Remifentanil-induced Hyperalgesia Research Articles

Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia

BackgroundThe perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches. MethodWe established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1β and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes. ResultsProteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1β and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3. ConclusionRemifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.

Remifentanil-induced hyperalgesia: the current state of affairs.

Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3 mcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated.

Ciprofol alleviates remifentanil-induced hyperalgesia by regulating α2GABAARs, NR2B, and P-CaMKIIα levels in the spinal cord and hippocampus.

Several studies have shown that propofol administration during surgery effectively attenuates remifentanil-induced hyperalgesia (RIH). Ciprofol, a novel intravenous sedative agent analogous to propofol, has not yet been proven efficacious in alleviating RIH. The present study aimed to investigate the effect of ciprofol on RIH and the possible mechanisms involved. The RIH model was established by an infusion of remifentanil (1 μg·kg-1·min-1) 60min in rats with incisional pain. Ciprofol (0.1, 0.25, and 0.4 mg·kg-1·min-1) was simultaneously infused to evaluate its effect on RIH. The antinociception of ciprofol was verified by measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). γ-aminobutyric acid type A receptor α2 subunit (α2GABAAR), N-methyl-d-aspartate receptor NR2B subunit (NR2B), calcium/calmodulin-dependent protein kinase II α (CaMKIIα), and phosphorylated CaMKIIα (P-CaMKIIα) in the spinal cord and hippocampus of rats were assessed by western blotting and immunohistochemistry. The results showed that ciprofol dose-dependently increased PWMT and PWTL values in RIH rats. Moreover, ciprofol upregulated α2GABAAR and downregulated NR2B and P-CaMKIIα in the rat spinal cord and hippocampus. Ciprofol alleviates RIH effectively, and the anti-hyperalgesic mechanisms may involve increasing α2GABAAR levels and decreasing NR2B and P-CaMKIIα levels in the spinal cord and hippocampus.

Puerarin attenuates remifentanil‑induced postoperative hyperalgesia via targeting PAX6 to regulate the transcription of TRPV1.

Remifentanil‑induced hyperalgesia (RIH) is characterized by the emergence of stimulation‑induced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequence‑specific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at ‑24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitation‑PCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and p‑NR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dose‑dependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p‑)NR2B. Nevertheless, the increased amount of p‑NR2B by RIH was dose‑dependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.

The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor-CaMKII pathway.

Remifentanil-induced hyperalgesia (RIH) is a common clinical phenomenon that limits the use of opioids in pain management. Esketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to prevent and treat RIH. However, the underlying effect mechanism of esketamine on RIH remains unclear. This study aimed to investigate the role and mechanism of esketamine in preventing and treating RIH based on the NMDA receptor-CaMKIIα pathway. In this study, an experimental animal model was used to determine the therapeutic effect of esketamine on pain elimination. Moreover, the mRNA transcription and protein expression levels of CaMKII and GluN2B were investigated to offer evidence of the protective capability of esketamine in ameliorating RIH. The results demonstrated that esketamine attenuated RIH by inhibiting CaMKII phosphorylation and downstream signaling pathways mediated by the NMDA receptor. Furthermore, ketamine reversed the upregulation of spinal CaMKII induced by remifentanil. These findings suggest that the NMDA receptor-CaMKII pathway plays a critical role in the development of RIH, and ketamine's effect on this pathway may provide a new therapeutic approach for the prevention and treatment of RIH.

Microglial Nrf2/HO-1 signaling gates remifentanil-induced hyperalgesia via suppressing TRPV4-mediated M1 polarization

