ATF3-Expressing Large-Diameter Sensory Afferents at Acute Stage as Bio-Signatures of Persistent Pain Associated with Lumbar Radiculopathy

Abstract

The mechanism of pain chronicity is largely unknown in lumbar radiculopathy (LR). The anatomical location of nerve injury is one of the important factors associated with pain chronicity of LR. Accumulating evidence has shown constriction distal to the dorsal root ganglion (DRG) caused more severe radiculopathy than constriction proximal to the DRG; thereby, the mechanism of pain chronicity in LR could be revealed by comparing the differences in pathological changes of DRGs between nerve constriction distal and proximal to the DRG. Here, we used 2 rat models of LR with nerve constriction distal or proximal to the DRG to probe how the different nerve injury sites could differentially affect pain chronicity and the pathological changes of DRG neuron subpopulations. As expected, rats with nerve constriction distal to the DRG showed more persistent pain behaviors than those with nerve constriction proximal to the DRG in 50% paw withdraw threshold, weight-bearing test, and acetone test. One day after the operation, distal and proximal nerve constriction showed differential pathological changes of DRG. The ratios of activating transcription factor3 (ATF3)-positive DRG neurons were significantly higher in rats with nerve constriction distal to DRG than those with nerve constriction proximal to DRG. In subpopulation analysis, the ratios of ATF3-immunoreactivity (IR) in neurofilament heavy chain (NFH)-positive DRG neurons significantly increased in distal nerve constriction compared to proximal nerve constriction; although, both distal and proximal nerve constriction presented increased ratios of ATF3-IR in calcitonin gene-related peptide (CGRP)-positive DRG neurons. Moreover, the nerve constriction proximal to DRG caused more hypoxia than did that distal to DRG. Together, ATF3 expression in NHF-positive DRG neurons at the acute stage is a potential bio-signature of persistent pain in rat models of LR.