Chronic pain after spine surgery (CPSS) is a complex disorder that affects 8%–40% of patients following lumbar spine surgery. This condition was previously known as failed back surgery syndrome but is now recognized as CPSS, as it includes patients who experience intractable back pain or radiating leg pain despite successful surgery or the absence of postoperative neural compression. The pathogenesis of CPSS is multifactorial, involving structural factors (such as fibrosis, epidural scar, nerve root compression) and non-structural factors (including inflammation, glial cell activation, and sensitization of primary sensory neurons). However, there is limited understanding of the underlying mechanisms, partly due to the absence of clinically relevant animal models that simulate the progression of CPSS in humans.
In this study, researchers aimed to develop a rat model that closely mirrors the clinical conditions of CPSS. The model was based on two sequential surgical procedures. Step 1 involved inserting a plastic rod into the left L5 intervertebral foramen, applying steady compression to the dorsal root ganglion (DRG) and spinal nerve, which is a common cause of low back pain (LBP). This initial step created a prolonged LBP-like condition, leading to mechanical and heat hypersensitivity in the ipsilateral hindpaw. Step 2 occurred seven days later when the rod was removed, followed by a full L5 laminectomy to mimic decompression surgery in LBP patients. The rod-induced pain sensitivity quickly resolved after removal, but the laminectomy after rod removal triggered heightened mechanical and heat sensitivity, impaired gait, and reduced spontaneous exploration, all of which are characteristic of CPSS.
The rats that underwent both procedures showed persistent pain hypersensitivity, which was confirmed by behavioral assessments such as mechanical, heat, and cold sensitivity testing. A significant reduction in paw withdrawal thresholds (PWT) to mechanical stimuli and paw withdrawal latency (PWL) to radiant heat was observed in the ipsilateral hindpaw, indicating persistent pain. These behavioral changes were most pronounced during the first two weeks post-surgery. Additionally, the rats exhibited impaired locomotor function, such as abnormal gait, and reduced exploratory activity, both of which are commonly seen in CPSS patients.
At the cellular level, patch-clamp recordings revealed a significant increase in the intrinsic excitability of small-diameter DRG neurons in CPSS rats, further supporting the presence of a sensitized pain pathway. To evaluate potential therapeutic interventions, the researchers administered Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), a peripherally acting mu-opioid receptor (MOR)-preferred agonist. DALDA treatment significantly alleviated pain hypersensitivity, reduced the capsaicin-induced rise in intracellular calcium levels ([Ca2+]i), and restored the increased excitability of DRG neurons, suggesting that peripheral mu-opioid receptor activation can mitigate CPSS symptoms.
This newly developed rat model for CPSS mirrors many clinical features of the condition, such as persistent pain hypersensitivity, abnormal gait, and changes in neuronal excitability, offering valuable insights into its underlying mechanisms. It also provides a platform for evaluating new therapeutic strategies to address CPSS and other neuropathic pain conditions.