Nerve growth factor-mediated Na+ channel plasticity of bladder afferent neurons in mice with spinal cord injury

Abstract

Aim: To investigate the effect of nerve growth factor (NGF) neutralization on Na⁺ channel plasticity of bladder afferent neurons in mice with spinal cord injury (SCI).

Main methods: Female C57/BL6 mice were randomly divided into spinal intact (SI) group, SCI group and SCI + NGF-Ab group. SCI was induced by spinal cord transection at the Th8/9 level. In SCI + NGF-Ab group, anti-NGF antibodies (10 μg·kg-1 per hour) were continuously administered for 2 weeks using osmotic pumps. Bladder afferent neurons were labelled with Fluoro‑gold (FG) injected into the bladder wall. L6-S1 dorsal root ganglion (DRG) neurons were dissociated and whole-cell patch clamp recordings were performed on FG-labelled neurons. Expression of Nav1.7 and Nav1.8 was examined by immunofluorescent staining.

Key findings: Whole-cell patch clamp recordings showed that TTX only partially inhibited action potentials (AP) and Na⁺ currents of bladder afferent neurons in SI mice, but it almost completely inhibited them in SCI mice. Total and TTX-sensitive Na⁺ currents were increased and TTX-resistant currents were decreased in bladder afferent neurons from SCI mice vs. SI mice. These changes in SCI mice were significantly reversed by NGF-antibody treatment. Immunostaining results showed the increased and decreased levels of Nav1.7 and Nav1.8, respectively, in FG-labelled bladder afferent neurons in SCI mice vs. SI mice, which was significantly reversed in SCI + NGF-Ab mice.

Significance: NGF mediates the Na⁺ channel plasticity with a shift from TTX-resistant Nav1.8 to TTX-sensitive Nav1.7 in bladder afferent neurons, which could be a possible underlying mechanism of bladder afferent hyperexcitability and detrusor overactivity after SCI.

Keywords: Bladder afferent neuron; Dorsal root ganglia; Na(+) channel; Nerve growth factor; Spinal cord injury.