An unmet medical need for more effective therapies of neuropathic pain exits. Here modulation of the glutaminergic system represents an unexplored possibility. Down-regulation ofglutamate transporters potentiates pain transmission by delaying the removal of glutamate from the synapse. In the spinal cord, glutamate transporter 1 (GLT–1) is responsible for more than 90% of the glutamate uptake. Ceftriaxone, a β-lactam, is believed to induce the expression of GLT–1 through the transcriptional factor (NF-ºB) pathway, which results in induced promoter activity and thereby increased synthesis of GLT-1 protein.
To evaluate the analgesic effect of ceftriaxone in the Chronic Constriction Injury (CCI) rat model of neuropathic pain and to investigate the pharmacodynamics of ceftriaxone in a chronic dosing regime.
In CCI rats, mechanical and thermal hypersensitivity, were determined with von Frey filaments and Hargreaves test, respectively. Groups of rats received ceftriaxone (200, 300 or 400 mg/kg, i.p.) once daily in 7–19 days and the control groups received vehicle.
From a total of 24 CCI operated rats, 16 rats developed both mechanical (withdrawal threshold ≤3g) and thermal hypersensitivity (latency threshold ≤13 s.). Ceftriaxone alleviated mechanical allodynia and thermal hyperalgesia in CCI operated. Daily dosing of ceftriaxone 200, 300 and 400 mg/kg reached the same withdrawal threshold levels as before the CCI surgery, after 18, 12 and 7 days, respectively. This indicates that the dynamic effect of ceftriaxone is not only dependent of the dose, but also the duration of administration. Thus, it seems that dose exposure above a certain threshold is necessary to induce protein synthesis.
The CCI model is a useful model to evaluate the anti-nociceptive effects of ceftriaxone. Increased dose do not only elevate effect magnitude but also the rate of with which the effect appears.
© 2012 Scandinavian Association for the Study of Pain