Acid modulation of tetrodotoxin-resistant Na⁺ channels in rat nociceptive neurons

Under pathological conditions including inflammation, ischemia and incision, extracellular pH falls down as low as 5.4. Although some mediators play pivotal roles in the development and maintenance of inflammatory hyperalgesia by affecting the functional properties of tetrodotoxin-resistant (TTX-R) Na⁺channels, the roles of tissue acidosis in nociceptive transmission mediated by TTX-R Na⁺ channels are largely unknown. In the present study, we have investigated the effect of acidic pH on TTX-R Na⁺ currents (I_Na) in small-sized sensory neurons isolated from rat trigeminal ganglia using a whole-cell patch clamp technique. Acidic pH decreased the peak amplitude of TTX-R I_Na in a pH-dependent manner, but weak acid (≥pH 6.0) had a minor inhibitory effect on the TTX-R I_Na. Acidic pH also significantly shifted both the activation and steady-state fast inactivation relationships toward depolarized potentials. In addition, acidic pH had little effect on the use-dependent inhibition, and significantly retarded the development of inactivation and accelerated the recovery from inactivation of TTX-R Na⁺ channels. The results suggest that weak acid (≥pH 6.0) makes TTX-R Na⁺ channels to be suitable for the repetitive activation at depolarized membrane potentials. Given that both tissue acidosis and inflammatory mediators in inflamed or injured tissues act synergistically to promote nociceptive transmission by affecting the functional properties of TTX-R Na⁺ channels, these channels would be, at least in part, a good target to treat inflammatory pain.