The interplay between the microbiota and opioid in the treatment of neuropathic pain.

Neuropathic pain (NP) is characterized by its complex and multifactorial nature and limited responses to opioid therapy; NP is associated with risks of drug resistance, addiction, difficulty in treatment cessation, and psychological disorders. Emerging research on gut microbiota and their metabolites has demonstrated their effectiveness in alleviating NP and augmenting opioid-based pain management, concurrently mitigating the adverse effects of opioids. This review addresses the following key points: (1) the current advances in gut microbiota research and the challenges in using opioids to treat NP, (2) the reciprocal effects and benefits of gut microbiota on NP, and (3) the interaction between opioids with gut microbiota, as well as the benefits of gut microbiota in opioid-based treatment of NP. Through various intricate mechanisms, gut microbiota influences the onset and progression of NP, ultimately enhancing the efficacy of opioids in the management of NP. These insights pave the way for further pragmatic clinical research, ultimately enhancing the efficacy of opioid-based pain management.

Swimming short fibrous nasal drops achieving intraventricular administration.

Adequate drug delivery across the blood-brain barrier (BBB) is a critical factor in treating central nervous system (CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization, the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2 (LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine (PLL) and negatively charged surface of fibers; this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.

Efficacy and safety of epidural block with lidocaine for refractory severe plaque psoriasis: An open-label pilot study in real world setting.

Epidural block using lidocaine, a non-selective blocker of voltage-gated sodium channels (Nav), has demonstrated efficacy in the treatment of severe plaque psoriasis in a limited number of cases. This study aimed to evaluate the effectiveness and safety of epidural lidocaine block in adult patients with severe, treatment-resistant plaque psoriasis. This was an open-label pilot study. Patients with severe plaque-type psoriasis unresponsive to at least one systemic treatment were enrolled for a 1-week epidural lidocaine block and followed up for 48 weeks. Thirty-six patients participated, with 32 completing the study. At the 12-week mark, there was a remarkable 59% improvement in the mean Psoriasis Area Severity Index (PASI) score (P < 0.001). By week 48, 28 out of 32 patients (87%) achieved PASI 75, while 18 out of 32 (56%) reached PASI 90. Within 7 days, 20 out of 21 patients (95%) reported a reduction in itch, with a mean itch reduction of 82% at day 1 and 94% at day 7. Notably, no severe side effects were observed. Epidural lidocaine block proved to be an effective and safe long-term treatment option for individuals with refractory severe plaque psoriasis.

Cortical changes in the brain of patients with hemifacial spasm.

OBJECTIVE: Hemifacial spasm (HFS) is a movement disorder characterized by involuntary muscle contractions on one side of the face. It is associated with disturbances in the brain's functional architecture. Despite this, the structural alterations in the brain related to HFS remain poorly understood. In this study, we investigated the cortical morphology changes in patients with HFS compared to healthy controls (HCs). METHODS: We analyzed 3D T1-weighted MRI images from 33 patients with left-sided primary HFS and 33 age- and sex-matched HCs. Measurements of cortical thickness (CTh), sulcal depth, local gyrification index (lGI), and fractal dimension were taken using a computational anatomy toolbox. A general linear model, accounting for age, gender, and total brain volume, was applied for statistical analyses. Significant clusters were then assessed for correlations with clinical parameters. RESULTS: The HFS patients displayed several cortical abnormalities when compared to HCs, including reduced CTh in the contralateral precentral gyrus and left orbitofrontal cortex, decreased sulcal depth in the left orbitofrontal cortex, and increased lGI in the right insula and superior temporal cortex. However, fractal dimension did not differ significantly between the groups. Additionally, in HFS patients, a notable negative correlation was found between the sulcal depth in the left orbitofrontal cortex and the Beck Depression Inventory-II scores. CONCLUSIONS: Our findings reveal that HFS is associated with specific surface-based morphological changes in the brain. These alterations contribute to a deeper understanding of the neurophysiological mechanisms involved in HFS and may have implications for future research and treatment strategies.

Hierarchical rhythmic propagation of corticothalamic interactions for consciousness: A computational study.

Clarifying the mechanisms of loss and recovery of consciousness in the brain is a major challenge in neuroscience, and research on the spatiotemporal organization of rhythms at the brain region scale at different levels of consciousness remains scarce. By applying computational neuroscience, an extended corticothalamic network model was developed in this study to simulate the altered states of consciousness induced by different concentration levels of propofol. The cortex area containing oscillation spread from posterior to anterior in four successive time stages, defining four groups of brain regions. A quantitative analysis showed that hierarchical rhythm propagation was mainly due to heterogeneity in the inter-brain region connections. These results indicate that the proposed model is an anatomically data-driven testbed and a simulation platform with millisecond resolution. It facilitates understanding of activity coordination across multiple areas of the conscious brain and the mechanisms of action of anesthetics in terms of brain regions.

