Remifentanil-induced Postoperative Hyperalgesia Research Articles

Toll-like receptor 4 signaling pathway in sensory neurons mediates remifentanil-induced postoperative hyperalgesia via transient receptor potential ankyrin 1.

Background: Remifentanil-induced postoperative hyperalgesia (RIH) refers to a state of hyperalgesia or aggravated pre-existing pain after remifentanil exposure. There has been considerable interest in understanding and preventing RIH. However, the mechanisms responsible for RIH are still not completely understood. Toll-like receptor 4 (TLR4), a classic innate immune receptor, has been detected in sensory neurons and participates in various nociceptive conditions, whereas its role in RIH remains unclear. Transient receptor potential ankyrin 1 (TRPA1) always serves as a nociceptive channel, whereas its role in RIH has not yet been investigated. This study aimed to determine whether the TLR4 signaling pathway in sensory neurons engaged in the development of RIH and the possible involvement of TRPA1 during this process. Methods: A rat model of remifentanil-induced postoperative hyperalgesia (RIH) was established, which presented decreased paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The mRNA and protein expression levels of TLR4, phosphorylated NF-κB, and TRPA1 in the dorsal root ganglion (DRG) from RIH model were analyzed by real-time PCR, western blot, and immunofluorescence. The TLR4 antagonist TAK-242 and the TRPA1 antagonist HC-030031 were applied to determine the role of sensory neuron TLR4 signaling and TRPA1 in RIH. Results: Compared with control, PWMT and PWTL were significantly decreased in RIH model. Moreover, the mRNA and protein expression of TLR4 and TRPA1 in DRG were upregulated after remifentanil exposure together with increased NF-κB phosphorylation. TLR4 antagonist TAK-242 mitigated mechanical pain in RIH together with downregulated expression of TLR4, phosphorylated NF-κB, and TRPA1 in DRG neurons. In addition, TRPA1 antagonist HC-030031 also alleviated mechanical pain and decreased TRPA1 expression in RIH without affecting TLR4 signaling in DRG. Conclusions: Taken together, these results suggested that activation of TLR4 signaling pathway engaged in the development of RIH by regulating TRPA1 in DRG neurons. Blocking TLR4 and TRPA1 might serve as a promising therapeutic strategy for RIH.

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.

P2Y1 purinergic receptor inhibition attenuated remifentanil-induced postoperative hyperalgesia via decreasing NMDA receptor phosphorylation in dorsal root ganglion

BackgroundRemifentanil-induced postoperative hyperalgesia is an intractable side effect of the clinical use of remifentanil, the mechanism of which remains obscure, especially in the peripheral nervous system. N-methyl-D-aspartate receptor (NMDAR) phosphorylation in dorsal root ganglion (DRG) plays a pronociceptive role in neuropathic pain. The contribution of the P2Y1 purinergic receptor (P2Y1R) in DRG to pain hypersensitivity derived from various origins and P2Y1R upregulation-induced NMDAR activation in neurons have also been uncovered. This study aimed to investigate whether P2Y1R participates in nociceptive processing in the DRG and spinal cord in remifentanil-induced postoperative hyperalgesia. MethodsRats with remifentanil-induced postoperative hyperalgesia were intrathecally injected with NMDAR antagonist MK801 or P2Y1R antagonist MRS2179 at 10 min prior to remifentanil infusion. Mechanical allodynia, heat hyperalgesia, and cold hyperalgesia were measured at −24 h, 2 h, 6 h, 24 h, and 48 h following remifentanil infusion. The P2Y1R expression and NMDAR expression and phosphorylation in DRG ipsilateral to the incision were detected by Western blot and immunofluorescence. ResultsIncision and remifentanil induced mechanical allodynia, heat hyperalgesia, and cold hyperalgesia accompanied by upregulated P2Y1R expression, increased NMDAR subunit NR1 expression and phosphorylation at Ser896, and NR2B expression and phosphorylation at Tyr1472 in DRG. Inhibition of NMDAR phosphorylation by MK801 effectively attenuated remifentanil-induced postoperative hyperalgesia. Furthermore, P2Y1R blockade by MRS2179 not only lessened remifentanil-evoked postoperative hypersensitivity to mechanical, heat, and cold stimuli, but also suppressed the increases in NR1 and NR2B expression and phosphorylation in DRG induced by incision and remifentanil. ConclusionThe process by which P2Y1R mediates NMDAR expression and phosphorylation represents a mechanism of remifentanil-induced postoperative hyperalgesia in the DRG and/or spinal cord.

