Remifentanil-induced Postoperative Hyperalgesia Research Articles

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia.

Treatment of remifentanil-induced postoperative hyperalgesia (RIH) remains a clinical challenge because the mechanisms are not fully understood. Matrix metalloproteinase-9 (MMP-9) is a key component in neuroinflammation because of its facilitation of pro-inflammatory cytokine maturation. Therefore, inhibition of MMP-9 may represent a novel therapeutic approach to the treatment of RIH. Sprague-Dawley rats were randomly divided into three groups: Control, Incision and Remifentanil. A right plantar surgical incision was performed in Group Incision, and intraoperative remifentanil (0.04 mg/kg, 0.4 ml) was infused subcutaneously for 30 min in Group Remifentanil. The results indicated that intraoperative remifentanil induced an up-regulation and activation of MMP-9 in DRGs but not spinal cords. MMP-9 was expressed primarily in DRG neurons co-expressing mu opioid receptors (MOR), and elicited interleukin-1β (IL-1β) cleavage in DRG neurons and satellite glial cells (SGCs). Intraperitoneal injection of N-acetyl-cysteine (NAC), a broadly used safe drug, significantly attenuated RIH via suppressing the activation of MMP-9 in DRGs. NAC inhibited the cleavage of IL-1β in DRGs, which is a critical substrate of MMP-9, and markedly suppressed glial activation and neuron excitability in spinal dorsal horn induced by remifentanil. These results demonstrated that NAC can effectively alleviate RIH via powerfully inhibiting MMP-9 activation in DRGs.

Activation of spinal alpha-7 nicotinic acetylcholine receptor shortens the duration of remifentanil-induced postoperative hyperalgesia by upregulating KCC2 in the spinal dorsal horn in rats.

BackgroundAccumulating evidence has shown that the signal from spinal brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl− cotransporter-2 plays a critical role in the process of pain hypersensitivity. The activation of alpha-7 nicotinic acetylcholine receptors could have an analgesic effect on remifentanil-induced postoperative hyperalgesia. Nevertheless, whether intrathecal administration of PNU-120596, an alpha-7 nicotinic acetylcholine receptors selective type II positive allosteric modulator, before surgery could affect the duration of remifentanil-induced postoperative hyperalgesia remains unknown, and the effects of alpha-7 nicotinic acetylcholine receptors activation on the brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl− cotransporter-2 signal in the spinal dorsal horn of rats with remifentanil-induced postoperative hyperalgesia is still enigmatic.ResultsWe demonstrated that the brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl− cotransporter-2 signal played a critical role in the development of remifentanil-induced postoperative hyperalgesia. Intrathecal administration of PNU-120596 (8 µg/kg, 15 min before surgery) was associated with earlier signs of recovery from remifentanil-induced postoperative hyperalgesia. Simultaneously, remifentanil-induced postoperative hyperalgesia-induced K+-Cl− cotransporter-2 downregulation was partly reversed and coincided with a decreased expression of brain-derived neurotrophic factor/tyrosine receptor kinase B in the spinal dorsal horn, approximately correlating with the time course of the nociceptive behavior. Moreover, intrathecal administration of the K+-Cl− cotransporter-2 inhibitor VU0240551 significantly reduced the analgesic effect of PNU-120596 on remifentanil-induced postoperative hyperalgesia.ConclusionsThe activation of alpha-7 nicotinic acetylcholine receptors induced a shorter duration of remifentanil-induced postoperative hyperalgesia by restoring the brain-derived neurotrophic factor/tyrosine receptor kinase B-K+-Cl− cotransporter-2 signal in the spinal dorsal horn of rats, which provides new insight into treatment in clinical postoperative pain management.

Intraoperative electroacupuncture relieves remifentanil-induced postoperative hyperalgesia via inhibiting spinal glial activation in rats.