Dexamethasone inhibits IL-8 via glycolysis and mitochondria-related pathway to regulate inflammatory pain.

BACKGROUND: Dexamethasone (Dexa) has been recently found to exert an analgesic effect, whose action is closely related to IL-8. However, whether dexamethasone induces antinociception via glycolysis and mitochondria-related pathways is still unclear. METHODS: Right hind paw inflammatory pain in mice was induced by intraplantar injection of Freund's Complete Adjuvant (FCA). Von Frey test was then used to measure the paw withdrawal threshold. The detection of glycolysis and mitochondrial pathway-related proteins and IL-8 were determined by Western blot and ELISA. The potential interaction between Dexa and fructose-1,6-bisphosphate (FBP, a PKM2 activator) was examined by simulation predictions using molecular docking. RESULTS: Intrathecal administration of Dexa (20 µg/20 µL) had an obvious analgesic effect in FCA-treated mice, which was counteracted by the glycolysis inhibitor 2-deoxyglucose (2-DG, 5 mg/20 µL) or the mitochondria-related pathway inhibitor oligomycin complex (Oligo, 5 µg/20 µL). In the glycolysis pathway, Dexa decreased GLUT3 and had no impact on HIF-1α expression during FCA-induced inflammation. Additionally, Dexa further increased the PKM2 level, accompanied by the formation of hydrogen bonds between Dexa and the PKM2 activator fructose-1,6-bisphosphate (FBP). In the mitochondrial pathway, Dexa downregulated the expression of Mfn2 protein but not the PGC-1α and SIRT-1 levels in the spinal cord. Moreover, both 2-DG and Oligo decreased Mfn2 expression. Finally, IL-8 level was reduced by the single or combined administration of Dexa, 2-DG, and Oligo. CONCLUSION: Dexa attenuated IL-8 expression via glycolysis and mitochondrial pathway-related proteins, thus mediating the analgesic effect during inflammatory pain.

An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction, long-term cognitive impairment, and increased morbidity and mortality. The current treatment for SAE is mainly symptomatic; the lack of specific treatment options and a poor understanding of the underlying mechanism of disease are responsible for poor patient outcomes. Fgr is a member of the Src family of tyrosine kinases and is involved in the innate immune response, hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. This study investigated the protection provided by an Fgr kinase inhibitor in SAE and the underlying mechanism(s) of action. METHODS: A cecal ligation and puncture (CLP)-induced mouse sepsis model was established. Mice were treated with or without an Fgr inhibitor and a PGC-1α inhibitor/activator. An open field test, a novel object recognition test, and an elevated plus maze were used to assess neurobehavioral changes in the mice. Western blotting and immunofluorescence were used to measure protein expression, and mRNA levels were measured using quantitative PCR (qPCR). An enzyme-linked immunosorbent assay was performed to quantify inflammatory cytokines. Mitochondrial membrane potential and morphology were measured by JC-1, electron microscopy, and the MitoTracker Deep Red probe. Oxidative stress and mitochondrial dysfunction were analyzed. In addition, the regulatory effect of Fgr on sirtuin 1 (SIRT1) was assessed. RESULTS: CLP-induced sepsis increased the expression of Fgr in the hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, the survival rate, cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Moreover, Fgr interacted with SIRT1 and reduced its activity and expression. In addition, activation of SIRT1/PGC-1α promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation of SIRT1/PGC-1α counteracted the benefits of the Fgr inhibitor. CONCLUSIONS: To our knowledge, this is the first report of Fgr kinase inhibition markedly ameliorating SAE through activation of the SIRT1/PGC-1α pathway, and this may be a promising therapeutic target for SAE.

Aberrant expression of FBXO22 is associated with propofol-induced synaptic plasticity and cognitive dysfunction in adult mice.

