Effects of isoflurane on tetrodotoxin-resistant Na⁺ channels in rat nociceptive sensory neurons: Roles of concentration and extracellular pH

Isoflurane is widely employed to induce unconsciousness, amnesia, immobility, and analgesia in general anesthesia. Voltage-gated Na⁺ channels are one of the molecular targets for volatile anesthetics; however, knowledge regarding how isoflurane modulates native tetrodotoxin-resistant (TTX-R) Na⁺ channels remains limited. We investigated the effects of isoflurane on TTX-R Na⁺ channels in acutely isolated rat nociceptive sensory neurons using the whole-cell patch-clamp technique. Isoflurane displayed biphasic effects on the peak current but inhibited the persistent current mediated by TTX-R Na⁺ channels in a concentration-dependent manner. At clinically relevant concentrations, isoflurane shifted the voltage-inactivation relationship to hyperpolarizing range but had no effect on the extent of use-dependent inhibition of TTX-R Na⁺ channels. Isoflurane accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na⁺ channels in a concentration-dependent manner. However, the effects of isoflurane on TTX-R Na⁺ channels were dampened under acidic pH conditions. Under current-clamp conditions, isoflurane at clinically relevant concentrations decreased the rheobase current, which is the minimum current required to generate action potentials, and increased the number of action potentials elicited by threshold current stimuli. In contrast, isoflurane decreased the number of action potentials elicited by strong current stimuli. Provided that surgery under general anesthesia necessarily results in tissue injury and inflammation, which subsequently induces a decrease in extracellular pH in injured tissues, the present results suggest that isoflurane at lower concentrations is expected to increase the excitability of nociceptive sensory neurons in inflamed tissues or incision sites. This could be the pharmacological basis of postoperative hyperalgesia.