Amitriptyline and carbamazepine utilize voltage-gated ion channel suppression to impair excitability of sensory dorsal horn neurons in thin tissue slice: An in vitro study

• Distribution of voltage-gated Na+ and K+ channels in lamina I–III is provided.
• Effect of drugs used for the treatment of neuropathic pain is investigated.
• Mode of action of drugs in the central nervous system is proposed.
• The antinociceptive effects rely on the firing rate reduction of tonically-firing neurons.
• Amitriptyline and carbamazepine reduces the firing rate of adapting-firing neurones.

Amitriptyline, carbamazepine and gabapentin are often used for the treatment of neuropathic pain. However, their analgesic action on central sensory neurons is still not fully understood. Moreover, the expression pattern of their target ion channels is poorly elucidated in the dorsal horn of the spinal cord. Thus, we performed patch-clamp investigations in visualized neurons of lamina I–III of the spinal cord. The expression of the different voltage-gated ion channels, as the targets of these drugs, was detected by RT-PCR and immunohistochemistry. Neurons of the lamina I–III express the TTX-sensitive voltage-gated Na+ as well as voltage-gated K+ subunits assembling the fast inactivating (A-type) currents and the delayed rectifier K+ currents. Our pharmacological studies show that tonically-firing, adapting-firing and single spike neurons responded dose-dependently to amitriptyline and carbamazepine. The ion channel inhibition consecutively reduced the firing rate of tonically-firing and adapting-firing neurons. This study provides evidence for the distribution of voltage-gated Na+ and K+ subunits in lamina I–III of the spinal cord and for the action of drugs used for the treatment of neuropathic pain. Our work confirms that modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs.