Pain Chronicity in Lumbar Radiculopathy: From Mechanisms to Translation

Lumbar radiculopathy (LR) is a prevalent neuropathic pain condition primarily caused by mechanical compression or irritation of spinal nerve roots. Although decompression or conservative treatment resolves acute symptoms in most patients, a substantial subset develops persistent chronic pain. Authors screened studies from PubMed for a narrative synthesis of lumbar radiculopathy models and mechanisms of pain chronicity. Clinical evidence identifies prolonged symptom duration and nerve root compression in foraminal stenosis as major predictors of pain persistence and poor surgical outcomes. Together with experimental evidence that sustained nerve root compression compromises dorsal root ganglion (DRG) perfusion, these findings suggest an underrecognized mechanism of pain chronicity: compression-induced DRG ischemia, hypoxia, and microenvironmental acidosis. This narrative review proposes a novel translational framework in which LR chronification arises from a self-perpetuating interaction among mechanical injury, neuroinflammation, and a hypoxic–acidic microenvironment. Sustained compression impairs intraganglionic microcirculation, promoting hypoxia and acidosis. This environment enhances reactive oxygen species production and drives maladaptive remodeling of voltage-gated sodium, calcium, and potassium channels, proton-sensitive acid-sensing ion channels, and transient receptor potential channels, thereby promoting neuronal hyperexcitability and ectopic firing. Concurrent satellite glial cell activation and macrophage infiltration sustain inflammatory signaling and further amplify neuronal sensitization. Importantly, current animal models inadequately isolate DRG ischemia–reperfusion injury or reproduce the clinical sequence of nerve root compression followed by decompression. We therefore advocate clinically relevant models enabling precise temporal control of DRG compression, oxygenation, and reperfusion. Targeting the hypoxic-acidic cascade and downstream channelopathies may offer a promising strategy to prevent the transition from acute to chronic LR.