Remifentanil-induced hyperalgesia (RIH) represents a significant clinical challenge due to the widespread use of opioids in pain management. However, the molecular and cellular mechanisms underlying RIH remain elusive. This study aimed to unravel the role of spinal cord microglia, focusing on the Nrf2/HO-1 signaling pathway and TRPV4 channels in the development of RIH. We used both in vivo and in vitro models to investigate the activation state of spinal cord microglia, the expression of TRPV4 channels, and the modulation of the Nrf2/HO-1 pathway under remifentanil exposure. In addition, we evaluated the potential therapeutic effects of dexmedetomidine, a perioperative α2-adrenergic agonist, on RIH and its related molecular pathways. Our results revealed a prominent role of spinal cord microglia in RIH, demonstrating an apparent microglial M1 polarization and increased TRPV4 channel expression. A notable observation was the downregulation of the Nrf2/HO-1 pathway, which was associated with increased neuroinflammation and mechanical allodynia. By upregulating or overexpressing Nrf2, we confirmed its ability to inhibit TRPV4 and thereby attenuate RIH-associated mechanical allodynia, M1 polarization, and neuroinflammation. Encouragingly, dexmedetomidine demonstrated therapeutic potential by positively modulating the Nrf2-TRPV4 nexus, attenuating mechanical allodynia, and reducing microglial inflammation. Our research highlights the critical role of spinal cord microglia in RIH mediated by the Nrf2-TRPV4 axis. The ability of dexmedetomidine to modulate this axis suggests its potential as an adjunctive therapy to remifentanil in mitigating RIH. Further studies are imperative to explore the broader implications and practical applicability of our findings.

Remifentanil-induced hyperalgesia in healthy volunteers: a systematic review and meta-analysis of randomized controlled trials.

Recent literature suggests that the withdrawal of remifentanil (RF) infusion can be associated with hyperalgesia in clinical and nonclinical settings. We performed a systematic review and a meta-analysis of randomized controlled trials with cross-over design, to assess the effect of discontinuing RF infusion on pain intensity and areas of hyperalgesia and allodynia in healthy volunteers. Nine studies were included. The intervention treatment consisted in RF infusion that was compared with placebo (saline solution). The primary outcome was pain intensity assessment at 30 ± 15 minutes after RF or placebo discontinuation, assessed by any pain scale and using any quantitative sensory testing. Moreover, postwithdrawal pain scores were compared with baseline scores in each treatment. Secondary outcomes included the areas (% of basal values) of hyperalgesia and allodynia. Subjects during RF treatment reported higher pain scores after discontinuation than during treatment with placebo [standardized mean difference (SMD): 0.50, 95% confidence interval (CI): 0.03-0.97; P = 0.04, I 2 = 71%]. A significant decrease in pain scores, compared with baseline values, was found in the placebo treatment (SMD: -0.87, 95% CI: -1.61 to -0.13; P = 0.02, I 2 = 87%), but not in the RF treatment (SMD: -0.28, 95% CI: -1.18 to 0.62; P = 0.54, I 2 = 91%). The area of hyperalgesia was larger after RF withdrawal (SMD: 0.55; 95% CI: 0.27-0.84; P = 0.001; I 2 = 0%). The area of allodynia did not vary between treatments. These findings suggest that the withdrawal of RF induces a mild but nonclinically relevant degree of hyperalgesia in HVs, likely linked to a reduced pain threshold.

Efficacy and safety of flurbiprofen‑axetil combined with nalbuphine pretreatment on remifentanil‑induced postoperative hyperalgesia: A randomized clinical trial.

Remifentanil-induced hyperalgesia (RIH) is a common and complicated issue in patients undergoing laparoscopic cholecystectomy (LC), which significantly reduces patient satisfaction. The present trial was designed to clarify the individual and combined effects of flurbiprofen-axetil and nalbuphine on remifentanil-induced hyperalgesia. This randomized double-blind clinical trial included 120 adult patients who underwent LC at The Second People's Hospital of Wuhu. The individuals were randomized into a flurbiprofen-axetil group (F group), nalbuphine group (N group), flurbiprofen-axetil combined with nalbuphine group (FN group) and saline group (S group). The four groups were given flurbiprofen-axetil (50 mg, iv.), nalbuphine (0.1 mg/kg, iv.), flurbiprofen-axetil (50 mg, iv.) combined with nalbuphine (0.1 mg/kg, iv.) or normal saline respectively prior to skin incision. The primary outcome was the postoperative mechanical pain thresholds at the inner forearm and peri-incisional area. The secondary outcomes were the visual analog scale (VAS) and Ramsay sedation scale at 0.5, 1, 4 and 24 h after surgery, and any other adverse events. The pain threshold of the medial forearm in the FN group did not differ from that in the F and N groups at 24 h after surgery (P=0.310 and P=0.910, respectively). However, the pain threshold around the incision in FN group was significantly lower than that in F and N groups 24 h after surgery (P=0.001). The VAS of the F group, N group and FN group were all significantly lower than that in the S group at 0.5, 1 and 24 h after surgery (P<0.001). No significant differences were observed in the incidence of adverse events between the four groups. Single flurbiprofen-axetil and single nalbuphine effectively prevented RIH 24 h after surgery in LC. The combination of the two analgesic drugs, with different mechanisms of action, was not superior to single therapy. The present study was registered with the Chinese Clinical Trial Registry (registration no. ChiCTR2100045347).

