Clickable Polymerization-Induced Emission Luminogens Toward Color-Tunable Modification of Non-Traditional Intrinsic Luminescent Polymers.

Non-traditional intrinsic luminescent (NTIL) polymer is an emerging field, and its color-tunable modification is highly desirable but still rarely investigated. Here, a click chemistry approach for the color-tunable modifications of NTIL polymers by introducing clickable polymerization-induced emission luminogen (PIEgen), is demonstrated. Through Cu-catalyzed azide-alkyne cycloaddition click chemistry, a series of PIEgens is successful prepared, which is further polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Interestingly, after clickable modification, these monomers are nonemissive in both solution and aggregation states; while, the corresponding polymers exhibit intriguing aggregation-induced emission (AIE) characteristics, confirming their PIEgen characteristics. By varying alkynyl substitutions, color-tunable NTIL polymers are achieved with emission wavelength varying from 448 to 498 nm, revealing a series of PIEgens and verifying the importance of modification of NTIL polymers. Further luminescence energy transfer application is carried out as well. This work therefore designs a series of clickable PIEgens and opens a new avenue for the modification of NTIL polymers via click chemistry, which may cause inspirations to the research fields including luminescent polymer, NTIL, click chemistry, AIE and modification.

Versatile Polymerization-Induced Emission Polymers from Barbier Polymerization of Cinnamic Esters with Tunable Emission.

Cinnamic ester is a common and abundant chemical substance, which can be extracted from natural plants. Compared with traditional esters, cinnamic ester contains α,ß-unsaturated carbonyl structure with multiple reactive sites, resulting in more abundant reactivities and chemical structures. Here, a versatile polymerization-induced emission (PIE) is successfully demonstrated through Barbier polymerization of cinnamic ester. Attributed to its abundant reactivities of α,ß-unsaturated carbonyl structure, Barbier polymerization of cinnamic esters with different organodihalides gives polyalcohol and polyketone via 1,2-addition and 1,4-addition, respectively, which is also confirmed by small molecular model reactions. Meanwhile, these organodihalides dependant polyalcohol and polyketone exhibit different non-traditional intrinsic luminescence (NTIL) from aggregation-induced emission (AIE) type to aggregation-caused quenching (ACQ) type, where novel PIE luminogens (PIEgens) are revealed. Further potential applications in explosive detection are carried out, where it achieves TNT detection sensitivity at ppm level in solution and ng level on the test paper. This work therefore expands the structure and functionality libraries of monomer, polymer and NTIL, which might cause inspirations to different fields including polymer chemistry, NTIL, AIE and PIE.

Effectiveness of perioperative low-dose esketamine infusion for postoperative pain management in pediatric urological surgery: a prospective clinical trial.

BACKGROUND: Postoperative pain is common in pediatric urological surgery. The study assess the impact of perioperative intravenous infusion of low-dose esketamine on postoperative pain in pediatric urological surgery. METHODS: Pediatric patients (n = 80) undergoing urological surgery were randomized into four groups. Patients in the control group were administered an analgesic pump containing only hydromorphone at a dose of 0.1 mg/kg (Hydromorphone Group 1, H1) or 0.15 mg/kg (Hydromorphone Group 2, H2). Patients in the experimental group were injected intravenously with 0.3 mg/kg of esketamine (Esketamine group 1, ES1) or equal volume of saline (Esketamine Group 2, ES2) during anesthesia induction. Esketamine 1.0 mg/kg and hydromorphone 0.1 mg/kg were added to the analgesic pump. Face, Leg, Activity, Crying, and Comfort (FLACC) scale or the Numerical Rating Scale (NRS) and adverse effects were recorded at 2, 6, 24, and 48 h postoperatively. Additionally, total and effective PCA button presses were recorded. RESULTS: In comparison to the H1 group, the pain scores were notably reduced at all postoperative time points in both the ES1 and H2 groups. The ES2 group exhibited lower pain scores only at 24 and 48 h postoperatively. When compared to the H2 group, there were no significant differences in pain scores at various postoperative time points in the ES2 group. However, the ES1 group demonstrated significantly lower pain scores at 6, 24 and 48 h postoperatively, and these scores were also significantly lower than those observed in the ES2 group. The total and effective number of PCA button presses in the ES1, ES2 and H2 group were lower than that in the H1 group (P < 0.001). The incidence of adverse effects within 48 h after surgery was 15% in ES1, 22% in ES2, 58% in H1, and 42% in H2, respectively (P = 0.021). CONCLUSIONS: The use of low-dose esketamine infusion in analgesia pump can effectively alleviates postoperative pain in pediatric urological patients, leading to a significant reduction in the number of analgesic pump button press. The combined approach of perioperative anesthesia induction and analgesia pump administration is recommended for optimal pain management in these patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry- ChiCTR2300073879 (24/07/2023).

Potential novel therapeutic strategies for neuropathic pain.