Store-Operated Calcium Channels Contribute to Remifentanil-Induced Postoperative Hyperalgesia via Phosphorylation of CaMKIIα in Rats.

PurposeThe mechanisms of remifentanil-induced postoperative hyperalgesia (RIPH) remain unclear. Store-operated calcium channels (SOCCs) are mainly comprised of stromal interaction molecules 1 (STIM1) and pore-forming subunits (Orai1). They were found to take a pivotal part in Ca2+-dependent procedures and involved in the development of central sensitization and pain. Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα), regulated by Ca2+/calmodulin complex, has been shown to have a crucial role in RIPH. This study aims to determine whether SOCCs contribute to RIPH via activating CaMKIIα.Materials and MethodsIntra-operative infusion of remifentanil (1.0 µg kg−1 min−1, 60 min) was used to establish a RIPH rat model. The SOCCs blocker (YM-58483) was applied intrathecally to confirm the results. Animal behavioral tests including paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were performed at −24, 2, 6, 24, 48 h after incision and remifentanil treatments. The protein expression of STIM1, Orai1, CaMKIIα, and p-CaMKIIα was assayed with Western blot, and the number of STIM1 and Orai1 positive cells was shown by immunofluorescence.ResultsRemifentanil administration significantly induced postoperative mechanical and thermal hyperalgesia, as well as increased STIM1 and Orai1 protein expression in the spinal dorsal horn. Furthermore, the intrathecal administration of YM-58483 effectively alleviated remifentanil-induced postoperative mechanical and thermal hyperalgesia according to the behavioral tests. In addition, YM-58483 suppressed the phosphorylation of CaMKIIα but had no effect on the expression of STIM1 and Orai1.ConclusionOur study demonstrated that SOCCs are involved in RIPH. The over-expressed STIM1 and Orai1 in the spinal cord contribute to RIPH via mediating the phosphorylation of CaMKIIα. Blockade of SOCCs may provide an effective therapeutic approach for RIPH.

A Role for Transmembrane Protein 16C/Slack Impairment in Excitatory Nociceptive Synaptic Plasticity in the Pathogenesis of Remifentanil-induced Hyperalgesia in Rats

Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C (TMEM16C)/Slack is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively, with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia (DRG) and spinal cord. Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanil-induced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

P2X4 receptor in the dorsal horn contributes to BDNF/TrkB and AMPA receptor activation in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats

The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain–related studies showed that P2X4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.

Spinal hevin mediates membrane trafficking of GluA1-containing AMPA receptors in remifentanil-induced postoperative hyperalgesia in mice

IntroductionHevin, a matricellular protein involved in tissue repair and remodeling, is crucial for initiation and development of excitatory synapses. Besides, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). This study aimed to investigate the correlation between spinal Hevin and AMPA receptors in remifentanil-induced postoperative hyperalgesia in mice. MethodsRemifentanil (1.33 μg/kg/min for 60 min) was subcutaneously injected into a mouse model of postoperative pain. The von Frey and hot plate tests were performed to assess mechanical and thermal hyperalgesia. The gene and protein expression of Hevin and the membrane trafficking of GluA1-containing AMPA receptors in the dorsal horn of spinal cord were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analysis. In addition, Hevin-shRNA, exogenous Hevin, and 1-naphtylacetyl-spermine (NASPM) were administrated intrathecally to assess the relationship between spinal Hevin and AMPA receptors. ResultsPerioperative administration of remifentanil can aggravate and prolong incision-induced mechanical and thermal hyperalgesia. Treatment with remifentanil increased the expression of spinal Hevin and the membrane trafficking of AMPA receptors. Additionally, knockdown of spinal Hevin attenuated pain hypersensitivity and downregulated membrane trafficking of AMPA receptors after treatment with remifentanil. Meanwhile, preadministration of NASPM reversed spontaneous pain and membrane trafficking of spinal GluA1-containing AMPA receptors induced by exogenous Hevin in naïve mice. ConclusionsSpinal Hevin was involved in the maintenance of remifentanil-induced postoperative hyperalgesia via modulating membrane trafficking of AMPA receptors.