Recent observation demonstrated that prolonged anesthesia modifies brain synaptic architecture in all ages, including adult. Propofol is the most commonly utilized anesthetics at clinic. Whether repeated administration of propofol modulates cognitive impairment in adults and changes synaptic plasticity remains, however, to be explored. In this study, we first discovered that repeated and prolonged exposure to propofol-induced cognitive impairment in adult rodents. Then, we examined the property of hippocampal primary neurons and slices after propofol treatment in mice, including synaptic protein profile, dendritic spine density, as well as synaptic transmission. We found the distinctive change of the F-box only protein 22 (FBXO22), an F-box E3 ligase, during this process and further explored its role. Knockdown experiments showed the downregulation of FBXO22 restored the changes by propofol treatment on hippocampal primary neurons and attenuated propofol-induced hippocampal dependent cognitive dysfunction. Our results showed that FBXO22 is involved in the regulation of repeated propofol treatment induced changes of synaptic plasticity and cognitive dysfunction in adult mice. Repeated propofol treatment leads to cognitive dysfunction by regulating FBXO22 in adult rodents.

The therapeutic potential of ultra-short-acting ß-receptor antagonists in perioperative analgesic: Evidence from preclinical and clinical studies.

Perioperative multimodal analgesia can reduce the side effects of a high concentration of opioids, improving the comfort of the patient. However, insufficient analgesia of this model has prompted researchers to explore new adjuvant analgesics. Recently, an increasing number of studies have found a low-grade analgesic effect in the clinical application of ultra-short-acting ß-adrenergic receptor antagonists, which are conventionally used as pharmacologic agents in the cardiovascular system. The mechanism by which ultra-short-acting ß-antagonists exert antinociceptive effects has not been clarified yet. In this review, we intend to address its potential reasons from the side of neurotransmitters, inflammatory cytokines, and signaling pathways, providing theoretical proof for the application of ß-adrenergic receptor antagonists in analgesia.

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients: A Randomized Clinical Trial.

Importance: Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity. Objective: To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients. Design, Setting, and Participants: This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle. Interventions: Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion. Main Outcomes and Measures: Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12. Results: A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] µg/dL vs 6.1 [3.4] µg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population. Conclusions and Relevance: Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression. Trial Registration: ClinicalTrials.gov Identifier: NCT02910206.

Influence of different regimens of volumetric therapy on perioperative intestinal flora in the surgical patients with pancreas tumor, a randomized controlled trial study.

BACKGROUND: It is not clear whether the perioperative intestinal microenvironment of patients undergoing pancreatic tumor surgery is affected by intraoperative fluid therapy. METHOD: Fifty-eight patients who underwent a confined excision of pancreas mass at this center were enrolled. The patients were grouped according to the random number table in these two groups: the liberal fluid infusion (LFI) group and the goal-directed fluid therapy (GDFT) group. Perioperative anesthesia management was carried out by the same team of anesthesiologists according to a preset anesthetic protocol. Fecal samples were collected twice: within 2 days before the surgery and at 6 to 8 days postoperatively. The collected fecal samples were sequenced through microbial diversity high-throughput 16 s-rDNA; and the differential changes of intestinal flora were analyzed. RESULTS: Main components of flora in the sample were significantly different between LFI and GDFT groups. As shown by the difference in species, in GDFT group, more constituent bacteria participated in the metabolism inside human body and the restoration of coagulation function, including: prevotella, roseburia, lachnospiracea, dialister and clostridium (P < 0.05); in LFI group, more constituent bacteria were opportunistic pathogenic bacteria, including: enterococcus, pseudomonas aeruginosa, and acinetobacter baumannii (P < 0.05). CONCLUSION: For surgical patients with pancreas tumor, there are significant differences of intestinal flora in diversity between GDFT and LFI. GDFT seems to play a more important role in protection and restoration of intestinal flora. CLINICAL TRIAL REGISTRATION: ChiCTR2000035187 .

Phosphorylation at Ser 727 Increases STAT3 Interaction with PKCε Regulating Neuron-Glia Crosstalk via IL-6-Mediated Hyperalgesia In Vivo and In Vitro.

