Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

Lv, Changcheng; Mao, Xia; Shu, Shu-Juan; Chen, Fei; Jiang, Lishan

doi:10.1159/000493144

Cited by 15 publications

(8 citation statements)

References 33 publications

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“…Heme oxygenase 1 and eNOS also have antioxidant activity (Sun et al, 2018). Pretreatment with BA decreases oxidative stress, effectively alleviating remifentanil-induced hyperalgesia (Lv et al, 2018). The IHC and Western blotting results demonstrated that SOD1, eNOS, and HO1 expression in the dermis of skin flaps was enhanced in the BA group.…”

Section: Discussionmentioning

confidence: 99%

Betulinic Acid Enhances the Viability of Random-Pattern Skin Flaps by Activating Autophagy

Bao

Alyafeai

et al. 2019

Front. Pharmacol.

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Random-pattern skin flap replantation is commonly used to repair skin defects during plastic and reconstructive surgery. However, flap necrosis due to ischemia and ischemia–reperfusion injury limits clinical applications. Betulinic acid, a plant-derived pentacyclic triterpene, may facilitate flap survival. In the present study, the effects of betulinic acid on flap survival and the underlying mechanisms were assessed. Fifty-four mice with a dorsal random flap model were randomly divided into the control, betulinic acid group, and the betulinic acid + 3-methyladenine group. These groups were treated with dimethyl sulfoxide, betulinic acid, and betulinic acid plus 3-methyladenine, respectively. Flap tissues were acquired on postoperative day 7 to assess angiogenesis, apoptosis, oxidative stress, and autophagy. Betulinic acid promoted survival of the skin flap area, reduced tissue edema, and enhanced the number of microvessels. It also enhanced angiogenesis, attenuated apoptosis, alleviated oxidative stress, and activated autophagy. However, its effects on flap viability and angiogenesis, apoptosis, and oxidative stress were reversed by the autophagy inhibitor 3-methyladenine. Our findings reveal that betulinic acid improves survival of random-pattern skin flaps by promoting angiogenesis, dampening apoptosis, and alleviating oxidative stress, which mediates activation of autophagy.

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Section: Discussionmentioning

confidence: 99%

Betulinic Acid Enhances the Viability of Random-Pattern Skin Flaps by Activating Autophagy

Bao

Alyafeai

et al. 2019

Front. Pharmacol.

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“…Hong et al 35 reported that spinal astrocyte activation and inflammatory reaction are involved in RIH. Lv et al 36 reported that the attenuation of RIH by betulinic acid was associated with a potential inhibition of oxidative stress and subsequent downregulation of IL-1β in the spinal dorsal horn. The current study showed that intraoperative infusion of remifentanil downregulated the nociceptive thresholds (PWT and PWL) at different time points (2, 6, 24, and 48 h) during the postoperative period ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Spinal NLRP3 inflammasome activation mediates IL-1β release and contributes to remifentanil-induced postoperative hyperalgesia by regulating NMDA receptor NR1 subunit phosphorylation and GLT-1 expression in rats

et al. 2022

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Background: Trafficking and activation of N-methyl-D-aspartate (NMDA) receptors play an important role in initiating and maintaining postoperative remifentanil-induced hyperalgesia (RIH). Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been linked to the development of inflammatory and neuropathic pain. We hypothesized that activation of NLRP3 inflammasome mediates IL-1β release and contributes to RIH in rats by increasing NMDA receptor NR1 (NR1) subunit phosphorylation and decreasing glutamate transporter-1 (GLT-1) expression. Methods: Acute exposure to remifentanil (1.2 μg/kg/min for 60 min) was used to establish RIH in rats. Thermal and mechanical hyperalgesia were tested at baseline (24 h before remifentanil infusion) and 2, 6, 24, and 48 h after remifentanil infusion. The levels of IL-1β, GLT-1, phosphorylated NR1 (phospho-NR1), and NLRP3 inflammasome activation indicators [NLRP3, Toll-like receptor 4 (TLR4), P2X purinoceptor 7 (P2X7R), and caspase-1] were measured after the last behavioral test. A selective IL-1β inhibitor (IL-1β inhibitor antagonist; IL-1ra) or three different selective NLRP3 inflammasome activation inhibitors [(+)-naloxone (a TLR4 inhibitor), A438079 (a P2X7R inhibitor), or ac-YVADcmk (a caspase-1 inhibitor)] were intrathecally administered immediately before remifentanil infusion into rats. Results: Remifentanil induced significant postoperative hyperalgesia, increased IL-1β and phospho-NR1 levels and activated the NLRP3 inflammasome by increasing TLR4, P2X7R, NLRP3, and caspase-1 expression, but it decreased GLT-1 expression in the L4-L6 spinal cord segments of rats, which was markedly improved by intrathecal administration of IL-1ra, (+)-naloxone, A438079, or ac-YVADcmk. Conclusion: NLRP3 inflammasome activation mediates IL-1β release and contributes to RIH in rats by inducing NMDA receptor NR1 subunit phosphorylation and decreasing GLT-1 expression. Inhibiting the activation of the NLRP3 inflammasome may be an effective treatment for RIH.