Dezocine attenuates the remifentanil-induced postoperative hyperalgesia by inhibition of phosphorylation of CaMKⅡα

Remifentanil, ultra-short-acting μ-opioid receptor agonist, has the greatest advantage in analgesia but could increase postoperative pain scores and induces postoperative hyperalgesia. Dezocine is a mixed opioid receptor partial agonist/antagonist and has been used for postoperative hyperalgesia management in clinical patients,but the potential molecular mechanism is still unclear. Ca2+/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ) has been reported involved in remifentanil-induced hyperalgesia (RIH) in previous studies, but the relationship between CaMKⅡ and dezocine in RIH is still unclear. To investigate the mechanism of dezocine in RIH, we used a remifentanil induced postoperative hyperalgesia (RIPH) in incisional pain model of mouse. We subcutaneously infused remifentanil (40 μg/kg) to induce postoperative hyperalgesia. Dezocine (1.5 mg/kg, 3.0 mg/kg, and 6.0 mg/kg) was infused subcutaneously with remifentanil using the apparatus pump for 30 min. Paw withdrawal thermal latency (PWTL) and paw withdrawal mechanical threshold (PWMT) were used to assess thermal hyperalgesia and mechanical allodynia. Western blotting analysis and immunohistochemistry analysis were used to assess the expression of phosphorylated CaMKⅡα (p-CaMKⅡα) in somatosensory cortex, hippocampus and spinal cord. Subcutaneous infusion of remifentanil enhanced postoperative pain induced by surgical incision and increased PWTL and PWMT. Dezocine dose-dependently decreased the PWTL and PWMT in RIPH model. Correlating with behavioral effects, dezocine inhibited remifentanil-induced up-regulation of p-CaMKⅡα expression in somatosensory cortex, hippocampus and spinal cord. Dezocine could attenuate RIPH by suppressing p-CaMKⅡα.

TRPV1 and spinal astrocyte activation contribute to remifentanil-induced hyperalgesia in rats.

Remifentanil is an ultra-short-acting µ-opioid receptor agonist, which is widely used in general anesthesia. However, comparing with other opioids, remifentanil often induces hyperalgesia. Accumulating evidence suggests that the transient receptor potential (TRP) channels and glial cells activation were involved in the development of neuropathic pain and hyperalgesia. However, whether the TRP channels and glial cells contribute to remifentanil-induced hyperalgesia is still unknown. In this study, we used the hot-plate and Von Frey tests to evaluate the thermal and mechanical hyperalgesia. Protein expressions of TRPV1 and protein kinase C (PKC) in dorsal root ganglion were assayed by western blotting and mRNA level of Trpv1, Trpa1, Trpv4, and Trpm8 were assayed by real-time PCR. TNF-α, IL-1β, and IL-6 levels in spinal cord were measured by ELISA. Immunofluorescence assay was applied to analyze the activation of astrocyte in spinal cord. Continuing infusion of remifentanil induced thermal hyperalgesia and mechanical allodynia, which were accompanied by upregulation of TRPV1 and PKC protein in dorsal root ganglion. Moreover, remifentanil also increased the TNF-α, IL-1β, and IL-6 levels and activates the astrocyte in spinal cord. Our findings suggested that TRPV1 is involved in the TRPV1-PKC signaling pathway, which contributes to the persistence of remifentanil-induced postoperative hyperalgesia. In addition, the spinal astrocyte activation and inflammatory reaction are involved in the remifentanil-induced postoperative hyperalgesia.

Ketamine reduces remifentanil-induced postoperative hyperalgesia mediated by CaMKII-NMDAR in the primary somatosensory cerebral cortex region in mice

Remifentanil is commonly used clinically for perioperative pain relief, but it may induce postoperative hyperalgesia. Low doses of ketamine have remained a common choice in clinical practice, but the mechanisms of ketamine have not yet been fully elucidated. In this study, we examined the possible effects of ketamine on calcium/calmodulin-dependent protein kinase II α (CaMKIIα) and N-methyl-d-aspartate receptor (NMDAR) subunit NR2B in a mouse model of remifentanil-induced postoperative hyperalgesia (RIPH) in the primary somatosensory cerebral cortex (SI) region. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess mechanical allodynia and thermal hyperalgesia, respectively, before and after intraoperative remifentanil administration. Before surgery, mice received intrathecal injections of the following drugs: ketamine, NMDA, BayK8644 (CaMKII activator), and KN93 (CaMKII inhibitor). Immunofluorescence was performed to determine the anatomical location and expression of activated CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα). Additionally, western blotting was performed to assess p-CaMKIIα and NMDAR expression levels in the SI region. Remifentanil decreased the PWMT and PWTL at 0.5 h, 2 h, and 5 h and increased p-CaMKIIα expression in the SI region. Ketamine increased the PWMT and PWTL and reversed the p-CaMKIIα upregulation. Both BayK8644 and NMDA reversed the effect of ketamine, decreased the PWMT and PWTL, and upregulated p-CaMKIIα expression. In contrast, KN93 enhanced the effect of ketamine by reducing hyperalgesia and downregulating p-CaMKIIα expression. These results suggested that ketamine reversed RIPH by inhibiting the phosphorylation of CaMKIIα and the NMDA receptor in the SI region in mice.

