Sodium channel expression and the molecular pathophysiology of pain after SCI

The chronic pain that develops as a result of spinal cord injury (SCI) is extremely debilitating and remains largely unmanageable by current therapeutic strategies. Voltage-gated sodium channels regulate the biophysical properties, and thus firing characteristics, of neurons. After SCI the repertoire of sodium channels produced by dorsal horn nociceptive neurons is altered, enabling neurons to fire at higher than normal rates in response to unchanged peripheral stimuli as well as to generate spontaneous discharges in the absence of stimuli, resulting in the genesis of neuropathic pain. Our results have shown increased expression of the Nav1.3 sodium channel in the spinal cord and thalamus. Nav1.3 upregulation allows dorsal horn neurons to generate ramp currents, enhanced persistent currents, and shifts in steady-state activation and inactivation. Further downstream, Nav1.3 causes increased spontaneous and evoked firing of neurons in the ventroposterior lateral (VPL) nucleus of the thalamus. Nav1.3 also underlies changes in burst firing properties of VPL neurons. The combination of spinal and thalamic generation and amplification of pain by Nav1.3 dysregulation contributes to post-SCI chronic pain. If proven to be similar in humans, targeting of this system after SCI may offer hope for treatment of clinical pain.