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“…A meta-analysis including 27 studies reported signi cant increases in acute pain after general anesthesia with remifentanil, leading to higher morphine requirements [16]. The roles of ROS and in ammation in OIH have attracted much attention [17]. It has been reported that remifentanil stimulates overproduction of proin ammatory cytokines and ROS, leading to the activation of neuronal NMDA receptors, which play an important role in OIH [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that remifentanil stimulates overproduction of proin ammatory cytokines and ROS, leading to the activation of neuronal NMDA receptors, which play an important role in OIH [18,19]. Also, excessive MMP-9 activity induced by remifentanil mediates extracellular matrix abnormalities, which can lead to a variety of neuropathological conditions including neuroin ammation and hyperalgesia [17,[20][21][22]. However, these effects have only been reported in animal studies.…”

Section: Discussionmentioning

confidence: 99%

The effect of opioid-free anesthesia on the quality of recovery after gynecological laparoscopy: study protocol for a prospective randomized controlled trial

Song

Choi

Chae

et al. 2021

Preprint

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Background: Because of the indiscriminate use of opioids during the perioperative period, opioid-free anesthesia (OFA) has been increasingly required. Nevertheless, the studies on the detailed techniques and effects of OFA are not sufficient. The Quality of Recovery-40 (QoR-40) questionnaire is a validated assessment tool for measuring recovery from general anesthesia. However, no study has used the QoR-40 to determine if OFA leads to better recovery than standard general anesthesia. Therefore, we aim to perform this study to determine the effects of OFA using dexmedetomidine and lidocaine on the quality of recovery as well as the various postoperative outcomes. Methods: The participants (n=78) will be allocated to one of the two groups; Study group will receive bolus and infusion of dexmedetomidine and lidocaine and Control group will receive remifentanil infusion during general anesthesia for gynecological laparoscopy. The other processes including anesthetic and postoperative care will be performed similarly in two groups. Intraoperative hemodynamic, anesthetic, and nociceptive variables will be recorded. Postoperative outcomes such as QoR-40, pain severity, opioid-related side effects will be assessed. Additionally, ancillary cytokine study (inflammatory cytokine, stress hormone, and reactive oxygen species) will be performed during study period. Discussion: This will be the first study to determine the effect of OFA, using the combination of dexmedetomidine and lidocaine, on the quality of recovery after gynecological laparoscopy compared with standard general anesthesia using remifentanil. The findings from this study will provide scientific and clinical evidence on the efficacy of OFA.Trial registration: ClinicalTrials.gov: NCT04409964. Registered on 28 May 2020.

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Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

Cited by 15 publications

References 33 publications

Betulinic Acid Enhances the Viability of Random-Pattern Skin Flaps by Activating Autophagy

Betulinic Acid Enhances the Viability of Random-Pattern Skin Flaps by Activating Autophagy

Spinal NLRP3 inflammasome activation mediates IL-1β release and contributes to remifentanil-induced postoperative hyperalgesia by regulating NMDA receptor NR1 subunit phosphorylation and GLT-1 expression in rats

The effect of opioid-free anesthesia on the quality of recovery after gynecological laparoscopy: study protocol for a prospective randomized controlled trial

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