Ceftriaxone suppresses the severity of paclitaxel-induced glutamate-mediated chronic pain in experimental animals.

Ceftriaxone has shown promise as a neuroprotective agent through its modulation of glutamate transporters, yet its precise role in chronic pain remains underexplored. This study aimed to investigate the central mechanisms underlying the transition to chronic pain, focusing on glutamatergic activity in the primary somatosensory cortex hind limb (S1HL) and posterior intralaminar thalamic nucleus (PIL) in a rat model. Female Wistar rats (n = 36) were randomly assigned to six groups. Neuropathic pain was induced using paclitaxel (2 mg/kg, administered intraperitoneally on days 0, 2, 4, and 6). Starting on day 27, animals received daily intraperitoneal treatment for 10 days with either ceftriaxone (200 mg/kg), penicillin (400,000 U/kg), clonidine (2.5 µg/kg), morphine (0.1 mg/kg), or saline (control). Ceftriaxone treatment significantly increased pain thresholds. Voltammetry analysis showed that glutamate reuptake time (T80) in the S1HL cortex, which was prolonged to approximately 8 s in the paclitaxel group, returned to near-normal values (3-3.5 s) with ceftriaxone. Gene expression analyses revealed that ceftriaxone upregulated all assessed glutamate transporters and enzymes, including GLT-1, GLAST, EAAC1, EAAT4, GluL, and GLS. Notably, GLT-1 expression increased ~ 5-fold in the control group and only ~ 2-fold in the paclitaxel group. These findings suggest that ceftriaxone enhances glutamate reuptake and reduces excitotoxicity in the cortex, contributing to pain relief. The study highlights a potential role for glutamate regulation in chronic pain mechanisms and supports further exploration of ceftriaxone as a candidate for managing glutamate-mediated neuropathic pain. This aligns with the broader goals of improving neurological health and promoting innovative therapeutic strategies.