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 (Nav1.7 and Nav1.8), and the motor neuron-specific Na+ channel (Nav1.6) 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 Nav1.7 and Nav1.8 currents but not of Nav1.6 currents. At clinically relevant concentrations (1–100 μM), BAB is thus a more potent inhibitor of peripheral TTX-sensitive TTXs, Nav1.7 and TTX-resistant NaV1.8 Na+ channels than of motor neuron axonal Nav1.6 Na+ channels. BAB had similar effects on the TTXr Na+ channels of rat DRG neurons and Nav1.8 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.