METHODS: A rat hyperalgesia model was induced using an intraplantar injection of Freund's complete adjuvant (FCA) or an intrathecal injection of IL-6. Mechanical allodynia was evaluated using von Frey filament tests after intrathecal injections of T-5224 (c-Fos/AP-1 inhibitor), minocycline (Mino, a specific microglia inhibitor), L-2-aminoadipic acid (LAA, an astroglial toxin), PKCε inhibitor peptide, APTSTAT3-9R (STAT3 inhibitor), or anti-IL-6 antibody. The c-Fos, GFAP, Iba-1, PKCε, STAT3, pSTAT3Tyr705 and pSTAT3Ser727, and IL-6 expression at the spinal cord level was assessed by Western blot analysis. The interactive effects of PKCε and STAT3 were determined using immunofluorescence staining and immunoprecipitation in vivo and in vitro. Interleukin-6 promoter activity was examined using luciferase assays. RESULTS: T-5224, Mino, and LAA attenuated FCA- or IL-6-mediated inflammatory pain, with a decrease in c-Fos, GFAP, Iba-1, PKCε, and IL-6 expression. PKCε inhibitor peptide and APTSTAT3-9R reversed FCA-induced nociceptive behavior, while decreasing pSTAT3Ser727, IL-6, c-Fos, GFAP, and Iba-1 expression and PKCε and STAT3 coexpression. Interleukin-6 promoter activity increased in the presence of PKCε and STAT3. The interaction with PKCε increased on phosphorylating STAT3 at Ser727 but not at Tyr705. CONCLUSION: STAT3 phosphorylation at Ser 727 and the interaction with PKCε contribute to hyperalgesia via the IL-6-mediated signaling pathway, thus regulating neuron-glia crosstalk during inflammatory pain.

Lidocaine Ameliorates Psoriasis by Obstructing Pathogenic CGRP Signaling‒Mediated Sensory Neuron‒Dendritic Cell Communication.

Psoriasis is a chronic immune-mediated skin disorder with the nervous system contributing to its pathology. The neurogenic mediators of psoriasis are elusive, and whether the intervention of the cutaneous nervous system can treat psoriasis remains to be determined. In this study, we conducted a pilot study using an epidural injection of lidocaine to treat patients with psoriasis. Lidocaine treatment markedly reduced patients' clinical scores and improved an imiquimod-induced rat model of psoriasis as competent as systemic delivery of a TNF-α antibody. Imiquimod application elicited aberrant cutaneous nerve outgrowth and excessive generation of neuropeptide calcitonin gene-related peptide from dorsal root ganglion neurons, both of which were inhibited by epidural lidocaine treatment. Single-cell RNA sequencing unveiled the overrepresentation of calcitonin gene-related peptide receptors in dermal dendritic cell populations of patients with psoriasis. Through disturbing calcitonin gene-related peptide signaling, lidocaine inhibited IL-23 production by dendritic cells cocultured with dorsal root ganglion neurons. Thus, epidural nerve block with lidocaine demonstrates an effective therapy for psoriasis, which suppresses both inordinate sensory nerve growth in the inflamed skin and calcitonin gene-related peptide-mediated IL-23 production from psoriatic dendritic cells.

The Role of SIRT1 in Neuropathic Pain from the Viewpoint of Neuroimmunity.

The current clinical first-line treatment of neuropathic pain still considers only the nervous system as the target, and its therapeutic effect is limited. An increasing number of studies support the opinion that neuropathic pain is a result of the combined action of the sensory nervous system and the related immune system. Under physiological conditions, both the nervous system and the immune system can maintain homeostasis by adjusting the mitochondrial function when sensing noxious stimulation. However, in the case of neuropathic pain, mitochondrial regulatory dysfunction occurs, which may result from the decreased expression of SIRT1. In this study, we review the role of SIRT1 in neuropathic pain from the viewpoint of neuroimmunity.

NLRP3-mediated Neuroinflammation Exacerbates Incisional Hyperalgesia and Prolongs Recovery After Surgery in Chronic Stressed Rats.