Purpose: To explore the potential therapeutic strategies of different types of neuropathic pain (NP) and to summarize the cutting-edge novel approaches for NP treatment based on the clinical trials registered on ClinicalTrials.gov. Methods: The relevant clinical trials were searched using ClinicalTrials.gov Dec 08, 2022. NP is defined as a painful condition caused by neurological lesions or diseases. All data were obtained and reviewed by the investigators to confirm whether they were related to the current topic. Results: A total of 914 trials were included in this study. They were divided into painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), sciatica (SC), peripheral nerve injury-related NP (PNI), trigeminal neuralgia (TN), chemotherapy-induced NP (CINP), general peripheral NP (GPNP) and spinal cord injury NP (SCI-NP). Potential novel therapeutic strategies, such as novel drug targets and physical means, were discussed for each type of NP. Conclusion: NP treatment is mainly dominated by drug therapy, and physical means have become increasingly popular. It is worth noting that novel drug targets, new implications of conventional medicine, and novel physical means can serve as promising strategies for the treatment of NP. However, more attention needs to be paid to the challenges of translating research findings into clinical practice.

Mapping the current trends and hotspots of vascular cognitive impairment from 2000-2021: A bibliometric analysis.

AIMS: To visualize the trends and hotspots in the scientific research related to vascular cognitive impairment (VCI) quantitatively and qualitatively. METHODS: Cross-sectional bibliometric analysis of publications that related to VCI was conducted. Publications were found by searching in the Web of Science Core Collection database (WoSCC) - Edition: Science Citation Index Expanded (SCI-Expanded) from January 2000 to December 2021. Publication type was restricted to article and review in the English language. The downloaded data were screened and analyzed in January 2022. RESULTS: In total, 16,264 publications were identified, with a steady increase in annual publications. The United States was the leading country in VCI research regarding publication numbers and national influence. National Institute of Aging had the highest influence among all the institutes in the field of VCI. Philip Scheltens was the most active author. The top five active authors' publications focused on pathobiology, neuroimaging standards, risk factors, prevention, and the standard diagnosis of vascular dementia (VaD). A co-cited publication clustering resulted in 19 main clusters, and the prevention, blood-brain barrier, cholesterol, cerebral amyloid angiopathy, and VaD were the top 5 clusters. Moreover, burst keywords detection revealed that the "small vessel disease" is the current hotspot in the field of VCI. CONCLUSIONS: This bibliometric analysis mapped the overall research structure of VCI and analyzed the current research trends and hotspots for future studies orientation. Neuroimaging, risk factors detection, and pathobiology are the current trends in VCI research. Small vessel disease and its mechanisms are the current hotspots of VCI research.

Research Trends and Hotspots on Herpes Zoster: A 10-Year Bibliometric Analysis (2012-2021).

Purpose: Herpes zoster infection, with its considerable burden to individuals and society, remains a challenge around the world. However, to the knowledge of the authors, little bibliometric quantitative or qualitative analysis has been carried out to evaluate herpes zoster research. This study aimed to use a bibliometric analysis to evaluate current publication trends and hotspots on herpes zoster research worldwide, in order to advance research in this field. Methods: Relevant publications from January 2012 to December 2021 were collected from the Web of Science Core Collection database. Citespace (V5.8.R3) was used to analyze the research points, including publication countries, institutions and authors, cited author, cited reference and their clustering, and keyword co-occurrence, and burst keyword to acquire research trends and hotspots. Results: A total of 9,259 publications were obtained, with a steady increase in the number of annual publications during the decade. Articles were the main type of publication. The United States is the leading country in this research, and the University of Colorado has the highest influence in this field. Oxman is the most representative author, with a main research interest in herpes zoster vaccines. The top five cited authors' publications focused on herpes zoster vaccines, molecular mechanisms, and postherpetic neuralgia. A co-citation map resulted 19 main clusters, and revealed that vaccines, postherpetic neuralgia, treatments, varicella zoster virus and its mechanisms, and epidemiology of herpes zoster were the current research focus after clustering co-cited publications. Human herpesviruses, antiviral prophylaxis, rheumatoid arthritis, recombinant zoster vaccine, varicella vaccination and postherpetic neuralgia were the top clusters after co-occurrence keywords analysis. Moreover, burst keywords detection showed that the subunit vaccine was the new hotspot in the field of herpes zoster. Conclusion: This bibliometric study defined the overall prospects in the field of herpes zoster and provided valuable instruction for the ongoing research. The keyword "subunit vaccine" indicated that a vaccine for herpes zoster prevention was the hotspot. Efforts to prevent varicella zoster virus infection will be essential to improve herpes zoster outcomes.

Emerging Trends and Hot Spots in Sepsis-Associated Encephalopathy Research From 2001 to 2021: A Bibliometric Analysis.

