Immune-neural crosstalk in chronic low back pain: from intervertebral disc degeneration to pain sensitization.

Chronic low back pain (CLBP) is a leading cause of disability, yet radiographic degeneration correlates poorly with symptoms. This mini-review examines how immune-neural crosstalk may link intervertebral disc degeneration to pain initiation and persistence. Degenerated nucleus pulposus and annulus fibrosus cells develop inflammatory and catabolic phenotypes and release mediators that may promote neural and vascular ingrowth, sensitize nociceptors, and increase dorsal root ganglion neuron excitability. Sustained peripheral input may engage spinal glial pathways and contribute to central sensitization. Pain may persist through expectation, learning, affective processes, and altered central prediction even when peripheral inflammatory input is limited. These interactions are bidirectional: immune signaling may affect mood, cognition, sleep, and threat processing, whereas stress, pain-related beliefs, and social context may modify immune and neural responses through autonomic and neuroendocrine pathways. Vertebral endplate inflammation, sometimes reflected by Modic type I changes, may mark an immune-associated phenotype. Although mechanistic and preclinical evidence supports targets such as NGF and pro-inflammatory cytokines, clinical benefit has been inconsistent, potentially because of safety concerns, patient heterogeneity, insufficient target engagement, and trial-design limitations. We propose a systems framework integrating inflammatory biomarkers, endplate imaging, quantitative sensory testing, neuroimmune imaging, and contextual measures. This framework may help distinguish inflammation-dominant, peripherally sensitized, central-sensitization-associated, nociplastic (pain arising from altered nociception), and mixed profiles. Validation requires prospective longitudinal studies, biomarker-stratified cohorts, and adequately powered randomized controlled trials.