BackgroundAccumulating studies have suggested that remifentanil, the widely-used opioid analgesic in clinical anesthesia, can activate the pronociceptive systems and enhance postoperative pain. Glial cells are thought to be implicated in remifentanil-induced hyperalgesia. Electroacupuncture is a complementary therapy to relieve various pain conditions with few side effects, and glial cells may be involved in its antinociceptive effect. In this study, we investigated whether intraoperative electroacupuncture could relieve remifentanil-induced postoperative hyperalgesia by inhibiting the activation of spinal glial cells, the production of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases.MethodsA rat model of remifentanil-induced postoperative hyperalgesia was used in this study. Electroacupuncture during surgery was conducted at bilateral Zusanli (ST36) acupoints. Behavior tests, including mechanical allodynia and thermal hyperalgesia, were performed at different time points. Astrocytic marker glial fibrillary acidic protein, microglial marker Iba1, proinflammatory cytokines, and phosphorylated mitogen-activated protein kinases in the spinal cord were detected by Western blot and/or immunofluorescence.ResultsMechanical allodynia and thermal hyperalgesia were induced by both surgical incision and remifentanil infusion, and remifentanil infusion significantly exaggerated and prolonged incision-induced pronociceptive effects. Glial fibrillary acidic protein, Iba1, proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α), and phosphorylated mitogen-activated protein kinases (p-p38, p-JNK, and p-ERK1/2) were upregulated after surgical incision, remifentanil infusion, and especially after their combination. Intraoperative electroacupuncture significantly attenuated incision- and/or remifentanil-induced pronociceptive effects, spinal glial activation, proinflammatory cytokine upregulation, and phosphorylated mitogen-activated protein kinase upregulation.ConclusionsOur study suggests that remifentanil-induced postoperative hyperalgesia can be relieved by intraoperative electroacupuncture via inhibiting the activation of spinal glial cells, the upregulation of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases.

Spinal mitochondrial-derived ROS contributes to remifentanil-induced postoperative hyperalgesia via modulating NMDA receptor in rats

BackgroundActivation of N-methyl-d-aspartate (NMDA) receptor by reactive oxygen species (ROS) in the spinal cord plays an important role in the development of hyperalgesia in several neuropathic pain models. The study examined the involvement of ROS-NMDA signaling pathway in remifentanil-induced postoperative hyperalgesia. MethodsNociceptive responses were measured by paw withdrawal mechanical threshold (PWT) and paw withdrawal thermal latency (PWL) before and up to day 5 after remifentanil infusion. Spinal delivery of MitoSOX red was performed to detect mitochondrial ROS. Changes in expression of NMDA receptor subunits (NR1 and NR2B) in the spinal cord were analyzed by immunofluorescence and Western blotting. Intraperitoneal injection of phenyl-N-tert-butylnitrone (PBN), a non-selective ROS scavenger, was administrated to investigate the role of ROS in remifentanil-induced postoperative hyperalgesia. ResultsIntraoperative infusion of remifentanil induced postoperative mechanical allodynia and thermal hyperalgesia. ROS production, phosphorylated NR1 and NR2B subunits of NMDA receptor were found to be significantly increased in the spinal dorsal horn after intraoperative remifentanil infusion. However, remifentanil-induced postoperative hyperalgesia was suppressed by pretreatment of PBN. In addition, reduction of ROS by PBN prevented enhanced phosphorylation of NR1 and NR2B subunits. ConclusionThese findings indicated that ROS-dependent activation of NMDA receptor in the spinal cord might be a potential mechanism underlying remifentanil-induced postoperative hyperalgesia.

The role of p38MAPK activation in spinal dorsal horn in remifentanil-induced postoperative hyperalgesia in rats

Objectives: Remifentanil may induce hyperalgesia. Recent studies implicate a close relationship between post-surgical hyperalgesia and phosphorylation and activation of p38 mitogen-activated protein kinase (p38MAPK) in the spinal microglia. This study aimed to investigate whether the combination of post-surgical and remifentanil-induced hyperalgesia worsens post-operative pain and whether phosphorylated p38MAPK (phospho-p38MAPK) in the spinal dorsal horn in rats is involved in remifentanil-induced postoperative hyperalgesia.Methods: Sprague-Dawley rats were randomly divided into six groups: control, incision only, remifentanil only, remifentanil + incision, remifentanil + incision + SB203580, and remifentanil + incision + DMSO. The p38MAPK inhibitor SB203580 and DMSO were injected intrathecally. A right plantar surgical incision was performed in the incision groups, and remifentanil was infused for 60 min in the remifentanil groups. Mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) of the bilateral hind paws were measured and the number of phospho-p38MAPK-positive cells in rat spinal dorsal horn sections was counted.Results: Intravenous remifentanil infusion decreased bilateral plantar PWL values from 1 h to 3 days after surgery, however there was no additive effect with incision-induced values. There was a significant increase in the number of dorsal horn phospho-p38MAPK-positive cells in the remifentanil + incision group compared to the incision group, but no increase in the number of these cells when remifentanil was given alone. Intrathecal pretreatment with SB203580 attenuated remifentanil + incision–induced postoperative hyperalgesia and significantly reduced activation of phospho-p38MAPK in spinal dorsal horn.Conclusions: Incision-induced and remifentanil-induced increases in hyperalgesia were not additive when incision and remifentanil were used together. Data on phospho-38MAPK activation in remifenanil-induced hyperalgesia were contradictory and need further clarification.

