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.