Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-κB signalling pathway and inhibiting the activation of spinal microglia and astrocytes

Abstract

Abstract. The pain induced by local acute inflammation results in mild to severe discomfort, in addition to the possibility of physiological dysfunction and psychiatric disorders, such as sleep disorders and depression. However, the pathogenesis of pain is yet to be fully elucidated. In the present study, the effects of bupivacaine were explored in rat models inflammatory pain in order to investigate the anti-pain mechanism of bupivacaine. Complete Freund's adjuvant (CFA) was injected into the right rear foot of the rats to establish a model of transient inflammation-induced pain. Rats were randomly divided into four groups (n=8): CFA, CFA plus bupivacaine, CFA plus saline and untreated. The mechanical withdrawal threshold (MWT) of the rats was detected prior to and following CFA injection, and the results demonstrated that the MWT in the right rear foot significantly decreased from the 1st day of CFA injection (P<0.01; n=8), as compared with the untreated controls. Bupivacaine treatment was demonstrated to significantly increase the MWT of rats treated with CFA stimulation, as compared with the CFA group (P<0.01). Rotarod testing was performed to assess the motor activity of the rats, and the results demonstrated no significant differences among the four groups (P>0.05). Furthermore, the respective body weights of the rats were determined every two days before and after CFA injection, and no significant differences were detected among the four groups (P>0.05). Western blot analysis was performed to analyze expression levels of IκB and nuclear factor (NF)-κB, and the results demonstrated that bupivacaine increased the expression of IκB and decreased the expression levels of NF-κB, as compared with the rats with CFA-induced inflammatory responses, suggesting that bupivacaine inhibited NF-κB activation in the dorsal horn of the lumbar spinal cord of the model rats. Furthermore, reverse transcription-quantitative polymerase chain reaction analysis was performed to analyze the expression levels of inflammatory cytokines, which demonstrated that bupivacaine significantly inhibited the expression of TNF-α, IL-1β and IL-6, as compared with the untreated group (P<0.01). Moreover, bupivacaine treatment significantly decreased the expression of spinal microglial marker OX42 and astrocyte marker-glial fibrillary acidic protein, as compared with the rats in the CFA group (P<0.01). The present findings demonstrated that treatment with bupivacaine significantly decreased the activation of microglia and astrocytes in rat models of inflammatory pain. Therefore, the present results may provide clarification of the pathogenesis and mechanism of inflammation-induced pain and may provide novel therapeutic strategies for the clinical treatment of pain.

Elevation of the Chemokine Pair CXCL10/CXCR3 Initiates Sequential Glial Activation and Crosstalk During the Development of Bimodal Inflammatory Pain after Spinal Cord Ischemia Reperfusion

“…Among these cytokines, TNF-α and IL-6 are known to function as potent proinflammatory cytokines during the reperfusion period [6,27,28]. Consistent with our observation of bimodal allodynia induced during IR injury, two periods of robust TNF-α production were previously observed in an in vivo study [6].…”

Loss of Microglia and Impaired Brain-Neurotrophic Factor Signaling Pathway in a Comorbid Model of Chronic Pain and Depression

“…The NF-κB pathway is well known for its role in inflammation, the regulation of cell differentiation, and apoptosis. In the nervous system, the NF-κB-p65/p50 dimer is a prime inducer of pro-inflammatory genes ( 49 ). Sustained activation of NF-κB induces a cycle of microglial activation, that can result in brain parenchymal and neuronal damage.…”

“…No difference was observed in the other three groups. Notably, previous studies have shown that phosphorylation of IκBa is responsible for its dissociation from NF-κB, after which free IκBa is rapidly degraded ( 49 ). Herein, RT-qPCR and western blotting analysis found that IκBa mRNA and protein levels increased in the comorbidity group, suggesting the possibility that additional cellular events serve to activate NF-κB ( 52 ).…”

Anti-inflammatory effects induced by ultralow concentrations of bupivacaine in combination with ultralow concentrations of sildenafil (Viagra) and vitamin D3 on inflammatory reactive brain astrocytes

“…Bupivacaine, a local anesthetic, has been proposed to attenuate inflammatory responses at concentrations much lower than those that block Na + channels [16,17]. Bupivacaine decreases the expression of nuclear factor (NF)-қB and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) [18]. Bupivacaine treatment in rat models of inflammatory pain decreased the activation of microglia and astrocytes [18].…”

“…Bupivacaine decreases the expression of nuclear factor (NF)-қB and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) [18]. Bupivacaine treatment in rat models of inflammatory pain decreased the activation of microglia and astrocytes [18].…”