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

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory pain. It is well established that NSAIDs exert their analgesic effects by inhibiting cyclooxygenase to prevent the production of prostaglandins; however, several NSAIDs including diclofenac also modulate other ion channels expressed in nociceptive neurons. In this study, we investigated the pH-dependent effects of diclofenac on tetrodotoxin-resistant (TTX-R) Na(+) channels in rat trigeminal sensory neurons by using the whole-cell patch clamp technique. Diclofenac decreased the peak amplitude of TTX-R Na(+) currents (INa) in a concentration dependent manner. While diclofenac had little effect on the voltage-activation relationship, it significantly shifted the steady-state fast inactivation relationship toward hyperpolarized potentials. Diclofenac increased the extent of use-dependent inhibition of TTX-R Na(+) currents. Diclofenac also significantly accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na(+) channels. The effects of diclofenac on TTX-R Na(+) channels were stronger at pH 6.0 than at pH7.4 for most of the parameters tested. Considering that the extracellular pH falls in inflamed tissues, and that TTX-R Na(+) channels expressed on nociceptive neurons are implicated in the prostaglandin-mediated development and maintenance of inflammatory hyperalgesia, our findings could provide an additional analgesic effect of diclofenac under acidic pH conditions.