Diclofenac-eugenol modulation of Kv7 and TRPV1 ion channels

Abstract Pharmacological targeting of ion channels represents a crucial avenue for pain management. Among these, the Kv7 family of ion channels plays a significant role controlling neuronal excitability and the generation and propagation of pain-related nerve impulses, thus mitigating excessive electrical signaling and curtailing the exaggerated transmission of pain signals. Pain management strategies often involve a multimodal approach, combining various medications with distinct mechanisms of action to achieve optimal outcomes. Eugenol possesses a spectrum of biological activities, including analgesic and anti-inflammatory properties. When used in conjunction with the anti-inflammatory drug diclofenac, eugenol demonstrates enhanced analgesic efficacy in animal models. We investigated the effects of diclofenac and eugenol on Kv7 and TRPV1 ion channels, both agents act as Kv7 activators, whereas diclofenac inhibits the TRPV1 current, and eugenol reduce the capsaicin-activated current presumably competing for the same binding site. Eugenol shows a time dependent biphasic effect on acid-activated TRPV1 current, first activating and then a slow decay of the current. When eugenol and diclofenac are used together, they limit the extent of depolarization of cells expressing Kv7 and TRPV1. Our results shed light on the combined effectiveness of eugenol and diclofenac in the treatment of acute pain.