Nrf2 mediates the antinociceptive activity of dexmedetomidine in an acute inflammatory visceral pain rat model by activating the NF‐κB sensor

Abstract

Dexmedetomidine (DEX) is a highly selective α2 adrenoceptor agonist. In this study, we evaluated the antalgic effect of DEX on acetic acid-induced acute inflammatory visceral pain (AIVP) in rats. Additionally, we evaluated the role of Nrf2 signalling in antinociception. We administered acetic acid to male Sprague Dawley rats that were treated with DEX or saline. Twenty rats were randomly classified into the following groups: normal, model, vehicle, or DEX group. Both q-RT PCR and enzyme-linked immunosorbent assay data suggested that interleukin 1β (IL-1β), tumour necrosis factor α, and IL-6 were upregulated in the spinal cord. Western blotting and q-RT PCR analyses were performed to detect the protein and mRNA expression levels of Nrf2, Keap1, and HO-1 in the spinal cord. The DEX group exhibited a significant downregulation in Nrf2/Keap1/HO-1 signal activation compared with the model group.Furthermore, we used the Nrf2 -/knockout AIVP rat model to determine the role of Nrf2 in the antinociceptive effect of DEX. We observed that the Nrf2 knockout blocked the Keap1/Nrf2/HO-1 signal transduction and partially abated the antinociceptive and the anti-inflammatory effects of DEX. Moreover, our data also indicated that DEX treatment decreased the activation and expression of nuclear factor (NF)-κB. However, Nrf2 silencing restored the expression of NF-κB and its phosphorylated form to physiological levels. In summary, our results suggested that Nrf2 signalling plays an important role in the antinociceptive effect of DEX in the AIVP rat model and that Nrf2 exerts its function by enhancing the activation of the NF-κB sensor.Significance of the study: Currently, using the behavioural parameters is not adequate for the diagnosis of AIVP, and there are no studies that have investigated the role and the mechanism of DEX in ameliorating visceral pain. In this study, we demonstrated that acetic acid stimulation in rats induces AIVP. Additionally, the administration of DEX inhibited the acute inflammation response and decreased the visceromotor reaction (behavioural) to algesia. Further, DEX inhibited the Keap1/ Nrf2 pathway, which was activated by acetic acid treatment. We suggest that suppressing the inflammatory response could partially regulate the antinociceptive effect of DEX through Nrf2-mediated NF-κB activation associated with AIVP.

A Novel Opioid-Sparing Analgesia Following Thoracoscopic Surgery: A Non-Inferiority Trial

“… 13 Anti-nociceptive effects of DEX to blunt increased MAP and HR have been confirmed especially. 14 Animal studies have shown that dexmedetomidine can inhibit acute inflammatory visceral pain through NF-κB activation 15 and chronic inflammatory visceral pain through the HDAC2 pathway and MEK/ERK/CREB pathway, suppressing visceral hypersensitivity. 16 , 17 Thus, a clinical trial demonstrated that DEX ameliorated visceral pain after abdominal surgery in patients via a dose-dependent inhibitory on C-fibers and Aα-fibers.…”

Ferroptosis as a mechanism of neurodegeneration in Alzheimer's disease

“…Several studies demonstrated that dexmedetomidine activates the Nrf2 signalling pathway to protect against inflammation and oxidative stress (Feng et al, 2021; Lan et al, 2020; Li, Wang, et al, 2019; Yang et al, 2021). Dexmedetomidine was also found to be protective against ferroptosis, demonstrated by recent cell culture studies (Chen et al, 2021; Qiu et al, 2020).…”

Anti-nociceptive Effects of Dexmedetomidine Infusion Plus Modified Intercostal Nerve Block During Single-port Thoracoscopic Lobectomy: A Double-blind, Randomized Controlled Trial

“…Dex (16,17) decreased noradrenergic release from the preoptic area of the hypothalamus, and thereby, disinhibited galanergic or GABAergic inhibitory projections to primary arousal nuclei from the pons and midbrain. Animal studies have shown that the systemic administration of Dex exerts pronounced antinociception against acute inflammatory visceral pain (18,19) or colorectal distension-induced visceral pain (20), but no clinical data are available. This was the first study directly examining the responsiveness of this drug to chest-related visceral pain.…”