Effect of dexmedetomidine on spinal p38MAPK expression during remifentanil-induced postoperative hyperalgesia in rats with incisional pain

Objective To evaluate the effect of dexmedetomidine on spinal p38 mitogen-activated protein kinase (p38MAPK) expression during remifentanil-induced hyperalgesia in rats with incisional pain. Methods Forty-eight healthy male Sprague-Dawley rats, aged 6 weeks, weighing 220-250 g, were randomly divided into 4 groups (n= 12 each) using a random number table: control group (group C), incision pain group (group IP), incision pain + remifentanil group (group IP+ R), and incision pain + remifentanil + dexmedetomidine group (group IP+ R+ D). After successful establishment of the model of incisionsal pian, remifentanil 1.0 μg/kg was infused for 4 h via the tail vein in group IP+ R; remifentanil 1.0 μg/kg was infused for 4 h via the tail vein, and dexmedetomidine 10 μg/kg was simultaneously infused for 4 h via the jugular vein in group IP+ R+ D; the equal volume of normal saline was infused for 4 h via the tail and jugular veins in C and IP groups.The mechanical paw withdrawal threshold (MWT) was measured at 24 h before operation (T0), and at 4, 6, 24 and 48 h after the end of drug infusion (T1-4). After measurement of MWT at T4, the expression of p38MAPK was determined using immuno-histochemistry. Results Compared with group C, the MWT was significantly decreased at T1-4, and the expression of p38MAPK was up-regulated at T4 in IP and IP+ R groups (P 0.05). Compared with group IP, the MWT was significantly decreased at T1-4, and the expression of p38MAPK was up-regulated at T4 in group P+ R, and the MWT was significantly increased at T1-4, and the expression of p38MAPK was down-regulated at T4 in group IP+ R+ D (P<0.05). Compared with group IP+ R, the MWT was significantly increased at T1-4, and the expression of p38MAPK was down-regulated at T4 in group IP+ R+ D (P<0.05). Conclusion The mechanism by which dexmedetomidine reduces hyperalgesia induced by remifentanil is related to down-regulation of spinal p38MAPK expression in the rats with incisional pain. Key words: Dexmedetomidine; Pain, postoperative; Hyperalgesia; p38 mitogen-activated protein kinases; Spinal cord

Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats

AimsRemifentanil is a short-acting and highly selective mu opiate agonist that is used in many clinical surgical situations for intraoperative pain relief. Under certain conditions, remifentanil can produce “paradoxical” hyperalgesia. This study aims to investigate mechanisms of actions mediating this “paradoxical” effect. MethodsSprague–Dawley rats were divided into 6 groups including control and treatment groups. The paw withdrawal mechanical threshold and the paw withdrawal thermal latency of the rats were tested. The changes of rat behaviors were measured at 24h before intrathecal injection and at 2h, 6h, 24h, and 48h after operation. According to the changes in behavioral indicators of pain, the specimens of all groups were collected at 2h, 6h, 24h, and 48h after the operation. The level of calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation in the spinal dorsal horn was analyzed by Western blotting. ResultsIntraoperative infusion of remifentanil induced postoperative hyperalgesia in the rats. Intrathecal KN93 injection increased nociceptive thresholds of paw withdrawal mechanical threshold and paw withdrawal thermal latency in a dose-dependent manner. Western blotting results showed that CaMKII phosphorylation in the spinal dorsal horn was increased significantly by remifentanil. Inhibition of CaMKII phosphorylation relieved the hyperalgesia pain state. ConclusionsIntrathecal injection of KN93 attenuates postoperative hyperalgesia induced by intraoperative infusion of remifentanil in rats through inhibiting spinal CaMKII phosphorylation.

