Spinal CCL1/CCR8 regulates phosphorylation of GluA1-containing AMPA receptor in postoperative pain after tibial fracture and orthopedic surgery in mice.

Chronic postoperative pain might be a pivotal component hindering recovery and regains the function after bone fracture and orthopedic surgery. However, the underlying mechanisms remain largely unclear. AMPA receptor of excitatory synapses is considered due to its critical role in pathologic pain. Chemokine CCL1 related neuroinflammation plays a role in excitatory synaptic transmission and nociceptive transduction. This study examined whether spinal CCL1 is associated with fracture-associated postoperative pain via AMPA receptor. We herein discovered that the tibial fracture with orthopedic surgery initiated and maintained chronic postoperative pain along with spinal up-regulation of CCL1/CCR8 expression and phosphorylation of GluA1-containing AMPA receptor. Central CCL1/CCR8 inhibition impaired mechanical and cold allodynia, and phosphorylated GluA1-containing AMPA receptor in the spinal dorsal horn. Intrathecal injection of GluA1-containing AMPA receptor antagonist NASPM alleviated fracture-related postoperative pain. Also, exogenous CCL1 delivery facilitated acute pain behaviors and spinal phosphorylation of GluA1-containing AMPA receptor in naïve mice, reversing by co-application of NASPM. Our current results indicated that spinal CCL1/CCR8-mediated GluA1-containing AMPA receptor activation is vital in the pathogenesis of fracture associated postoperative pain in mice.

The Effect of Interventional Pain Management on Treating Postherpetic Neuralgia.

BACKGROUND: Herpes zoster (HZ) is identified to induce postherpetic neuralgia (PHN) which is difficult to cure. PHN-related pain brings patients not only physical discomfort but also mental depression and anxiety. Currently, the main purpose of PHN treatment is to reduce patients' pain. Now treatment combining some international pain management and drug therapy has come up. AIMS AND OBJECTIVE: This study aims to evaluate the effect of interventional management through meta-analysis. MATERIALS AND METHODS: Interventional pain management was defined as a direct strategy on nerve through physical or chemical method. Drug therapy was always regarded as control. Potentially relevant articles were searched in PubMed, EMBASE, and the Cochrane Library through key words by consensus. Pain severity was evaluated by a validated visual analog scale (VAS). Moreover, the weighted mean difference was used to calculate pain intensity. Some trails recorded the efficiency rate and odds ratio was used to calculate the effectiveness. Statistical heterogeneity was measured by the value of I 2, and when statistical I 2 > 50%, subgroup analysis was used to seek for the source of heterogeneity. RESULTS: Pulsed radiofrequency (PRF) combined with medication reduced the VAS scores at 1, 2, 4, and 8 weeks after treatment. The nerve block combined with medication reduced VAS scores at 8 weeks after treatment, but there is no difference between the results of medication alone at 1, 2, and 4 weeks after treatment. CONCLUSION: The interventional mean of PRF combined with medication has a good effect on PHN. The effect of nerve block combined with medication on PHN seems to be the same as that of medication alone. Besides, a long period with high-quality randomized controlled trial should be done to verify the results.

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

BACKGROUND: Remifentanil 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. METHODS: The 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). RESULTS: Remifentanil-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. CONCLUSION: Our 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.

Spinal Protein Kinase Mζ Regulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking and Dendritic Spine Plasticity via Kalirin-7 in the Pathogenesis of Remifentanil-induced Postincisional Hyperalgesia in Rats.

BACKGROUND: Intraoperative remifentanil anesthesia exaggerates postoperative pain sensitivity. Recent studies recapitulate the significance of protein kinase Mζ in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated pathologic pain. Kalirin-7, a Rho guanine nucleotide exchange factor, coordinates AMPA receptor trafficking and dendritic spine plasticity. This study examines whether protein kinase Mζ and Kalirin-7 contribute to remifentanil-induced postincisional hyperalgesia via AMPA receptor. METHODS: Plantar incision was performed 10 min after the start of remifentanil infusion (1 µg · kg · min for 60 min). Paw withdrawal threshold (primary outcome), spinal protein kinase Mζ activity, Kalirin-7 expression, AMPA receptor trafficking, and spine morphology were assessed. Protein kinase Mζ inhibitor and Kalirin-7 knockdown by short hairpin RNA elucidated the mechanism and prevention of hyperalgesia. Whole-cell patch-clamp recording analyzed the role of protein kinase Mζ in spinal AMPA receptor-induced current. RESULTS: Remifentanil reduced postincisional paw withdrawal threshold (mean ± SD, control vs. hyperalgesia, 18.9 ± 1.6 vs. 5.3 ± 1.2 g, n = 7) at postoperative 48 h, which was accompanied by an increase in spinal protein kinase Mζ phosphorylation (97.8 ± 25.1 vs. 181.5 ± 18.3%, n = 4), Kalirin-7 production (101.9 ± 29.1 vs. 371.2 ± 59.1%, n = 4), and number of spines/10 µm (2.0 ± 0.3 vs. 13.0 ± 1.6, n = 4). Protein kinase Mζ inhibitor reduced remifentanil-induced hyperalgesia, Kalirin-7 expression, and GluA1 trafficking. Incubation with protein kinase Mζ inhibitor reversed remifentanil-enhanced AMPA receptor-induced current in dorsal horn neurons. Kalirin-7 deficiency impaired remifentanil-caused hyperalgesia, postsynaptic GluA1 insertion, and spine plasticity. Selective GluA2-lacking AMPA receptor antagonist prevented hyperalgesia in a dose-dependent manner. CONCLUSIONS: Spinal protein kinase Mζ regulation of GluA1-containing AMPA receptor trafficking and spine morphology via Kalirin-7 overexpression is a fundamental pathogenesis of remifentanil-induced hyperalgesia in rats.