Antisense oligodeoxynucleotides against dynamin-related protein 1 reduce remifentanil-induced hyperalgesia by modulating spinal N-methyl-D-aspartate receptor expression in rats.

Spinal N-methyl-D-aspartate (NMDA) receptor activation is attributed to remifentanil-induced hyperalgesia (RIH). However, the specific mechanism and subsequent treatment is still unknown. Previous studies have shown that the dynamin-related protein 1 (DRP1)-mitochondria-reactive oxygen species (ROS) pathway plays an important role in neuropathic pain. This study examined whether antisense oligodeoxynucleotides against DRP1 (AS-DRP1) could reverse RIH. The authors first measured changes in paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) at 24 hours before remifentanil infusion and 4, 8, 24, and 48 hours after infusion. The expression levels of DRP1 and NR2B were measured after behavioral testing using Western blotting. In addition, DRP1 expression was knocked down by intrathecal administration of AS-DRP1 to investigate the effects of DRP1 on RIH. The behavioral testing, the expression levels of spinal DRP1 and NR2B, and dorsal mitochondrial superoxide were measured. Changes in mitochondrial morphology were assessed using electron microscopy. After remifentanil exposure, upregulation of spinal DRP1 and NR2B was observed along with a reduction in PWMT and PWTL. In addition, AS-DRP1 improved RIH-induced PWTL and PWMT (P < 0.001 and P < 0.001) and reduced remifentanil-mediated enhancement of spinal DRP1 and NR2B expression (P = 0.020 and P = 0.022). More importantly, AS-DRP1 reversed RIH-induced mitochondrial fission (P = 0.020) and mitochondrial superoxide upregulation (P = 0.031). These results indicate that AS-DRP1 could modulate NMDA receptor expression to prevent RIH through the DRP1-mitochondria-ROS pathway.

Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial.