BACKGROUND: Postoperative pain management has increasingly become a public health problem worldwide. Psychological factors can be considered as independent risk factors for the intensity of postoperative pain and the occurrence of postoperative chronic pain. OBJECTIVES: As stress events could facilitate NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in the central nervous system, we aimed to explore the role of perioperative NLRP3-mediated neuroinflammation in the exacerbation of incisional hyperalgesia in stressed rats. STUDY DESIGN: Experimental trial in rats. SETTING: Department of Anesthesiology, Shanghai, China. METHODS: All animal experimental procedures were approved by the Animal Care and Use Committee of Shanghai Jiaotong University School of Medicine. This study was conducted in rat models of chronic restraint stress and hind paw incision model. Serum corticosterone level measurement and emotion-related behavioral tests were used to confirm that chronic restraint stress can cause depression-like behavior in rats. Pain behavior after surgery was assessed by withdrawal response to von Frey filament application. Immunofluorescence staining and  the Western blot test were used to evaluate the protein level of NLRP3, IL-1beta, C-fos in the basolateral amygdala (BLA) and GluN2B-containing N-methyl-D-aspartate (NMDA) receptors (GluN2B) expression in the central nucleus of the amygdala (CeA), respectively. Intra-BLA cannulation and microinjection of an NLRP3 specific inhibitor--MCC950 (0.5 µL, 2 µg/µL) were applied to the stressed rats for 4 days perioperatively to explore whether the stress-induced postoperative hyperalgesia and GluN2B expression in CeA can be altered. RESULTS: The results showed that chronic restraint stress exposure led to depressive behavior in rats. Moreover, chronic restraint stress exposure increased NLRP3 and interleukin 1 beta (IL-1beta) expression in the basolateral amygdala (BLA), as well as exacerbated postoperative hyperalgesia and prolonged the recovery time of postoperative pain. Meanwhile, GluN2B expression in the CeA of the stressed group was higher than that of the control incision group. Inhibition of NLRP3 reversed the exacerbation of postoperative hyperalgesia by stress exposure, and down-regulated GluN2B expression in the CeA. LIMITATIONS: The upstream mechanism by which NLRP3 is elevated in stressed rats was not explored. CONCLUSION: These findings suggest that chronic restraint stress may influence postoperative hyperalgesia and NLRP3-mediated neuroinflammation, which may in turn contribute to stress-induced postoperative pain exacerbation.

Regulation and drug modulation of a voltage-gated sodium channel: Pivotal role of the S4-S5 linker in activation and slow inactivation.

Voltage-gated sodium (NaV) channels control excitable cell functions. While structural investigations have revealed conformation details of different functional states, the mechanisms of both activation and slow inactivation remain unclear. Here, we identify residue T140 in the S4-S5 linker of the bacterial voltage-gated sodium channel NaChBac as critical for channel activation and drug effects on inactivation. Mutations at T140 either attenuate activation or render the channel nonfunctional. Propofol, a clinical anesthetic known to inhibit NaChBac by promoting slow inactivation, binds to a pocket between the S4-S5 linker and S6 helix in a conformation-dependent manner. Using 19F-NMR to quantify site-specific binding by saturation transfer differences (STDs), we found strong STDs in inactivated, but not activated, NaChBac. Molecular dynamics simulations show a highly dynamic pocket in the activated conformation, limiting STD buildup. In contrast, drug binding to this pocket promotes and stabilizes the inactivated states. Our results provide direct experimental evidence showing distinctly different associations between the S4-S5 linker and S6 helix in activated and inactivated states. Specifically, an exchange occurs between interaction partners T140 and N234 of the same subunit in activation, and T140 and N225 of the domain-swapped subunit in slow inactivation. The drug action on slow inactivation of prokaryotic NaV channels seems to have a mechanism similar to the recently proposed "door-wedge" action of the isoleucine-phenylalanine-methionine (IFM) motif on the fast inactivation of eukaryotic NaV channels. Elucidating this gating mechanism points to a possible direction for conformation-dependent drug development.

αCaMKII in the lateral amygdala mediates PTSD-Like behaviors and NMDAR-Dependent LTD.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca2+/calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA). Consistently, increasing αCaMKII in the LA not only caused PTSD-like behaviors such as impaired fear extinction and anxiety-like behaviors, but also attenuated N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at thalamo-lateral amygdala (T-LA) synapses, and reduced GluA1-Ser845/Ser831 dephosphorylation and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Suppressing the elevated αCaMKII to normal levels completely rescued both PTSD-like behaviors and the impairments in LTD, GluA1-Ser845/Ser831 dephosphorylation, and AMPAR internalization. Intriguingly, deficits in GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization were detected not only after impaired fear extinction, but also after attenuated LTD. Our results suggest that αCaMKII in the LA may be a potential molecular determinant of PTSD. We further demonstrate for the first time that GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization are molecular links between fear extinction and LTD.

Segmental Zoster Paresis: A Literature Review.