Evaluation of the effect of ketamine on remifentanil-induced hyperalgesia: a double-blind, randomized study

Abstract study objectiveOpioids are associated with hyperalgesia that can reduce their analgesic effect. The aim of this study was to determine whether the addition of ketamine reduces remifentanil-induced hyperalgesia; improves its analgesic effect; and alters interleukin 6 (IL-6), IL-8, and IL-10 levels. DesignThis is a prospective, randomized, double-blind study. SettingThe setting is in a operating room and ward in a university hospital. PatientsThere are 56 patients, aged ≥18 years, American Society of Anesthesiologists I or II, who underwent laparoscopic cholecystectomy. InterventionsAnesthesia was induced with remifentanil, 50% oxygen, and isoflurane. Patients randomized to group 1 received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients randomized to group 2 received remifentanil (0.4 μg/kg per minute) and saline solution. Postoperative analgesia was achieved using morphine via patient-controlled analgesia. MeasurementsThe measurements were postoperative pain intensity during 24 hours; morphine consumption; time to first morphine supplementation; hyperalgesia (using monofilaments and an algometer) and allodynia (using a soft brush) in the thenar eminence of the nondominant hand and in the periumbilical region 24 hours after surgery; extent of hyperalgesia using a 300-g monofilament near the periumbilical region 24 hours after surgery; and serum levels of IL-6, IL-8, and IL-10. Main resultsGroups were similar for baseline characteristics. There were no differences in pain intensity, time to first request of morphine, and total 24 hours dose of morphine between groups. There was a difference in hyperalgesia using monofilaments 24 hours after the surgery in the thenar eminence of the nondominant hand, with a better profile for the experimental group. However, there were no differences in hyperalgesia using an algometer, in allodynia using a soft brush; in extent of hyperalgesia; or in levels of IL-6, IL-8, and IL-10. ConclusionsIt was not possible to demonstrate that the addition of ketamine (5 μg/kg per minute) is effective in preventing or reducing remifentanil-induced postoperative hyperalgesia in laparoscopic cholecystectomy.

Spinal Peroxynitrite Contributes to Remifentanil-induced Postoperative Hyperalgesia via Enhancement of Divalent Metal Transporter 1 without Iron-responsive Element–mediated Iron Accumulation in Rats

Hyperalgesia is one of the negative consequences following intraoperative analgesia with remifentanil. Peroxynitrite is a critical determinant in nociceptive process. Peroxynitrite inactivates iron-sulfur cluster that results in mitochondrial dysfunction and the release of iron, leading to mitochondrial iron accumulation. Iron accumulation mediated by divalent metal transporter 1 (DMT1) plays a key role in N-methyl-D-aspartate neurotoxicity. This study aims to determine whether peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via DMT1-mediated iron accumulation. Behavior testing was performed in rat model at different time points. Three-nitrotyrosine, nitrated manganese superoxide dismutase, and DMT1 with/without iron-responsive element [DMT1(+)IRE and DMT1(-)IRE] in spinal cord were detected by Western blot and immunohistochemistry. Spinal iron concentration was measured using the Perl stain and atomic absorption spectrophotometer. Hydrogen-rich saline imparting selectivity for peroxynitrite decomposition and iron chelator was applied in mechanistic study on the roles of peroxynitrite and iron, as well as the prevention of hyperalgesia. Remifentanil induced thermal and mechanical hyperalgesia at postoperative 48 h. Compared with control, there were higher levels of 3-nitrotyrosine (mean ± SD, hyperalgesia vs. control, 1.22 ± 0.18 vs. 0.25 ± 0.05, n = 4), nitrated manganese superoxide dismutase (1.01 ± 0.1 vs. 0.19 ± 0.03, n = 4), DMT1(-)IRE (1.42 ± 0.19 vs. 0.33 ± 0.06, n = 4), and iron concentration (12.87 ± 1.14 vs. 5.26 ± 0.61 μg/g, n = 6) in remifentanil-induced postoperative hyperalgesia, while DMT1(+)IRE was unaffected. Eliminating peroxynitrite with hydrogen-rich saline protected against hyperalgesia and attenuated DMT1(-)IRE overexpression and iron accumulation. Iron chelator prevented hyperalgesia in a dose-dependent manner. Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and "iron-targeted" therapies.

The efficacy of N-methyl-d-aspartate receptor antagonists on improving the postoperative pain intensity and satisfaction after remifentanil-based anesthesia in adults: a meta-analysis