Several factors may lead to increased postoperative pain sensitivity, of which remifentanil-induced hyperalgesia (RIH) is one of the main factors. High-dose remifentanil exposure during anesthesia may induce RIH. Esketamine may prevent RIH by antagonizing N-methyl-D-aspartate (NMDA) receptors, thereby reducing the postoperative pain sensitivity. This study examined the effects of different esketamine doses on pain sensitivity in patients undergoing thyroidectomy and determined the optimal dose. This study included 117 patients who received elective thyroidectomy. They were randomized into four groups: saline group (group C), esketamine 0.2mg·kg-1 group (group RK1), esketamine 0.4mg·kg-1 group (group RK2), and esketamine 0.6mg·kg-1 group (group RK3). Five minutes before anesthesia induction, the same volume of study drugs were injected respectively in groups C, RK1, RK2, and RK3. Remifentanil was pumped at the same rate of 0.3µg·kg-1·min-1 during surgery to ensure uniformity. This study's primary outcomes were the mechanical pain thresholds measured before surgery, as well as at 30min, 6h, 24h, and 48h after surgery. Hyperalgesia, rescue analgesia, numerical rating scale (NRS) score, and adverse reactions were recorded. Compared with baseline, the mechanical pain threshold was significantly decreased in group C [(94.67 ± 22.85) versus (112.00 ± 36.62) versus (161.33 ± 53.28) g, P < 0.001 at 30min, P < 0.001 at 6h] and group RK1 [(102.86 ± 24.17) versus (114.29 ± 41.05) versus (160.00 ± 54.98) g, P < 0.001 at 30min, P < 0.001 at 6h] around the surgical incision, and in group C [(112.00 ± 31.78) versus (170.67 ± 56.26) g, P < 0.001 at 30min, (118.67 ± 34.42) versus (170.67 ± 56.26) g, P = 0.001 at 6h] and group RK1 [(114.29 ± 45.17) versus (175.71 ± 54.80) g, P = 0.001 at 30min, (121.43 ± 38.46) versus (175.71 ± 54.80) g, P = 0.002 at 6h] on the forearm at 30min and 6h after surgery; compared with group C, the mechanical pain threshold was higher in group RK2 [(142.76 ± 50.06) versus (94.67 ± 22.85) g, P < 0.001 at 30min, (145.52 ± 49.83) versus (112.00 ± 36.62) g, P < 0.001 at 6h] and group RK3 [(140.00 ± 40.68) versus (94.67 ± 22.85) g, P < 0.001 at 30min, (150.67 ± 56.50) versus (112.00 ± 36.62) g, P = 0.010 at 6h] around the surgical incision, and in group RK2 [(149.66 ± 39.50) versus (112.00 ± 31.78) g, P = 0.006 at 30min, (156.55 ± 47.23) versus (118.67 ± 34.42) g, P = 0.005 at 6h] and group RK3 [(145.33 ± 51.18) versus (112.00 ± 31.78) g, P = 0.018 at 30min, (154.67 ± 47.54) versus (118.67 ± 34.42) g, P = 0.008 at 6h] on the forearm at 30min and 6h after surgery. Group RK3 had more glandular secretions than the other three groups (P = 0.042). Intravenous injection of esketamine 0.4mg·kg-1 before anesthesia induction is a suitable dose to reduce pain sensitivity in patients undergoing thyroidectomy without increasing adverse reactions. However, future research needs to be extended to other populations. Registered at the Chinese Clinical Trials Registry http://www.chictr.org.cn/ (09/06/2022, ChiCTR-2200060741).

Blocking SphK/S1P/S1PR1 axis signaling pathway alleviates remifentanil-induced hyperalgesia in rats

Recent research shows a correlation between altered sphingolipid metabolism and nociceptive processing. Activation of the sphingosine-1-phosphate receptor 1 subtype (S1PR1) by its ligand, sphingosine-1-phosphate (S1P), causes neuropathic pain. However, its role in remifentanil-induced hyperalgesia (RIH) has not been investigated. The purpose of this research was to establish if the SphK/S1P/S1PR1 axis mediated remifentanil-induced hyperalgesia and identify its potential targets. This study examined the protein expression of ceramide, sphingosine kinases (SphK), S1P, and S1PR1 in the spinal cord of rats treated with remifentanil (1.0 μg/kg/min for 60 min). Prior to receiving remifentanil, rats were injected with SK-1 (a SphK inhibitor); LT1002 (a S1P monoclonal antibody); CYM‐5442, FTY720, and TASP0277308（the S1PR1 antagonists); CYM-5478 (a S1PR2 agonist); CAY10444 (a S1PR3 antagonist); Ac-YVAD-CMK (a caspase-1 antagonist); MCC950 (the NOD-like receptor protein 3 (NLRP3) inflammasome antagonist); and N-tert-Butyl-α-phenylnitrone (PBN, a reactive oxygen species (ROS) scavenger). Mechanical and thermal hyperalgesia were evaluated at baseline (24 h prior to remifentanil infusion) and 2, 6, 12, and 24 h following remifentanil administration. The expression of the NLRP3-related protein (NLRP3, caspase-1), pro-inflammatory cytokines (interleukin-1β(IL-1β), IL-18), and ROS was found in the spinal dorsal horns. In the meantime, immunofluorescence was used to ascertain if S1PR1 co-localizes with astrocytes. Remifentanil infusion induced considerable hyperalgesia in addition to increased ceramide, SphK, S1P, and S1PR1, NLRP3-related protein (NLRP3, Caspase-1, IL-1β, IL-18) and ROS expression, and S1PR1 localized astrocytes. By blocking the SphK/S1P/S1PR1 axis, remifentanil-induced hyperalgesia was reduced, as was the expression of NLRP3, caspase-1, pro-inflammatory cytokines (IL-1β, IL-18) and ROS in the spinal cord. In addition, we observed that suppressing NLRP3 or ROS signal attenuated the mechanical and thermal hyperalgesia induced by remifentanil. Our findings indicate that the SphK/SIP/S1PR1 axis regulates the expression of NLRP3, Caspase-1, IL-1β, IL-18 and ROS in the spinal dorsal horn to mediate remifentanil-induced hyperalgesia. These findings may contribute to pain and SphK/S1P/S1PR1 axis research positively, and inform the future study of this commonly used analgesic.

