Ceftriaxone and clavulanic acid induce antiallodynia and anti-inflammatory effects in rats using the carrageenan model

Abstract

Introduction: Ceftriaxone (CFX) and clavulanic acid (CA) are 2 β-lactam molecules widely used as antibiotics. However, several reports of their antiallodynic properties have been published in recent years. Although this effect has been considered mostly due to a GLT1 overexpression, these molecules have also been proven to induce direct immunomodulation. In this work, we determine the acute analgesic effect of CFX and CA in an inflammatory pain model and assess if their administration may induce anti-inflammatory effects.

Methods: The carrageenan (Carr) test was used as an inflammatory pain model. Both mechanical and thermal responses were analyzed after CFX and CA administration at different times. A plethysmometer was used to determine inflammation. Also, TNF-α and IL-10 serum concentrations were determined by enzyme-linked immunosorbent assay.

Results: Both CFX and CA induced a significant thermal antiallodynic effect 3 and 24 h after administration. Furthermore, CA induced a mechanical antiallodynic effect 30, 60, and 90 min after administration. Moreover, a significant anti-inflammatory effect was found for both molecules 24 h after Carr injection. Also, both CA and CFX modulated TNF-α and IL-10 serum concentrations at different times.

Conclusion: Our results provide evidence that both CFX and CA cause an analgesic effect on a Carr inflammatory pain model and that said analgesic effect differs between each β-lactam molecule. Furthermore, this effect may be related to an anti-inflammatory effect of both molecules and a direct TNF-α and IL-10 serum concentration modulation.

Keywords: TNF-α concentration; analgesic effect; antiallodynic properties; ceftriaxone; clavulanic acid; inflammatory pain; β-lactam molecules.

Figure 1

Mechanical allodynia induced by Carr and the analgesic effect of drug administration. Notes: (A) Antiallodynic effect of DIC (10 mg/kg, IP) during 180 min; (B) antiallodynic effect of DIC (10 mg/kg, IP) at 0, 24, and 48 h; (C) antiallodynic effect of CFX (200 mg/kg, IP) during 180 min; (D) antiallodynic effect of CFX (200 mg/kg, IP) at 3, 24, and 48 h; (E) antiallodynic effect of CA (10 mg/kg, IP) during 180 min; (F) antiallodynic effect of CA (10 mg/kg, IP) at 3, 24, and 48 h. Values are the mean ± SEM of 8 rats per group. *p<0.05 vs Carr group (2 way ANOVA followed by a Dunnett post hoc test). Abbreviations: ANOVA, analysis of variance; CA, clavulanic acid; Carr, carrageenan; CFX, ceftriaxone; DIC, diclofenac; IP, intraperitoneal; PWT, paw withdrawal threshold; SEM, standard error of the mean.

Figure 2

Thermal allodynia induced by Carr and the antiallodynic effect of drug administration. Notes: (A) Antiallodynic effect of DIC (10 mg/kg, IP) at 3 and 24 h; (B) antiallodynic effect of CFX (200 mg/kg, IP) at 3 and 24 h; (C) antiallodynic effect of CA (10 mg/kg, IP) at 3 and 24 h. Values are the mean ± SEM of 8 rats per group. *p<0.05 vs Carr group (2 way ANOVA followed by a Dunnett post hoc test). Abbreviations: ANOVA, analysis of variance; CA, clavulanic acid; Carr, carrageenan; CFX, ceftriaxone; DIC, diclofenac; IP, intraperitoneal; PWL, paw withdrawal latency; SEM, standard error of the mean.

Figure 3

TPV and anti-inflammatory effects of drug administration: 0, 3, and 24 h after Carr administration. Notes: Values are the mean ± SEM of 8 rats per group. *p<0.05 vs Carr group at the corresponding time (2 way ANOVA followed by a Dunnett post hoc test). Abbreviations: ANOVA, analysis of variance; CA, clavulanic acid; Carr, carrageenan; CFX, ceftriaxone; DIC, diclofenac; IP, intraperitoneal; SEM, standard error of the mean; TPV, total paw volume.

Figure 4

Cytokine serum concentration. Notes: (A) TNF-α serum concentration at 3, 24, and 48 h after Carr intraplantar administration. (B) IL-10 serum concentration at 3, 24, and 48 h after Carr intraplantar administration. Values are the mean ± SEM of 4 rats per group. *p<0.05 vs Carr group at the corresponding time (2 way ANOVA followed by a Dunnett post hoc test). Abbreviations: ANOVA, analysis of variance; CA, clavulanic acid; Carr, carrageenan; CFX, ceftriaxone; DIC, diclofenac; IP, intraperitoneal; SEM, standard error of the mean.