BackgroundRemifentanil could induce opioid-induced hyperalgesia and tolerance, which would increase pain intensity after the operation. N-methyl-d-aspartate (NMDA) receptor antagonists have been used to prevent these adverse effects while the efficacy is still controversial. We evaluated the effectiveness of NMDA receptor antagonists in reducing postoperative pain and analgesic consumption after remifentanil-based anesthesia. MethodsFull published reports of randomized controlled trials on adults investigating the effects of intravenous administration of NMDA receptor antagonists compared with placebo for preventing remifentanil-induced postoperative hyperalgesia and tolerance were searched in PubMed, Embase, Springer, and the Cochrane Central Register of Controlled Trials. Postoperative pain scores, analgesic consumption, time to first analgesic request, satisfaction scores, and opioid-related and other adverse effects have been evaluated. Results were combined using fix or random-effects model when appropriate. ResultsA total of 14 randomized controlled trials with 729 patients were included in the final analysis. Compared with placebo, NMDA receptor antagonists reduced the pain scores at 0, 4, 6, 8, 12, and 24 hours postoperatively (P < .05), reduced the cumulative analgesic consumption of 0-6, 0-24, and 0-48 hours after the operation (P < .05), prolonged the first time to request analgesic (P < .05), and promoted the satisfaction scores (P < .05). There was no difference in the incidence of postoperative nausea and vomiting, psychological adverse effects, and shivering. Subgroup analysis was conducted on different interventions (ketamine and magnesium); the results are in line with general results. ConclusionsN-methyl-d-aspartate receptor antagonists can prevent the increase of analgesic consumption and pain intensity induced by remifentanil, and it can improve the postoperative satisfaction of patients.

Neuron-restrictive silencer factor in periaqueductal gray contributes to remifentanil-induced postoperative hyperalgesia via repression of the mu-opioid receptor

BackgroundThe ultra-short-acting mu-opioid receptor (MOR) agonist remifentanil induces postoperative hyperalgesia both in preclinical and clinical research studies. However, the precise mechanisms remain unclear, although changes in opioid receptor expression might be a correlative feature. Neuron-restrictive silencer factor (NRSF) functions as a crucial regulator of MOR expression in specific neuronal cells. Using a mouse model of incisional postoperative pain, we assessed the expression of MOR and NRSF and investigated whether disruption of NRSF expression could prevent the postoperative nociceptive sensitization induced by surgical incision and subcutaneous infusion of remifentanil. MethodsPaw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were independently used to assess mechanical allodynia and thermal hyperalgesia after surgery and cerebral ventricle injection of NRSF antisense oligonucleotide. Western blotting analyses were preformed to assess the expression levels of MOR and NRSF. ResultsNRSF expression levels were enhanced after intraoperative infusion of remifentanil, resulting in repression of MOR expression in the periaqueductal gray (PAG). NRSF blockade with an NRSF antisense oligonucleotide significantly enhanced the expression levels of MOR and alleviated mechanical allodynia and thermal hyperalgesia induced by intraoperative infusion of remifentanil. ConclusionNRSF functions as a negative regulator of MOR in PAG and contributes to remifentanil-induced postoperative hyperalgesia. NRSF in PAG may be a potential target for this pain therapy.

Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro.

Several studies have demonstrated that intraoperative remifentanil infusions have been associated with opioid-induced hyperalgesia (OIH). Activation of delta opioid receptor (DOR) and augmentation of N-methyl-d-aspartate (NMDA) receptor expression and function may play an important role in the development of OIH. The aim of this study was to investigate whether DOR inhibition could prevent remifentanil-induced hyperalgesia via regulating spinal NMDA receptor expression and function in vivo and in vitro. A rat model of remifentanil-induced postoperative hyperalgesia was performed with the DOR agonist deltorphin-deltorphin II or the DOR antagonist naltrindole injected intrathecally 10 min before remifentanil infusion. Mechanical and thermal hyperalgesia were measured at -24h, 2, 6, 24 and 48 h after remifentanil infusion. Western blot was applied to detect the membrane and total expression of DOR and NMDA receptor subunits (NR1, NR2A and NR2B) in spinal cord L4-L6 segments. In addition, whole-cell patch-clamp recording was used to investigate the effect of DOR inhibition on NMDA receptor-induced current in spinal cord slices in vitro. We found that membrane trafficking of DOR, NR1 and NR2B subunits in the spinal cord increased after remifentanil administration and surgery. The DOR antagonist naltrindole could attenuate mechanical and thermal hyperalgesia without affecting baseline nociceptive threshold, reduce membrane expression of DOR and decrease the membrane and total expressions of NR1 and NR2B subunits. Furthermore, the amplitude and the frequency of NMDA receptor-induced current were significantly increased by remifentanil incubation in neurons of the dorsal horn, which was reversed by the application of naltrindole. The above results indicate that inhibition of DOR could significantly inhibit remifentanil-induced hyperalgesia via modulating the total protein level, membrane trafficking and function of NMDA receptors in the dorsal horn of spinal cord, suggesting that naltrindole could be a potential anti-hyperalgesic agent for treating OIH.

Glycogen synthase kinase-3β inhibition prevents remifentanil-induced postoperative hyperalgesia via regulating the expression and function of AMPA receptors.