Spinal microRNA-134-5p targets glutamate receptor ionotropic kainate 3 to modulate opioid induced hyperalgesia in mice.

Background: Fentanyl and its analogs are extensively used for pain relief. However, their paradoxically pronociceptive effects often lead to increased opioids consumption and risk of chronic pain. Compared to other synthetic opioids, remifentanil has been strongly linked to acute opioid hyperalgesia after exposure [remifentanil-induced hyperalgesia (RIH)]. The epigenetic regulation of microRNAs (miRNAs) on targeted mRNAs has emerged as an important pathogenesis in pain. The current research aimed at exploring the significance and contributions of miR-134-5p to the development of RIH. Methods: Both the antinociceptive and pronociceptive effects of two commonly used opioids were assessed, and miRNA expression profiles in the spinal dorsal horn (SDH) of mice acutely exposed to remifentanil and remifentanil equianalgesic dose (RED) sufentanil were screened. Next, the candidate miRNA level, cellular distribution, and function were examined by qPCR, fluorescent in situ hybridization (FISH) and Argonaute-2 immunoprecipitation. Furthermore, bioinformatics analysis, luciferase assays, miRNA overexpression, behavioral tests, golgi staining, electron microscopy, whole-cell patch-clamp recording, and immunoblotting were employed to investigate the potential targets and mechanisms underlying RIH. Results: Remifentanil induced significant pronociceptive effects and a distinct miRNA-profile from sufentanil when compared to saline controls. Among top 30 differentially expressed miRNAs spectrum, spinal miR-134-5p was dramatically downregulated in RIH mice but remained comparative in mice subjected to sufentanil. Moreover, Glutamate Receptor Ionotropic Kainate 3 (Grik3) was a target of miR-134-5p. The overexpression of miR-134-5p attenuated the hyperalgesic phenotype, excessive dendritic spine remodeling, excitatory synaptic structural plasticity, and Kainate receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in SDH resulting from remifentanil exposure. Besides, intrathecal injection of selective KA-R antagonist was able to reverse the GRIK3 membrane trafficking and relieved RIH. Conclusion: The miR-134-5p contributes to remifentanil-induced pronociceptive features via directly targeting Grik3 to modulate dendritic spine morphology and synaptic plasticity in spinal neurons.

Nalmefene vs. dexmedetomidine for prevention of postoperative hyperalgesia in patients undergoing laparoscopic gynecological surgery with remifentanil infusion: A randomized double-blind controlled trial.

Intraoperative remifentanil infusion may paradoxically induce post-surgical hyperalgesia. Dexmedetomidine reportedly reduces opioid-induced hyperalgesia. Nalmefene selectively reverses several side-effects of opioids without impairing analgesia. Herein, this randomized, double-blind controlled trial investigated whether nalmefene, dexmedetomidine, and both drugs combined prevent remifentanil-induced hyperalgesia. One hundred and fifty patients undergoing elective laparoscopic gynecological surgery under desflurane anesthesia randomly received either intraoperative sufentanil 0.20μgkg-1 (Group S), or remifentanil 0.20μgkg-1min-1 (Group R), or remifentanil and pre-anesthesia nalmefene 0.20μgkg-1 (Group N), or remifentanil and pre-anesthesia dexmedetomidine 0.50μgkg-1 (Group D), or remifentanil and the combination of dexmedetomidine 0.25μgkg-1 and nalmefene 0.10μgkg-1 (Group DN). The threshold of postoperative mechanical hyperalgesia (primary outcome) was measured with von Frey filaments. We also recorded pain intensity, analgesic consumptions, hyperalgesic area, and side-effects for 24h postoperatively. Compared with Group S, remifentanil reduced hyperalgesic threshold on the forearm [mean 89.4 (SD 13.7) vs. 62.2 (10.7) g, p < 0.001] at postoperative 24h. Pain threshold on the forearm at postoperative 24h was significantly lower in Group R than in Groups N, D and DN [62.2 (10.7) vs. 71.1 (12.3), 72.4 (12.9) and 78.0 (13.8)g]. Compared with Group R, Postoperative pain intensity, analgesic consumption and hyperalgesic area were lower likewise in Groups D and DN. However, the incidence of intraoperative bradycardia was lower and post-anesthesia recovery time was shorter in Group DN than Group D. Preoperative therapy of dexmedetomidine and nalmefene combined attenuates postoperative hyperalgesia in patients undergoing laparoscopic gynecological surgery under desflurane-remifentanil anesthesia.