BACKGROUND: Herpes zoster is an acute infectious skin disease that is induced by the re-activation of the virus incubated in nerve ganglions following initial infection with varicella-zoster virus in childhood. Herpes zoster mainly affects sensory nerves, resulting in severe acute pain, which is also the most common reason for medical intervention in this patient group. The concurrent involvement of motor nerves could induce the symptoms of segmental zoster paresis, which is manifested by localized asymmetric myasthenia, whose range generally follows the distribution of myomere with skin rashes. Due to the low incidence and unspecific clinical manifestations, segmental zoster paresis has not been sufficiently recognized by clinicians, and can easily be misdiagnosed. OBJECTIVE: To summarize the previous studies on segmental zoster paresis and analyze the pathogeneses, diagnosis, and treatment of this disease, as well as stress the challenges in current treatment, which could provide useful evidence for the clinical diagnosis and better the treatment of patients with segmental zoster paresis in the future. STUDY DESIGN: We conducted a narrative review. SETTING: Hospitals, neurology departments, pain departments, and private practices. METHODS: We searched PubMed and Chinese CNKI libraries using the terms "herpes zoster," "muscle paresis," "segmental zoster paresis," and "motor nerve." Clinical trials, reviews, and case reports were collected and reviewed. RESULTS: As a rare complication following varicella-zoster virus infection, segmental zoster paresis has not been sufficiently recognized by clinicians, and there are still no guidelines available to guide the clinical treatments. The exact mechanism of segmental zoster paresis is still unclear. Electromyographic and magnetic resonance imaging examinations could be used as auxiliary diagnostic methods for segmental zoster paresis. Early regular anti-viral therapy could substantially decrease the risk of herpes zoster related complications. Combined application of glucocorticoids and some other physical therapy may also be useful in certain patients. The general prognosis of segmental zoster paresis is relatively good, with 67% patients achieving complete or almost complete recovery of the muscle function. LIMITATIONS: More clinical trials are needed to clarify the exact mechanisms and best treating methods. CONCLUSION: As the symptom in most segmental zoster paresis patients is self-limited, and the patients' prognosis is generally good, early diagnosis of the disease is especially important, due to the avoidance of unnecessary diagnostic procedures and incorrect treatments. Standard treatment guidelines regarding the functional rehabilitation are still needed for patients with refractory segmental zoster paresis.

Efficacy of scopolamine plus propofol in the treatment of recalcitrant psoriasis: A pilot study.

Accumulating evidence suggests that botulinum neurotoxins (BoNTs), which inhibit acetylcholine release, can be used for treating plaque psoriasis. The therapeutic effects of scopolamine occur through antagonism of central muscarinic acetylcholine receptors. Thus, scopolamine has potential for the treatment of psoriasis. We aimed to evaluate the efficacy and safety of scopolamine plus propofol for the treatment of recalcitrant psoriasis. Twelve patients with recalcitrant psoriasis were enrolled. Patients received intravenous injection of scopolamine plus propofol for 5 consecutive days per month for a total of 3 months. Clinical efficacy was evaluated using a Psoriasis Area and Severity Index (PASI) score. Efficacy outcome was ≥75% reduction in PASI score (PASI75) from baseline. Two patients were lost to follow-up. At week 8, two of 10 patients (20%) achieved PASI75, and at week 12, seven of 10 (70%) achieved PASI75. Treatment was well tolerated, with no reported adverse events. Our study revealed the efficacy and safety of scopolamine plus propofol for the treatment of recalcitrant psoriasis. Scopolamine plus propofol therapy may be a new treatment for recalcitrant psoriasis.

Substance P Mediates Estrogen Modulation Proinflammatory Cytokines Release in Intervertebral Disc.

Intervertebral disc degeneration (IDD) is a main contributor to low back pain. A close relationship exists between inflammation and pain. Estrogen can affect inflammation and may play a crucial role in IDD and pain. Substance P (SP) can also regulate the expression of pro-inflammatory cytokines in intervertebral disc (IVD). This study aimed to investigate the potential role of SP in estrogen regulation of IDD. Nine-week-old C57BL/6 female mice were divided into four groups as follows: sham surgery (sham), ovariectomy (OVX), ovariectomy plus estrogen replacement therapy (ERT) group (OVX+E2), and ovariectomy, ERT plus neurokinin 1 receptor (NK1R) agonist (OVX+E2+G). Serum E2, body, and uterus weight were recorded. Immunohistochemistry study and quantitative real-time PCR were used for SP, NK1R, IL-1ß, IL-6, and TNF-α examination and comparison in IVD at protein and gene levels. After OVX, the gene and protein expression of TNF-α, IL-1ß, IL-6, SP, and NK1R in NP cells significantly increased compared with the sham group. ERT can reverse these impacts. ERT plays anti-inflammatory and anti-hyperalgesic roles in IDD of OVX mice. The estrogen-induced changes of the pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, are significantly inhibited by NK1R agonists. SP may be a mediator of estrogen regulating pro-inflammatory factors in IDD. Estrogen may affect IVD inflammation through two ways: one is to directly affect the level of pro-inflammatory cytokines and the other is by means of modulation of SP.