Many studies have confirmed that brief remifentanil exposure can enhance pain sensitivity. We previously reported that activation of glycogen synthase kinase-3β (GSK-3β) contributes to remifentanil-induced hyperalgesia via regulating N-methyl-D-aspartate receptor plasticity in the spinal dorsal horn. In this study, we demonstrated that GSK-3β inhibition prevented remifentanil-induced postoperative hyperalgesia via regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression and function in the spinal dorsal horn. Using a rat model of remifentanil-induced incision hyperalgesia, mechanical and thermal pain was tested 1 day before infusion and 2 hours, 6 hours, 1 day, 2 days, 3 days, 5 days, and 7 days after infusion. Western blot analysis was used to detect AMPAR subunit (GluR1 and GluR2) trafficking, AMPAR phosphorylation status, and GSK-3β activity in the spinal dorsal horn. Furthermore, whole-cell patch-clamp recording was used to analyze the effect of GSK-3β inhibition on AMPAR-induced current in the spinal dorsal horn. Membrane AMPAR subunit GluR1 was upregulated in the spinal cord in remifentanil-induced postoperative hyperalgesia rats (275 ± 36.54 [mean ± SD] vs 100 ± 9.53, P = 0.0009). Selective GSK-3β inhibitors, LiCl and TDZD, treatment ameliorates remifentanil-induced postoperative hyperalgesia, and this was associated with the downregulated GluR1 subunit in the membrane fraction (254 ± 23.51 vs 119 ± 14.74, P = 0.0027; 254 ± 23.51 vs 124 ± 9.35, P = 0.0032). Moreover, remifentanil incubation increased the amplitude and the frequency of AMPAR-induced current in dorsal horn neurons (61.09 ± 9.34 pA vs 32.56 ± 6.44 pA, P = 0.0009; 118.32 ± 20.33 milliseconds vs 643.67 ± 43.29 milliseconds, P = 0.0002), which was prevented with the application of LiCl and TDZD, respectively. Remifentanil-induced postoperative pain induced an increase in pGluR1 Ser845 and Rab5, which was prevented with the application of LiCl and TDZD. These results indicate that amelioration of remifentanil-induced postoperative hyperalgesia by GSK-3β inhibition is attributed to downregulated AMPAR GluR1 expression in the membrane fraction and inhibition of AMPAR function via altering pGluR1 and Rab5 expression in the spinal dorsal horn.

Changes of Mu-opioid receptor and neuron-restrictive silencer factor in periaquductal gray in mouse models of remifentanil-induced postoperative hyperalgesia

To determine the changes of Mu-opioid receptor (Mor) and neuron-restrictive silencer factor (NRSF) in periaquductal gray (PAG) in mouse models of remifentanil-induced postoperative hyperalgesia. Thirty-two Kun-Ming mice were randomly divided into 4 groups (8 mice in each group): Group C (mice underwent a sham procedure and saline was infused subcutaneously over a period of 30 min), Group I (mice underwent a surgical incision and the same volume of saline), Group R (mice underwent a sham procedure and remifentanil was infused subcutaneously at the moment of surgical incision over a period of 30 min), and group IR (mice underwent a surgical incision and remifentanil). Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) tests were performed 24 h before the operation and 2, 6, 24, and 48 h after the operation. The specimens were collected after behavioral testings at 48 h. The expressions of Mor and NRSF in mice's PAG neurons were determined by Western blot. Mechanical allodynia and thermal hyperalgesia developed in Group I, R and IR (P<0.01). Intraoperative infusion of remifentanil enhanced mechanical allodynia and thermal hyperalgesia in mice with planta incision (P<0.01). In Group R and Group IR, the expression of Mor was significantly lower (P<0.01) and NRSF was significantly higher (P<0.01) when compared with Group C and Group I. Intraoperative infusion of remifentanil induces postoperative hyperalgesia in mouse models, accompanied with decreased expressions of Mor and increased of NRSF level in PAG neurons, which may be involved in remifentanil induced hyperalgesia.

Intrathecal administration of roscovitine prevents remifentanil-induced postoperative hyperalgesia and decreases the phosphorylation of N-methyl-D-aspartate receptor and metabotropic glutamate receptor 5 in spinal cord.