Intraperitoneal gardiquimod protects against hepatotoxicity through inhibition of oxidative stress and inflammation in mice with sepsis.

Many reports recapitulate the contribution of reactive oxygen species (ROS) over-accumulation to the organ damage; it is of significance to strictly target ROS production. In this study, we evaluated the potential role of TLR7 agonist gardiquimod (GDQ) in oxidative stress (OS) in liver injury induced by sepsis. Here, we observed that intraperitoneal pretreatment with GDQ dramatically elevated the septic survival rate and effectively attenuated the septic liver injury. Interestingly, the increased ROS and inflammatory factor IL-6 levels were reversed after GDQ intervention. Subsequently, Western blot was employed to determine the definite mechanism. As expected, it was showed that the upregulation of c-Jun N-terminal kinase (JNK)/c-Jun pathway in liver of septic animals was considerably suppressed by GDQ pre-exposure. Our current result highlight that pre-administration of GDQ ameliorated sepsis induced hepatotoxicity and reduced the generation of IL-6 and OS responses, which was associated with downregulation of JNK/c-Jun pathway. Our strategies might be ultimately beneficial in mitigating liver injury symptom.

PICK1 Regulates the Expression and Trafficking of AMPA Receptors in Remifentanil-Induced Hyperalgesia.

BACKGROUND: Remifentanil is used widely in clinical anesthesia because it induces more rapid and more common hyperalgesia than other opioid analgesics. Activation of N-methyl-D-aspartate (NMDA) receptors takes a pivotal part in remifentanil-induced hyperalgesia. Like NMDA receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are excitatory ion glutamate receptors in postsynaptic membrane, which are involved in the transmission of both acute and chronic pain. Protein interacting with C kinase 1 (PICK1) plays an important role in NMDA receptor-mediated internalization of glutamate receptor 2 (GluR2)-containing AMPARs and contributes to the induction and maintenance of inflammation-induced pain. This study aimed to test the hypothesis that PICK1 contributes to remifentanil-induced hyperalgesia by regulating AMPAR expression and trafficking in the spinal cord. METHODS: Using a rat model of remifentanil-induced hyperalgesia by intravenous infusion of remifentanil, we first measured changes in mechanical and thermal hyperalgesia at 24 hours before remifentanil infusion and 2, 6, 24, and 48 hours after infusion. PICK1 mRNA and protein expression and AMPAR subunit expression and trafficking in the spinal cord were then detected by reverse transcription-qualitative polymerase chain reaction, immunohistochemistry, and Western blot. In addition, we knocked down PICK1 expression by intrathecal administration of PICK1 antisense oligodeoxynucleotide to investigate the effects of PICK1 deficiency on remifentanil-induced hyperalgesia and the expression and trafficking of AMPARs. RESULTS: A significant time-group interaction was found for nociceptive thresholds (paw withdrawal threshold and paw withdrawal latency; all P < .0001). Remifentanil infusion induced distinct hyperalgesia at different time points (P < .0001), which was partly reversed by PICK1 knockdown (P < .007). Besides, remifentanil infusion increased the expression of PICK1 mRNA and protein (P < .0001) and the membrane GluR1 and GluR2 internalization in spinal dorsal horn neurons (P < .0011). More importantly, PICK1 deficiency could attenuate remifentanil-induced GluR2 internalization in the spinal cord dorsal horn (P < .01) but had no effect on remifentanil-induced membrane GluR1 expression (P ≥ .985). CONCLUSIONS: These results indicate that PICK1 deficiency might reverse remifentanil-induced hyperalgesia through regulating GluR2-containing AMPAR expression and trafficking in the spinal cord dorsal horn.