Prolonged Analgesia by Spinal Cord Stimulation Following a Spinal Injury Associated With Activation of Adult Neural Progenitors

Abstract

Objectives: Responses of spinal progenitors to spinal cord stimulation (SCS) following spinal cord injury (SCI) in rats were assessed to reveal their potential contribution to SCS‐induced analgesia.

Methods: Spinal epidural electrodes were implanted in rats at T12 rostral to a quadrant dorsal horn injury at T13. Further groups additionally received either a microlesion to the dorsolateral funiculus (DLF) or gabapentin (10 mg/kg). SCS was performed at 25 Hz for 10 minutes on day 4 (early SCS) and at 10 Hz for 10 minutes on day 8 (late SCS) after injury. Paw withdrawal threshold (PWT) was measured before injury, 30 minutes before or after SCS, and before cull on day 14, followed by immunostaining assessment.

Results: Paw withdrawal thresholds in uninjured animals (51.0 ± 4.0 g) were markedly reduced after SCI (17.3 ± 2.2 g). This was significantly increased by early SCS (38.5 ± 5.2 g, P < 0.01) and further enhanced by late SCS (50.9 ± 1.9 g, P < 0.01) over 6 days. Numbers of neural progenitors expressing nestin, Sox2, and doublecortin (DCX) in the spinal dorsal horn were increased 6 days after SCS by 6‐fold, 2‐fold, and 2.5‐fold, respectively (P < 0.05 to 0.01). The elevated PWT evoked by SCS was abolished by DLF microlesions (48.9 ± 2.6 g vs. 19.0 ± 3.9 g, P < 0.01) and the number of nestin‐positive cells was reduced to the level without SCS (P < 0.05). Gabapentin enhanced late SCS‐induced analgesia from 37.0 ± 3.9 g to 54.0 ± 0.8 g (P < 0.01) and increased gamma‐aminobutyric acid (GABA)‐ergic neuronal marker vesicular GABA transporter–positive newborn cells 2‐fold (P < 0.01).

Conclusions: Spinal progenitor cells appear to be activated by SCS via descending pathways, which may be enhanced by gabapentin and potentially contributes to relief of SCI‐induced neuropathic pain.