N-methyl-D-aspartate receptor (NMDAR) and metabotropic glutamate receptor 5 (mGluR5) play an important role in nociceptive processing and central sensitization. Our previous study showed that tyrosine phosphorylation of NMDAR subunit 2B (NR2B) at Tyr1472 in spinal dorsal horn contributes to the postoperative hyperalgesia induced by remifentanil. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity, learning, memory and pain signaling via regulating the phosphorylation of NMDAR and mGluR5. In the present study, a rat model of postoperative pain was used to investigate the role of Cdk5 in spinal dorsal horn in remifentanil-induced hyperalgesia and the intervention of pretreatment with Cdk5 inhibitor roscovitine. Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous) significantly enhanced mechanical allodynia and thermal hyperalgesia induced by plantar incision during the postoperative period (each lasting between 2 h and 48 h), which were attenuated by pretreatment with roscovitine. Correlated with the pain behavior changes, Western blotting revealed that there was a significant increase in the expression of Cdk5 and its activator p35/p25, and further the kinase activity of Cdk5 in spinal dorsal horn after intraoperative infusion of remifentanil. The phosphorylation of NR2A at Ser1232, the phosphorylation of NR2B at Tyr1472 and the phosphorylation of mGluR5 at Ser1167 were also significantly up-regulated. Furthermore, these increases were attenuated by pretreatment with roscovitine. These results suggested that Cdk5 may contribute to remifentanil-induced postoperative hyperalgesia via regulating the phosphorylation of NMDAR and mGluR5 in spinal dorsal horn. These findings provide experimental evidence for the further application of Cdk5 inhibitor in preventing remifentanil-induced hyperalgesia.

Intrathecal Injection of JWH015 Attenuates Remifentanil-Induced Postoperative Hyperalgesia by Inhibiting Activation of Spinal Glia in a Rat Model

Hyperalgesia and neuroinflammation are associated with glia, which consists of macroglia and microglia. In this study, we used a selective cannabinoid receptor type 2 (CB2) agonist JWH015 to investigate remifentanil-induced postoperative hyperalgesia. Mechanical allodynia and thermal hyperalgesia after postoperative hyperalgesia and intrathecal injection of JWH015 were assessed by the paw withdrawal mechanical threshold and paw withdrawal thermal latency tests. We used immunohistochemistry and immunoblotting to investigate the effect of JWH015 on CB2 receptor, NR2B subunits, activated glial cells, and proinflammatory cytokine expression in rats after remifentanil-induced postoperative hyperalgesia. Postoperative hyperalgesia was induced by intraoperative infusion of remifentanil. Glial cells were activated, and expression levels of several genes were significantly increased, including interleukin 6, tumor necrosis factor α, CB2, and the NR2B subunit phosphorylated at Tyr-1472 (p-NR2B). Intrathecal injection of JWH015 significantly inhibited glial cell activation, suppressed expression of interleukin 6, tumor necrosis factor α, and p-NR2B, and stimulated CB2 expression, thus attenuating postoperative hyperalgesia. However, these phenomena were abolished in the group that was preadministered with AM630. The activation of glia, the production of proinflammatory cytokines, and the expression of CB2 and p-NR2B in the spinal dorsal horn increase significantly during the process of remifentanil-induced hyperalgesia. These changes can be regulated by pretreatment with JWH015, which may be the main mechanism underlying the antihyperalgesia effects of JWH015.

Inhibition of Glycogen Synthase Kinase-3β Prevents Remifentanil-Induced Hyperalgesia via Regulating the Expression and Function of Spinal N-Methyl-D-Aspartate Receptors In Vivo and Vitro

A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH). N-methyl-D-aspartate (NMDA) receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3β (GSK-3β) modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3β inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3β activity as well as NMDA receptor subunits (NR1, NR2A and NR2B) expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3β inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch-clamp recording. We found that remifentanil infusion at 1 μg·kg-1·min-1 and 2 μg·kg-1·min-1 caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3β activity in spinal cord dorsal horn. GSK-3β inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of GSK-3β can significantly ameliorate remifentanil-induced hyperalgesia via modulating the expression and function of NMDA receptors, which present useful insights into the mechanistic action of GSK-3β inhibitor as potential anti-hyperalgesic agents for treating OIH.