Effect of remifentanil on iron metabolism in spinal dorsal horn neurons of rats

Objective To evaluate the effect of remifentanil on iron metabolism in spinal dorsal horn neurons of rats. Methods The primary spinal dorsal horn neurons of rats were seeded in the culture plate at a density of 2×105 cells/well and divided into 4 groups using a random number table method: control group (C group, n=40), remifentanil group (R group, n=40), divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] siRNA group (siRNA group, n=32) and DMT1(-)IRE siRNA plus remifentanil group (siRNA+ R group, n=32). siRNA and siRNA+ R groups were subjected to DMT1(-)IRE siRNA transfection on day 3 of culture.R and siRNA+ R groups were incubated for 60 min in the solution with remifentanil at a final concentration of 40 nmol/L.The contents of reactive oxygen species (ROS) and Fe2+ were determined by fluorescent probe method, the malondialdehyde(MDA)content was detected by TBA method, and the content of labile iron pool (LIP) was detected by calcein AM and iron chelator at the end of incubation with remifentanil in R and siRNA+ R groups and at the corresponding time points in the other groups.The expression of DMT1(-)IRE and DMT1(+ )IRE was determined by Western blot in C and R groups. Results Compared with C group, the expression of DMT1(-)IRE in the spinal dorsal horn neurons was significantly up-regulated, the contents of Fe2+, LIP, ROS and MDA were increased (P 0.05). Compared with R group, the contents of Fe2+, LIP, ROS and MDA in the spinal dorsal horn neurons were significantly decreased in siRNA+ R group (P<0.05). Conclusion Remifentanil increases the iron content of spinal dorsal horn neurons by activating DMT1(-)IRE, which may be associated with the mechanism of remifentanil-induced postoperative hyperalgesia in rats. Key words: Piperidines; Hyperalgesia; Iron; Spinal cord

Role of spinal P2X4 receptor in remifentanil-induced postoperative hyperalgesia

To explore the role of P2X4 receptor in opioid-induced hyperalgesia (OIH). Methods: A total of 30 Sprague-Dawley (SD) male rats were randomly divided into 5 groups: a saline (N0) group, a remifentanil at 0.5 μg/(kg.min) (R1) group, a remifentanil at 1.0 μg/(kg.min) (R2) group, a remifentanil at 1.5 μg/(kg.min) (R3) group, and a remifentanil at 5.0 μg/(kg.min) (R4) group. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured at follow time points to optimize the dosages: the day before treatment (T1), 30 min after tail intravenous catheterization (T2), and 30 min (T3), 1 h (T4), 2 h (T5), 24 h (T6) after withdrawal from remifentanil. Then, the rats were randomly divided into 2 groups: a saline group (N group), a remifentanil at 1.0 μg/(kg.min) group (R group). The PWMT and PWTL were measured at follow time points: T1, T2, and T4. The lumbar enlargement of spine was selected at 1 h after withdrawal from remifentanil, and the expression of P2X4 receptor mRNA and protein was examined in OIH. Additional male rats were selected and randomly divided into 2 groups: a plantar incision surgery followed by saline treatment group (I+N group), a plantar incision surgery followed by remifentanil treatment group (I+R group). The PWMT and PWTL were measured at follow time points: T1, T2, T3, T4, T5, T6, 48 h (T7) and 72 h (T8) after withdrawal from remifentanil. The lumbar enlargement of spine was selected at 1 h after withdrawal from remifentanil, the expression of P2X4 receptor mRNA and protein was examined by PCR and Western blotting, and the microglial activation in spine 1 h after withdrawal from remifentanil were assessed by immunofluorescence. Results: The pain thresholds including PWMT and PWTL in different groups were as follows: R4 group<R3 group<R2 group<R1 group at T3 and T5 (all P<0.05). At T4, the PWMT and PWTL in the R4 group were lower than those in the R2 group, while in the R4 group they were lower than those in the R3 group (both P<0.05). Meanwhile, the PWMT and PWTL in the R2 group, the R3 group and the R4 group at T4 were lower than those in the other time points (all P<0.05). Compared with the N group, the rats in the R group had a lower PWMT and PWTL at T4 (both P<0.05), but there was no significant difference in P2X4 receptor protein and mRNA expression in the lumbar enlargement of spine between the R group and the N group. Compared with the I+N group, the pain threshold including PWMT and PWTL at T4, T5, and T6 in the I+R group was significantly decreased (all P<0.05). Meanwhile, compared with the I+N group, the expressions of P2X4 receptor mRNA and protein in rat spinal cord in the I+R group were significantly up-regulated, and the microglia was activated (all P<0.05). Conclusion: Remifentanil pumped via tail intravenous can result in the hyperalgesia, but the spinal P2X4 receptor might be not relevant to remifentanil-induced hyperalgesia. Remifentanil incision pain can cause significant hyperalgesia in rats, and the spinal P2X4 receptors and microglial activation is involved in the remifentanil-induced postoperative hyperalgesia.

