The Role of Potassium Channel Activation in Celecoxib-Induced Analgesic Action

BACKGROUND AND PURPOSE Celecoxib (CXB) is a widely prescribed COX-2 inhibitor used clinically to treat pain and inflammation. Recently, COX-2 independent mechanisms have been described to be the targets of CXB. For instance, ion channels such as the voltage-gated sodium channel, L-type calcium channel, Kv2.1, Kv1.5, Kv4.3 and HERG potassium channel were all reported to be inhibited by CXB. Our recent study revealed that CXB is a potent activator of Kv7/M channels. M currents expressed in dorsal root ganglia play an important role in nociception. Our study was aimed at establishing the role of COX-2 independent M current activation in the analgesic action of CXB. METHODS AND RESULTS We compared the effects of CXB and its two structural analogues, unmethylated CXB (UMC) and 2,5-dimethyl-CXB (DMC), on Kv7/M currents and pain behavior in animal models. UMC is a more potent inhibitor of COX-2 than CXB while DMC has no COX-2 inhibiting activity. We found that CXB, UMC and DMC concentration-dependently activated Kv7.2/7.3 channels expressed in HEK293 cells and the M-type current in dorsal root ganglia neurons, negatively shifted I-V curve of Kv7.2/7.3 channels, with a potency and efficiency inverse to their COX-2 inhibitory potential. Furthermore, CXB, UMC and DMC greatly reduced inflammatory pain behavior induced by bradykinin, mechanical pain behavior induced by stimulation with von Frey filaments and thermal pain behavior in the Hargreaves test. CXB and DMC also significantly attenuated hyperalgesia in chronic constriction injury neuropathic pain. CONCLUSION CXB, DMC and UMC are openers of Kv7/M K(+) channels with effects independent of COX-2 inhibition. The analgesic effects of CXBs on pain behaviors, especially those of DMC, suggest that activation of Kv7/M K(+) channels may play an important role in the analgesic action of CXB. This study strengthens the notion that Kv7/M K(+) channels are a potential target for pain treatment.