Efficacy of Dexmedetomidine vs. Remifentanil for Postoperative Analgesia and Opioid-Related Side Effects after Gynecological Laparoscopy: A Prospective Randomized Controlled Trial.

Remifentanil is widely used for intraoperative analgesia, but often causes remifentanil-induced hyperalgesia (RIH) and related side effects. Dexmedetomidine, a non-opioid analgesic, has been used as an alternative to remifentanil to prevent RIH. We aimed to investigate the effect of dexmedetomidine on postoperative recovery after gynecological laparoscopy. Ninety-six adult patients undergoing elective gynecological laparoscopy were randomly assigned to the dexmedetomidine or remifentanil groups. The primary outcome was the pain score at 30 min after surgery. The secondary outcomes were intraoperative adverse events (hypotension and bradycardia) and postoperative opioid-related side effects (nausea, vomiting, requirement for rescue analgesics, and shivering). We also performed an ancillary cytokine study to evaluate oxidative stress, one of the causes of RIH. Compared with the remifentanil group, the dexmedetomidine group had lower pain scores at 30 min after surgery (4.0 ± 1.9 vs. 6.1 ± 2.0, mean ± SD, p < 0.001) and lower incidence of intraoperative hypotension and postoperative nausea, vomiting, and shivering. Furthermore, the proportion of patients requiring rescue analgesics was significantly lower in the dexmedetomidine than in the remifentanil group (25% vs. 66.7%, p < 0.001). Cytokine levels did not differ between the groups. Dexmedetomidine showed a better analgesic effect with minimal opioid-related side effects and is considered superior to remifentanil for intraoperative analgesia.

Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel-mediated neural circuit basis for RIH that can guide analgesic development.

Opioid-induced hyperalgesia: Are thalamic T-type calcium channels treatment targets?

Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.

Comparison of pregabalin with magnesium sulfate in the prevention of remifentanil-induced hyperalgesia in patients undergoing rhinoplasty: A randomized clinical trial.

ObjectiveRemifentanil is usually used for controlled hypotension during rhinoplasty under general anesthesia (G/A). One of the complications of the remifentanil is postoperative hyperalgesia. In this study, we compare the effectiveness of pregabalin with that of Mg sulfate in postoperative remifentanil‐induced hyperalgesia prevention.MethodsIn this prospective, randomized, double‐blinded placebo‐controlled trial, 105 patients who candidates rhinoplasty with G/A were enrolled and randomly allocated into three groups. Patients in group A received 300 mg pregabalin before anesthesia. They received physiologic saline infusion during the perioperative period. Those in group B received placebo capsules before anesthesia and intravenous Mg sulfate 30 mg/kg during the perioperative period. Those in group C received a placebo capsule before anesthesia and normal intravenous saline during the operation. Then, pain severity, sedation score, postoperative nausea and vomiting (PONV) were assessed and compared.ResultsIn the Mg sulfate and placebo group, the mean numerical rating scale in the postoperative period was higher compared to the pregabalin group (p < .001). The mean total amount of morphine requirement, meanwhile the 24 h post‐operation, was significantly decreased in the pregabalin group compared to the other groups (p < .001). Participants in the pregabalin group had less PONV compared to those in the pregabalin and placebo groups (p = .015).ConclusionsIn patients undergoing G/A with remifentanil for rhinoplasty, preoperative 300 mg pregabalin could effectively prevent not only remifentanil‐induced hyperalgesia but also PONV.Level of evidence1b.

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.