TRPV1 channel contributes to remifentanil-induced postoperative hyperalgesia via regulation of NMDA receptor trafficking in dorsal root ganglion.

BackgroundRemifentanil is widely used in general anesthesia due to its reliability and rapid onset. However, remifentanil-induced postoperative hyperalgesia might be a challenge nowadays. Accumulating evidence suggests that the transient receptor potential vanilloid 1 (TRPV1) was involved in the development of neuropathic pain and hyperalgesia. However, the contribution of TRPV1 in modulating remifentanil-induced postoperative hyperalgesia is still unknown. The aim of this study is the contribution of TRPV1 to the surface expression of N-methyl-d-aspartate (NMDA) receptors in remifentanil-induced postoperative hyperalgesia.MethodsThe hot plate test and the Von Frey test were performed to evaluate thermal and mechanical hyperalgesia. Capsazepine (CPZ) was administrated intrathecally to confirm our results. TRPV1, NMDA receptors, CaMKII (calcium/calmodulin-dependent kinase II), and protein kinase C (PKC) in the dorsal root ganglion (DRG) were detected by Western blotting. Immunofluorescence assay was applied to analyze the distribution of TRPV1 and the relationship between TRPV1 and NMDA receptor subunit 1 (NR1).ResultsRemifentanil-induced both thermal and mechanical postoperative hyperalgesia. Here, we found the membrane trafficking of NR1, possibly due to the activation of TRPV1 in DRG neurons after remifentanil infusion. Furthermore, intrathecal injection of CPZ was able to relieve remifentanil-induced postoperative hyperalgesia according to a behavioral test and CPZ confirmed that TRPV1 is involved in NR1 trafficking. In addition, CaMKII/PKC but not protein kinase A (PKA) contributed to remifentanil-induced postoperative hyperalgesia.ConclusionOur study demonstrates that TRPV1 receptors are involved in remifentanil-induced postoperative hyperalgesia. TRPV1 contributes to the persistence of remifentanil-induced postoperative hyperalgesia through the trafficking of NMDA receptors via the activation of CaMKII-PKC signaling pathways in DRG neurons.

Intervention strategies for prevention of remifentanil-induced postoperative hyperalgesia

Background Remifentanil is a ultra-short-acting μ-opioid receptor agonist. Because remifentanil possesses high efficacy, rapid onset, short half-life time and fast clearance, it has been widely used for anesthesia. However, the incidence of remifentanil-induced hyperalgesia (RIH) remains relatively high, which poses great challenges to postoperative management. Objective To explore the effective intervention strategy for the prevention of RIH. Content Like other opioid drugs, remifentanil, after repetitive and long-term administration, causes drug tolerance and pain hypersensitivity. RIH may follow central sensitization of both ascending and descending pathways to facilitate pain transduction. A large amount of clinical trials tried to prevent RIH using various medications, such as, agonists for α2-drenoreceptor, opioid drugs, antagonists for NMDA receptors, non-steroid anti-inflammatory drugs, and calcium channel blockers, etc. Trend Further studies in the field are required to advance the understanding of the development of RIH, which may result in better strategies to prevent and treat this condition. Key words: Remifentanil; Hyperalgesia; Prevention

Electro-acupuncture stimulation prevents remifentanil-induced postoperative hyperalgesia by suppressing spinal microglia in rats.

