Novel Approaches to Understanding and Treating Spinal Cord Injury Neuropathic Pain

Neuropathic pain is among the most disabling sequelae of spinal cord injuries (SCIs), with prevalence estimated from 65-80%. Common pain descriptors include “sharp, burning, electrical, stabbing, pins-and-needles, squeezing, pressure” sensations. These pains are always perceived in body regions of partial or complete sensory loss from the SCI. Scientific understanding of these pain perceptions has been perplexing, particularly in individuals experiencing these pains in regions of the body of complete paralysis, who are otherwise unable to detect any painful stimulus–no matter how severe–to that paralyzed body region. Historically, failed attempts to treat this pain through spinal cord transection at the SCI site have led to the prevailing thought that changes to the brain’s pain-perceiving centers were the primary source of these pains.

Our work at the Falci Institute for Spinal Cord Injuries has shown that plasticity of second-order neurons in the dorsal root entry zone (DREZ)—where pain signals are normally processed—leads to spontaneous electrical hyperactivity, sending pain signals to brain pain centers, even without first receiving painful peripheral stimuli for processing. We have also learned that these hyperactive DREZs follow a novel somatotopic map of pain generation and body region perception, implicating the sympathetic nervous system as a route for transmission to the brain.

With detection and surgical ablation of these DREZs, we achieve 100% relief of pain in approximately 85% of patients suffering severe SCI neuropathic pain that has been refractory to all pharmacological management. Biopsy of this pain-causal DREZ tissue along with interspersed electrically “normal” non-pain-causal DREZ tissue, before ablation, has enabled comparative proteomic analyses that have revealed proteins that are associated with neuropathic pain. In our largest analysis to date (approximately 5,000 proteins analyzed for each comparative sample) we found that approximately 1% of the proteins showed more than a two-fold over-abundance in the pain causal tissue with statistical significance (FDR<0.05). We have established proof of principle for our drug target discovery platform with an ongoing Phase 3 clinical trial investigating a repurposed drug to one of our overly abundant proteins. While our analyses have focused on SCI neuropathic pain, we believe the insights from this work may inform therapies for neuropathic pain more broadly.