Spinal Actions of the NSAID Diclofenac on Nociceptive Transmission in Comparison to the K7 Channel Opener Flupirtine.

NSAIDs are the drugs most commonly used to alleviate pain. Despite being a heterogeneous group of compounds, all of them share a mechanism of action based on blockade of COXs enzymes, which confers them anti-inflammatory and analgesic properties. Diclofenac is a NSAID with preferred activity on COX-2 isozymes, but additionally, other targets may be implicated in its analgesic activity. Among them, diclofenac may facilitate the activity of K7 channels, that have been previously recognized as potential therapeutic targets in analgesia. In this study, the antinociceptive actions of diclofenac acting at the spinal level and the role of K7 channels in its effects were evaluated. Electrophysiological recordings of spinal reflexes and responses of dorsal horn neurons were obtained using in vitro spinal cord preparations from neonatal mice. Diclofenac, applied at clinically relevant concentrations to the entire preparation, depressed wind-up of spinal reflexes with a pattern similar to that of flupirtine, an analgesic with activity as K7 channel opener. Depressant actions of both compounds were strongly reduced after K7 channel blockade with XE-991, indicating the implication of these channels in the observed effects. Flupirtine, but not diclofenac, also reduced action potential firing of dorsal horn neurons in response to electrical activation of nociceptive afferents, suggesting differences in the actions of both compounds on K7 channel configurations present in sensory areas of the cord. Results demonstrate previously unknown central actions of diclofenac on K7 channels located in spinal circuits, expanding the knowledge about its pharmacological actions.