The aim of the present study was to assess the effect of electro-acupuncture (EA) stimulation on remifentanil-induced postoperative hyperalgesia (RIPH) and the possible involvement of spinal microglia suppression. A model of RIPH was established using adult male Sprague-Dawley rats by administration of remifentanil at 0.08 mg/kg intravenously for 60 min. The Huantiao and Yanglingquan acupoints were stimulated continuously by EA (2 Hz, ~1 mA) for 90 min from before paw incision to the end of remifentanil administration. Sham acupoints were stimulated by EA in the sham group. Paw withdrawal threshold (PWT) and paw thermal withdrawal latency (PWL) were determined. Cluster of differentiation (CD)11b, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels in spinal cord samples were measured using immunohistochemistry and ELISA. PWT and PWL values were decreased following the administration of remifentanill; however, following EA, PWT and PWL values increased compared with the sham group (P<0.05), indicating that EA alleviates remifentanil-induced RIPH. CD11b, TNF-α, IL-1β and IL-6 levels were increased following remifentanil administration and these effects were counteracted by EA (all P<0.05). In the sham group, no significant differences were observed in PWT and PWL values or CD11b, TNF-α, IL-1β and IL-6 levels compared with the control group, suggesting that EA was responsible for the reduction in CD11b and pro-inflammatory cytokine expression following remifentanil administration. The results of the present study demonstrated that EA at the Huantiao and Yanglingquan acupoints may reduce remifentanil-induced postoperative hyperalgesia, likely by inhibiting spinal microglia via reduction of CD11b and pro-inflammatory cytokine expression. However, these results are preliminary and require further validation.

Remifentanil-induced postoperative hyperalgesia: current perspectives on mechanisms and therapeutic strategies.

The use of remifentanil in clinical practice offers several advantages and it is used for a wide range of procedures, ranging from day-surgery anesthesia to more complex procedures. Nonetheless, remifentanil has been consistently linked with development of opioid-induced hyperalgesia (OIH), which is described as a paradoxical increase in sensitivity to painful stimuli that develops after exposure to opioid treatment. The development of OIH may cause several issues, delaying recovery after surgery and preventing timely patient’s discharge. Moreover, it causes patient’s discomfort with higher pain scores, greater use of analgesics, and associated side effects. Remifentanil is the opioid most convincingly associated with OIH, and hereby we provide a review of remifentanil-induced hyperalgesia, describing both the underlying mechanisms involved and the available studies investigating experimental and clinical pharmacologic approaches aiming at reducing its incidence and degree.

Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial

BackgroundIntraoperative use of a high-dose remifentanil may induce postoperative hyperalgesia. Low-dose naloxone can selectively reverse some adverse effects of opioids without compromising analgesia. We thus hypothesized that the intraoperative use of a high-dose remifentanil combined with a low-dose naloxone infusion reduces postoperative hyperalgesia compared with the use of remifentanil alone. MethodsPatients undergoing elective thyroid surgery were randomly assigned into one of three groups, depending on the intraoperative effect-site concentration of remifentanil, with or without a continuous infusion of naloxone: 4 ng ml−1 remifentanil with 0.05 μg kg−1 h−1 naloxone in the high-remifentanil with naloxone group, and 4 or 1 ng ml−1 remifentanil with a placebo in the high- or low-remifentanil groups, respectively. We measured the pain thresholds (primary outcome) to mechanical stimuli using von Frey filaments and incidence of hyperalgesia on the peri-incisional area 24 h after surgery. We also measured pain intensity, analgesic consumptions and adverse events up to 48 h after surgery. ResultsThe pain threshold presented as von Frey numbers [median (interquartile range)] was significantly lower in the high-remifentanil group (n=31) than in the high-remifentanil with naloxone (n=30) and the low-remifentanil (n=30) groups [3.63 (3.22–3.84) vs 3.84 (3.76–4.00) vs 3.80 (3.69–4.08), P=0.011]. The incidence of hyperalgesia was also higher in the high-remifentanil group than in the other groups [21/31 vs 10/30 vs 9/30, P=0.005]. Postoperative pain intensity, analgesic consumptions and adverse events were similar between groups. ConclusionsThe intraoperative use of low-dose naloxone combined with high-dose remifentanil reduced postoperative hyperalgesia but not pain. Clinical trial registrationNCT02856087.

