac in rat nociceptive neurons

“…It should be also noted that diclofenac can accumulate in inflamed tissues (Brune, 2007), and this drug is often applied topically on the skin at higher concentrations, especially in the inflamed area (Singh and Roberts, 1994). Diclofenac also inhibits ASICs to prevent the generation of acid-mediated action potentials at peripheral terminals (Gwanyanya et al, 2012;Voilley et al, 2001), and has side effects including cardiac toxicity because of its higher affinity to cardiac Na + channels (Fei et al, 2006). Thus, topical diclofenac could be useful for the treatment of inflammatory pain, such as ischemic myalgia and arthritis.…”

“…Diclofenac is known to modulate a number of ion channels including voltage-gated Na + , K + , and Ca 2+ channels (Gwanyanya et al, 2012). It inhibits both TTX-R and TTX-S Na + channels in dorsal root ganglion neurons (Lee et al, 2003), and other preparations (Acosta et al, 2007;Fei et al, 2006;Kuo et al, 2000;Yang and Kuo, 2005).…”

“…In addition, since the binding affinity of diclofenac for TTX-R Na + channels can be greatly elevated at acidic pH, the direct inhibition of TTX-R Na + channels would be, at least in part, responsible for the analgesic effects mediated by diclofenac at clinically relevant concentrations of acidic pH such as in inflamed tissues. In addition to TTX-R Na + channels, diclofenac also modulates other ion channels, which may be related to the generation and conduction of nociceptive transmission (Gwanyanya et al, 2012). For example, diclofenac inhibits TTX-S Na + channels with an EC 50 value of 14 μM in sensory neurons (Lee et al, 2003).…”

“…Therefore, nonsteroidal anti-inflammatory drugs (NSAIDs), which block COXs to prevent the production of PGs, are useful drugs for the treatment of inflammatory pain (Simmons et al, 2004). However, COX inhibition might not be the only mechanism for NSAID analgesia, as several NSAIDs modulate many ion channels in nociceptive neurons (for review, Gwanyanya et al, 2012). For example, aspirin and diclofenac are known to block ASICs expressed on peripheral nociceptive neurons (Voilley et al, 2001).…”