Inhibition of Voltage-Gated Na+ Channels by Bupivacaine Is Enhanced by the Adjuvants Buprenorphine, Ketamine, and Clonidine

Background and objectives: Regional anesthesia includes application of local anesthetics (LAs) into the vicinity of peripheral nerves. Prolongation or improvement of nerve blocks with LAs can be accomplished by coapplication with adjuvants, including buprenorphine, ketamine, and clonidine. While the mechanisms mediating prolonged or improved LA-induced effects by adjuvants are poorly understood, we hypothesized that they are likely to increase LA-induced block of voltage-gated Na channels. In this study, we investigated the inhibitory effects of the LA bupivacaine alone and in combination with the adjuvants on neuronal Na channels.

Methods: Effects of bupivacaine, buprenorphine, ketamine, and clonidine on endogenous Na channels in ND7/23 neuroblastoma cells were investigated with whole-cell patch clamp.

Results: Bupivacaine, buprenorphine, ketamine, and clonidine are concentration- and state-dependent inhibitors of Na currents in ND7/23 cells. Tonic block of resting channels revealed an order of potency of bupivacaine (half-maximal inhibitory concentration [IC50] 178 ± 8 μM) > buprenorphine (IC50 172 ± 25) > clonidine (IC50 824 ± 55 μM) > ketamine (IC50 1377 ± 92 μM). Bupivacaine and buprenorphine, but not clonidine and ketamine, induced a strong use-dependent block at 10 Hz. Except for clonidine, all substances enhanced fast and slow inactivation. The combination of bupivacaine with one of the adjuvants resulted in a concentration-dependent potentiation bupivacaine-induced block.

Conclusions: We demonstrate that buprenorphine, ketamine, and clonidine directly inhibit Na channels and that they potentiate the blocking efficacy of bupivacaine on Na channels. These data indicate that block of Na channels may account for the additive effects of adjuvants used for regional anesthesia.