Glycogen Synthase Kinase-3β Contributes to Remifentanil-Induced Postoperative Hyperalgesia via Regulating N-Methyl-D-Aspartate Receptor Trafficking

Although remifentanil provides perfect analgesia during surgery, postoperative hyperalgesia after remifentanil administration might be a challenge to anesthesiologists. The trafficking and activation of N-methyl-D-aspartate (NMDA) receptors have a pivotal role in the development and maintenance of remifentanil-induced postoperative hyperalgesia. However, the underlying mechanisms of hyperalgesia are poorly elucidated. We designed the present study to examine the hypothesis that glycogen synthase kinase (GSK)-3β could contribute to remifentanil-induced postoperative hyperalgesia via regulating NMDA receptor trafficking in the spinal cord. Using a rat model of remifentanil-induced postoperative hyperalgesia, we first tested thermal and mechanical hyperalgesia at baseline (24 hours before incision) and 2, 6, 24, and 48 hours after remifentanil infusion. GSK-3β mRNA and protein expression and NMDA receptor subunits (NR1, NR2A, and NR2B) trafficking in the spinal cord L4-L6 segments were then measured using real-time polymerase chain reaction and Western blot analysis. Furthermore, we investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on remifentanil-induced postoperative hyperalgesia and NMDA receptor subunits trafficking. Remifentanil induced significant postoperative hyperalgesia, as indicated by increased paw withdrawal latencies and thresholds to thermal and mechanical stimulation, which were markedly improved by pretreatment with TDZD-8. Moreover, remifentanil infusion increased the expression of GSK-3β mRNA and protein as well as the GSK-3β activity in the spinal cord. More importantly, intraoperative infusion of remifentanil increased NMDA receptor subunits (NR1 and NR2B) trafficking from the intracellular pool to surface pool in the spinal cord, which was significantly attenuated by TDZD-8. The above results suggest that activation of GSK-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating NMDA receptor subunits (NR1 and NR2B) trafficking in the spinal cord. Inhibition of GSK-3β may be an effective novel option for the treatment of remifentanil-induced postoperative hyperalgesia.

Dexmedetomidine prevents remifentanil-induced postoperative hyperalgesia and decreases spinal tyrosine phosphorylation of N-methyl-d-aspartate receptor 2B subunit

Numerous studies have demonstrated that prolonged opioid exposure can enhance pain sensitivity that presents as opioid-induced hyperalgesia (OIH). Activation of spinal α2-adrenergic receptor may play an important role in the development of OIH. Dexmedetomidine is an α2-adrenergic agonist that has been shown to synergize with opioids. The aim of this study was to investigate the antihyperalgesia effects of dexmedetomidine on remifentanil-induced postinfusion hyperalgesia in a rat model of incision pain. We also evaluated whether the antihyperalgesic effects of dexmedetomidine were associated with suppression of NMDAR excitability, as measured by a reduction in spinal cord NR2B phosphorylation. Dexmedetomidine (12.5 μg/kg, 25 μg/kg, 50 μg/kg) was administered subcutaneously 30 min before plantar incision. Pretreatment with dexmedetomidine significantly decreased remifentanil-induced hyperalgesia, as indicated by increased paw withdrawal latencies and thresholds to thermal and mechanical stimulation respectively. Correlated with the pain behavior changes, Western blotting experiments also revealed that dexmedetomidine could decrease NR2B subunit phosphorylation (Tyr1472 site) in the dorsal horn, which was upregulated after remifentanil infusion. These results suggest that dexmedetomidine can efficiently alleviate OIH and it may be an effective novel option for the treatment of OIH. Our data also provide evidence that dexmedetomidine's anti-hyperalgesic effect may depend on its ability to modulate spinal cord NMDAR activation via suppression of NR2B phosphorylation.

Preventive efficacy of NMDA receptor antagonists on remifentanil-induced postoperative hyperalgesia: a Meta- analysis

Objective To systematically review the preventive efficacy of N-methyl-D-aspartate (NMDA) receptor antagonists on remifentanil-induced postoperative hyperalgesia.Methods Pubmed,EMBase,Springer and Cochrane Controlled Trials Register were searched to identify all randomized controlled trials(RCTs) about efficacy of NMDA receptor antagonists for preventing remifentanil-induced postoperative hyperalgesia.The quality of the studies was evaluated by the method recommended by Cochrane Collaboration.The data was extracted,including postoperative analgesic consumption,pain scores,time for first analgesic request and the incidence of adverse effects.Meta-analysis was conducted using the Cochrane Collaboration's RevMan 5.0 software.Results Fourteen RCTs involving 623 patients were included in our Meta-analysis.NMDA receptor antagonists significantly decreased pain scores at 4 h after operation ( P ＜ 0.05),and had no effect on postoperative analgesic consumption,time for first analgesic request and the incidence of adverse effects ( P ＞ 0.05).Conclusion NMDA receptor antagonists (ketamine and magnesium)can not prevent the occurrence of postoperative hyperalgesia induced by remifentanil. Key words: Receptors, N-mmethyl-D-aspartate ; Piperidines ; Hyperalgesia; Meta-analysis