Efficacy of different low-doses of nalmefene in preventing remifentanil-induced postoperative hyperalgesia

Objective To evaluate the efficacy of different low-doses of nalmefene in preventing remifentanil-induced postoperative hyperalgesia. Methods One hundred American Society of Anesthesiologist physical status Ⅰor Ⅱpatients, aged 20-64 yr, wih body mass index of 18-25 kg/m2, scheduled for elective gynecological laparoscopic surgery under general anesthesia, were divided into 4 groups(n=25 each)using a random number table: control group(group C)and different doses of nalmefene groups(N1, N2 and N3 groups). In N1, N2 and N3 groups, nalmefene 0.2, 0.3 and 0.5 μg/kg(diluted to 5 ml in normal saline)were intravenously injected, respectively, at 5 min before anesthesia induction, while the equal volume of normal saline was given in group C. Anesthesia was induced with midazolam 0.05 mg/kg, sufentanil 0.3 μg/kg, etomidate 0.3 mg/kg and rocuronium 0.6 mg/kg.The patients were mechanically ventilated after tracheal intubation.Anesthesia was maintained by IV infusion of remifentanil 0.3 μg·kg-1·min-1 and inhalation of 4%-6% desflurane, bispectral index value was maintained at 45-60, and muscle relaxation was maintained with intermittent IV boluses of rocuronium.After admission to postanesthesia care unit, patient-controlled analgesia(PCA)was performed, and PCA solution contained sufentanil 1 μg/ml in 100 ml of normal saline.PCA pump was programmed to deliver a 0.5 ml bolus dose with a lockout interval of 15 min and background infusion at 2 ml/h.Numeric rating scale score was maintained <4.The time for remifentanil infusion was recorded.The consumption of sufentanil was recorded in 0-1, 1-3, 3-6, 6-12 and 12-24 h periods after surgery, and the occurrence of nausea, vomiting, tachycardia, hypertension and shivering was also recorded within 24 h after surgery. Results Compared with group C, the postoperative consumption of sufentanil was significantly reduced in 0-1 h and 1-3 h periods after surgery in group N1 and in 0-1, 1-3, 3-6 and 6-12 h periods after surgery in group N2, and the incidence of postoperative nausea was significantly decreased in N1, N2 and N3 groups(P<0.05). The consumption of sufentanil in 3-6 h period after surgery was significantly lower in group N2 than in group N1(P<0.05). Conclusion The optimal dose of nalmefene is 0.3 μg/kg when used to prevent remifentanil-induced postoperative hyperalgesia. Key words: Morphinane; Piperidines; Hyperalgesia

Magnesium sulphate attenuate remifentanil-induced postoperative hyperalgesia via regulating tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord

BackgroundRemifentanil induced hyperalgesia (RIH) is characterized by stimulation evoked pain including allodynia and thermal hyperalgesia after remifentanil infusion. N-methyl-D-aspartate (NMDA) receptor was reported to be involved in the progress of RIH. We hypothesized that intrathecal MgSO4 could relieve hyperalgesia after remifentanil infusion via regulating phosphorylation of NMDA receptor NR2B subunit activity in this study.MethodsThirty two rats were randomly allocated into control group, model of RIH group, RIH plus 100ug MgSO4 group, RIH plus 300ug MgSO4 group. Mechanical and thermal hyperalgesia were tested at -24th h, 2nd h, 6th h, 24th h, 48th h after remifentanil infusion. Following sacrifice of rats after the last behavioral test, we performed the western blot to detect the expression of spinal phosphorylated NMDA receptor NR2B subunit (pNR2B) in the L4-L5 segments.ResultsIntrathecal MgSO4 (100, 300 μg) dose-dependently reduced thermal and mechanical hyperalgesia from 2 h to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of pNR2B. Nevertheless, the increased amount of pNR2B by RIH was dose-dependently suppressed by intrathecal infusion of MgSO4 in rats.ConclusionsRemifentanil induced hyperalgesia/allodynia could be ameliorated by Mg-mediated blockade targeting the NR2B subunit in NMDA receptors.

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.