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. Acute exposure to remifentanil (1.2μg/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. 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. 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.

KCC2 receptor upregulation potentiates antinociceptive effect of GABAAR agonist on remifentanil-induced hyperalgesia.

GABAergic system disinhibition played an important role in the pathogenesis of remifentanil-induced hyperalgesia (RIH). K+-Cl--cotransporter-2 (KCC2) has the potential to enhance the strength of GABAergic signaling function. However, few reports have focused on the additive analgesic effect of KCC2 enhancer and GABAA receptor agonist on the spinal dorsal horn. Therefore, we evaluated the role of GABA type A receptor (GABAAR) agonist (muscimol), KCC2 enhancer (CLP257) in remifentanil-induced hyperalgesia, as well as GABA and KCC2 receptors responses in the dorsal spinal horn. Remifentanil started to reduce paw withdrawal mechanical thresholds at postoperative 4 h and lasted to 72 h. The RIH associated decreases in spinal GABA release was transient. The amount of spinal GABA transmitter by microdialysis was observed to be decreased at the beginning and reached bottom at 150 min, then returned to the baseline level at 330 min. The synthesis and transportation of GABA transmitter were inhibited, characterized as spinal GAD67 and GAT1 downregulation after the establishment of RIH model. The effect of RIH on GABA receptor downregulation was linked to the reduced expression of spinal KCC2 receptor. This decrease in KCC2 expression has coincided with an early loss of GABA inhibition. KCC2 enhancer, which is reported to lead to a reduction in intracellular Cl−, can enhance GABA-mediated inhibitory function. Both muscimol and CLP257 could dose-dependently inhibit mechanical hypersensitivity caused by remifentanil-induced downregulation of GABAAα2R and KCC2, respectively. Compared with muscimol acting alone, the joint action of CLP257 and muscimol showed a higher pain threshold and less c-fos expression via upregulation of KCC2 and GABAAα2R. Taken together, these findings suggested that the RIH was initiated by decreased GABA release. Downregulation of GABAAα2R and KCC2 receptor contributed to spinally mediated hyperalgesia in RIH. KCC2 enhancer was proved to potentiate antinociceptive effect of GABAAR agonist in RIH.

Artesunate Reduces Remifentanil-induced Hyperalgesia and Peroxiredoxin-3 Hyperacetylation via Modulating Spinal Metabotropic Glutamate Receptor 5 in Rats

The experimental investigations on the pathogenesis of remifentanil-induced hyperalgesia (RIH) have been primarily conducted, but the effective treatment of RIH remains unclear. Recent reports highlight the necessity of ionotropic glutamate receptors in oxidative damage in spinal nociceptive transduction. Artesunate, the 1st-line anti-malaria drug, has been identified to be valid in removing superoxide in several pathological conditions. This study evaluated whether artesunate inhibits RIH via regulating metabotropic glutamate receptor 5 (mGluR5) and mitochondrial antioxidant enzyme peroxiredoxin-3 in rats. Artesunate was injected intrathecally 10 min before intravenous infusion of remifentanil (1 μg·kg−1·min−1 for 60 min) in rats. The antinociception of artesunate was verified by assessment of paw withdrawal mechanical threshold and paw withdrawal thermal latency. Spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation were examined. Also, both the mGluR5 agonist DHPG and antagonist MPEP were utilized to explore the involvement of mGluR5 in the anti-hyperalgesic property of artesunate. Here, we found that artesunate (10 μg and 100 μg but not 1 μg) prevented RIH in a dose-dependent manner. Artesunate reduced remifentanil-related spinal over-expression of mGluR5 gene and protein, and hyperacetylation of peroxiredoxin-3. Intrathecal application of MPEP (10 nmol and 100 nmol but not 1 nmol) inhibited behavioral RIH and peroxiredoxin-3 acetylation. Moreover, hyperalgesia and peroxiredoxin-3 hyperacetylation were attenuated after the combination of artesunate (1 μg) and MPEP (1 nmol). Additionally, artesunate treatment reversed acute pain and peroxiredoxin-3 hyperacetylation following spinal exposure to DHPG. In conclusion, intrathecal injection of artesunate impairs RIH by down-regulating spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation-mediated oxidative stress in rats.