Preventive Treatment With Ceftriaxone Attenuates Neuropathic Pain and Anxiety‐Like Behaviour in a Mouse Model of Partial Sciatic Nerve Ligation

BACKGROUND: Neuropathic pain is associated with anxiety-like disorders, suggesting shared neurobiological mechanisms. Glutamatergic dysregulation and impaired astrocytic glutamate uptake, particularly via the astrocytic transporter GLT-1, have been implicated in central sensitization and associated affective disorders. Ceftriaxone, a β-lactam antibiotic known to enhance GLT-1 expression, may represent a potential strategy to alleviate pain-related anxiety. METHODS: Neuropathic pain was induced in mice using partial sciatic nerve ligation (PSNL). Ceftriaxone (200 mg/kg/day) or saline was administered intraperitoneally. Mechanical allodynia and thermal hypersensitivity were assessed using the von Frey and Hargreaves tests. Anxiety-like behaviour was evaluated in the elevated plus maze and an open field. Central sensitization was examined through c-Fos expression in dorsal spinal cord sections. Microglial and astrocytic activation were analysed by immunohistochemistry, while GLT-1 expression was assessed by RT-qPCR and Western blot. RESULTS: Preventive ceftriaxone treatment reduces mechanical allodynia, thermal hypersensitivity and the development of anxiety-like behaviour following PSNL. In the elevated plus maze, ceftriaxone treatment prevented the increase in closed-arm exploration and resting time while preserving head-dipping behaviour. In the open field, ceftriaxone-receiving mice preserved centre exploration behaviour compared to saline-treated mice. These behavioural effects were accompanied by increased GLT-1 expression in the spinal cord that coincided with a reduced lesion-induced c-Fos expression and a decreased microglial and astrocytic activation. CONCLUSIONS: Ceftriaxone mitigates neuropathic pain and its associated anxiety-like phenotype through modulation of glutamatergic signalling, attenuation of central sensitization and reduction of glial reactivity. These findings support GLT-1 regulation as a promising therapeutic target in pain-related affective disorders. SIGNIFICANCE STATEMENT: Neuropathic pain is often associated with anxiety, but the underlying mechanisms remain unclear. Increasing evidence suggests that disrupted glutamatergic homeostasis contributes to both conditions. Here, we evaluated ceftriaxone, a β-lactam antibiotic that prevents the downregulation of the astrocytic glutamate transporter GLT-1, in a mouse model of neuropathic pain induced by partial sciatic nerve ligation. Ceftriaxone reduced both pain hypersensitivity and anxiety-like behaviour, supporting glutamate homeostasis as a promising therapeutic target.