Effect of Ceftiofur on Hyperalgesia and Allodynia in a Rat Neuropathic Pain Model: The Role of Immune Processes

Abstract

Objective: Inflammatory and immune mechanisms play important roles in the pathogenesis of neuropathic pain. Ceftiofur, a third-generation cephalosporin, has anti-inflammatory effects by inhibiting tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor (NF)-κB, and mitogen-activated protein kinase (MAPK) signaling. This study aimed to investigate the effect of ceftiofur on hyperalgesia and allodynia in neuropathic rats and to define the possible contribution of immune mechanisms to this effect. Methods: A neuropathic pain model was performed by ligating the right sciatic nerve. Mechanic hyperalgesia and allodynia were measured using an analgesia meter and dynamic plantar esthesiometer, respectively. Following sciatic nerve ligation, ceftiofur was administered intraperitoneally (10 and 20 mg/kg/day) for 14 days. The control group received saline. Pain thresholds were recorded pre- and postoperatively on days 3, 7, 10, and 14. Protein was extracted from lumbar spinal cord tissue on day 14, and TNF-α, IL-1β, p65 NF-κB, p38 MAPK, and inducible nitric oxide synthase (iNOS) were evaluated by Western blotting. Results: Neuropathic rats showed decreased pain thresholds in analgesia meter and esthesiometer measurements. Ceftiofur 20 mg/kg/day significantly alleviated hyperalgesia, but not allodynia, and the increased iNOS and IL-1β expression was attenuated in neuropathic rats at both doses while decreasing p38 MAPK expression only at 20 mg/kg/day. TNF-α and p65 NF-κB expression remained unchanged 14 days after surgery. Conclusions: Ceftiofur has anti-inflammatory effects by decreasing iNOS, IL-1β, and p38 MAPK expression in lumbar spinal cord, and treatment of neuropathic rats with repeated doses of ceftiofur for 14 days results in antihyperalgesic effects.

Downregulation of iNOS, IL-1β, and P2X7 Expression in Mast Cells via Activation of PAR4 Contributes to the Inhibition of Visceral Hyperalgesia in Rats

“…Our results demonstrated that PAR4 activation decreased tryptase, IL-1 β , iNOS, and P2X7 at the protein and mRNA levels in association with the regulation of p38 and ERK1/2 phosphorylation. The suppression of these inflammatory mediators through regulation by MAPK signals after the PAR4-AP treatment of the BMMCs provided a molecular mechanism for the inhibition of visceral hypersensitivity [ 33 , 34 ]. However, additional evidence is needed, and related interesting questions, for example, questions concerning interactions or crosstalk with inflammatory mediators, are worthy of further investigation.…”