Modulation of peripheral Na⁺ channels and neuronal firing by n-butyl-p-aminobenzoate

n-butyl-p-aminobenzoate (BAB), a local anesthetic, is administered epidurally in cancer patients to treat pain that is poorly controlled by other drugs that have a number of adverse effects. The purpose of the study was to unravel the mechanisms underlying the apparent selective pain suppressant effect of BAB. We used the whole-cell patch-clamp technique to record Na⁺ currents and action potentials (APs) in dissociated, nociceptive dorsal root ganglion (DRG) cells from rats, two types of peripheral sensory neuron Na ⁺ channels (Na_v1.7 and Na_v1.8), and the motor neuron-specific Na⁺ channel (Na_v1.6) expressed in HEK293 cells. BAB (1-100 μM) inhibited, in a concentration-dependent manner, the depolarization evoked repetitive firing in DRG cells, the three types of Na ⁺ current expressed in HEK293 cells, and the TTXr Na⁺ current of the DRG neurons. BAB induced a use-dependent block that caused a shift of the inactivation curve in the hyperpolarizing direction. BAB enhanced the onset of slow inactivation of Na_v1.7 and Na_v1.8 currents but not of Na_v1.6 currents. At clinically relevant concentrations (1-100 μM), BAB is thus a more potent inhibitor of peripheral TTX-sensitive TTXs, Na_v1.7 and TTX-resistant Na_V1.8 Na⁺ channels than of motor neuron axonal Na_v1.6 Na ⁺ channels. BAB had similar effects on the TTXr Na⁺ channels of rat DRG neurons and Na_v1.8 channels expressed in HEK293 cells. The observed selectivity of BAB in treating cancer pain may be due to an enhanced and selective responsiveness of Na⁺ channels in nociceptive neurons to this local anesthetic.