Ligustrazine Combined with Sinomenine Alleviates Central Sensitization in CCI-Induced Neuropathic Pain in Rats by Restoring Metabolic Homeostasis in the Spinal Dorsal Horn

Background: Neuropathic pain (NP) is a chronic pain condition caused by a lesion or disease of the somatosensory nervous system. Its development and persistence are closely associated with peripheral nociceptive input, central sensitization, neuroimmune dysregulation, and remodeling of the local metabolic microenvironment. Our previous studies demonstrated that combined treatment with ligustrazine and sinomenine ameliorates early sciatic nerve pathological damage and systemic metabolic disturbances in rats with chronic constriction injury (CCI). However, whether this combination modulates central sensitization in NP remains unclear. Objective: This study aimed to evaluate the effects of combined ligustrazine and sinomenine treatment on pain-related behaviors and motor function during the maintenance phase of CCI-induced neuropathic pain and to investigate the potential mechanisms underlying its attenuation of central sensitization, with particular emphasis on metabolic remodeling, neurotransmitter homeostasis, and associated regulatory molecules in the spinal dorsal horn. Methods: A rat model of CCI was established, and animals were treated with ligustrazine combined with sinomenine (12.5 + 12.5, 25 + 25, or 50 + 50 mg/kg) for 7 consecutive days. Mechanical withdrawal threshold, cold hypersensitivity, and gait behavior were assessed. A multiplex assay was used to profile 12 plasma inflammatory cytokines and pain-related mediators. Integrated transcriptomic and metabolomic analyses of the spinal dorsal horn were subsequently performed to identify key altered pathways. Oxylipin profiling, targeted neurotransmitter analysis, and quantification of metabolites associated with the arginine–polyamine pathway were further conducted to characterize alterations in the local metabolic microenvironment associated with central sensitization. Finally, quantitative real-time PCR (qRT-PCR) and Western blotting were used to evaluate molecules related to polyamine metabolism, redox homeostasis, and central sensitization. Results: Combined ligustrazine and sinomenine treatment improved pain-related behaviors and gait dysfunction in CCI rats and partially normalized systemic inflammatory dysregulation. The ipsilateral-to-contralateral maximum contact-area ratio decreased from 102.8 ± 9.0% in the Sham group to 53.1 ± 9.7% in the Model group and recovered to 85.5 ± 4.4% in the high-dose group. Metabolomic and transcriptomic analyses identified 54 differential metabolites and 130 differentially expressed genes, respectively, following treatment. Integrated multi-omics analysis highlighted arginine-related metabolic pathways, together with alterations in neurotransmitter, polyamine, oxylipin, and redox homeostasis.