Mechanistic Insights Into Wnt/β‐Catenin Pathway Modulation in Chronic Low Back Pain and Anxiety‐ and Depression‐Related Behaviour in Male Sprague Dawley Rats

BACKGROUND: Chronic nonspecific low back pain (CNLBP) is a prevalent global health issue. Previous studies have demonstrated comorbidity between hyperalgesia and mood disorders in nerve growth factor (NGF)-induced CNLBP rat models. The Wnt/β-catenin signalling pathway plays a pivotal role in chronic pain pathogenesis by modulating glial cell activation and synaptic plasticity. However, the mechanism of this pathway underlying CNLBP and related emotional disorders remains unclear. METHODS: Mechanical and thermal hypersensitivity were measured via Von Frey and hot/cold plate tests, while anxiety-like and depression-like behaviours were evaluated through the elevated plus maze (EPM), open field (OFT), and forced swim tests (FST). Additionally, electrophysiology, immunofluorescence, and western blot were employed to investigate the underlying mechanisms in CNLBP model rats. Furthermore, the effects of intrathecal IWR-1 (a Wnt/β-catenin signalling pathway inhibitor) on CNLBP rats were examined. RESULTS: The Wnt/β-catenin signalling pathway was activated in NGF-CNLBP model rats. Three consecutive days of intrathecal IWR-1 administration significantly alleviated mechanical hyperalgesia (≥ 10 days), cold hyperalgesia (≥ 9 days), and heat hyperalgesia (≥ 4 days), while improving anxiety-like behaviours in CNLBP rats. IWR-1 reduced ACC pyramidal neuron excitability and excitatory transmission and suppressed glial activation in the spinal dorsal horn in CNLBP rats. Notably, IWR-1 selectively downregulated spinal NR1 (N-methyl-D-aspartate receptor subunit 1) protein expression level in CNLBP rats. CONCLUSIONS: Inhibiting spinal Wnt/β-catenin signal pathway attenuates CNLBP-related hyperalgesia and anxiety and modulates ACC neuronal excitability, glial activity, and NR1 expression. SIGNIFICANCE STATEMENT: Modulating the spinal Wnt/β-catenin signalling pathway may be pivotal for elucidating the mechanisms underlying hyperalgesia and anxiety-like behaviour in chronic nonspecific low back pain (CNLBP).