Study Objectives: To evaluate sepsis-associated encephalopathy (SAE) research and to quantitatively and qualitatively predict research hot spots using bibliometric analysis. Methods: We extracted relevant publications from the Web of Science Core Collection on July 28, 2021. We investigated the retrieved data by bibliometric analysis (e.g. co-cited and cluster analysis, keyword co-occurrence) using the software CiteSpace and VOSviewer, the Online Analysis Platform of Literature Metrology (http://bibliometric.com/) and Bibliometrix to analyse and predict the trends and hot spots in this field. Main Results: We identified 1,582 published articles and reviews on SAE from 2001 to 2021. During this period, the number of manuscripts on SAE increased steadily and peaked in 2021. The USA and China were the leading countries that had a critical impact on SAE research. Among all institutions, Vanderbilt University and Pittsburgh University held leading positions and became central in the collaboration network. Among all the journals, Critical Care Medicine published the maximum number of manuscripts in the field of SAE within 20 years. Dal-Pizzol Felipe was the most productive author (61 papers) and received the largest number of citations (930 citations). Co-citation cluster analysis revealed that the most popular terms on SAE in the manner of cluster labels were critical illness, sepsis-associated encephalopathy, polymicrobial sepsis, posterior reversible encephalopathy syndrome, rat brain, intensive care unit, prior sepsis, molecular hydrogen, inflammation drive, metabolic encephalopathies, delirium pathophysiology, and clinical neuroscience. Keyword burst detection indicated that neuroinflammation, blood-brain barrier (BBB) and mitochondria dysfunction were the current research hot spots. Conclusions: Our study revealed that neuroinflammation, blood-brain barrier, and mitochondria dysfunction had been the research foci of SAE over the past 20 years. These have emerged as the basis for transformation from basic research to clinical application in finding effective methods for the prevention and treatment of SAE.

Electroacupuncture relieves neuropathic pain by inhibiting degradation of the ecto-nucleotidase PAP in the dorsal root ganglions of CCI mice.

BACKGROUND: Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs). METHODS: We applied EA in male C57 mice subjected to chronic constriction injury (CCI) and assessed extracellular ATP and 5'-nucleotidease expression in DRGs. Specifically, we used a luminescence assay, quantitative reverse transcriptase-polymerase chain reaction, Western blotting, immunohistochemistry and nociceptive-related behavioural changes to gather data, and we tested for effects after PAP expression was inhibited with an adeno-associated virus (AAV). Moreover, membrane PAP degradation was investigated in cultured DRG neurons and the inhibitory effects of EA on this degradation were assessed using immunoprecipitation. RESULTS: EA treatment alleviated CCI surgery-induced mechanical pain hypersensitivity. Furthermore, extracellular ATP decreased significantly in both the DRGs and dorsal horn of EA-treated mice. PAP protein but not mRNA increased in L4-L5 DRGs, and inhibition of PAP expression via AAV microinjection reversed the analgesic effect of EA. Membrane PAP degradation occurred through a clathrin-mediated endocytosis pathway in cultured DRG neurons; EA treatment inhibited the phosphorylation of adaptor protein complex 2, which subsequently reduced the endocytosis of membrane PAP. CONCLUSIONS: EA treatment alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice by inhibiting membrane PAP degradation via reduced endocytosis and subsequently promote ATP dephosphorylation in DRGs. SIGNIFICANCE: In a mouse model of chronic pain, electroacupuncture treatment increased levels of prostatic acid phosphatase (PAP: an ecto-nucleotidase known to relieve pain hypersensitivity) by inhibiting PAP degradation in dorsal root ganglions. This promoted extracellular ATP dephosphorylation, inhibited glia activation and eventually alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice. Our findings represent an important step forward in clarifying the mechanisms of pain relief afforded by acupuncture treatment.

Publication Trends and Hot Spots in Chronic Postsurgical Pain (CPSP) Research: A 10-Year Bibliometric Analysis.

PURPOSE: Aging populations and increasing quality of life requirements have attracted growing efforts to study chronic postsurgical pain (CPSP). However, a diverse range of factors are involved in CPSP development, which complicates efforts to predict and treat this disease. To advance research in this field, our study aimed to use bibliometric analysis to quantitatively and qualitatively evaluate CPSP research and predict research hot spots over the last 10 years. METHODS: Relevant publications between 2011 and 2020 were extracted from the Web of Science Core Collection database. CiteSpace software (v5.7.R2) and the Online Analysis Platform of Literature Metrology were used to analyze research attributes including countries and authors, keywords and co-occurrence, and burst detection to predict trends and hot spots. RESULTS: A total of 2493 publications were collected with the number of annual publications showing nearly threefold increase over the past decade. Articles were the primary publication type with the United States as the leading country and the center of national collaboration. Johns Hopkins University provided the leading influence within the CPSP field. Postoperative pain, multimodal analgesia, quality of life, opioid, microglia, cesarean delivery, inguinal hernia, chronification, genetic polymorphism, and lidocaine were the top 10 clusters in co-occurrence cluster analysis. Moreover, burst detection was shown that epidural analgesia, nerve injury, total hip arthroplasty were the new hot spots within the CPSP field. CONCLUSION: Bibliometric mapping not only defined the overall structure of CPSP-related research but its collective information provides crucial assistance to direct ongoing research efforts. The prominent keywords including "risk factor" and "multimodal analgesia" indicate that CPSP prevention and new treatment methods remain hot spots. Nonetheless, the recognition that CPSP is complex and changeable, proposes comprehensive biopsychosocial approaches are needed, and these will be essential to improve CPSP interventions and outcomes.

Preoperative Chronic Pain as a Risk Factor for Early Postoperative Cognitive Dysfunction in Elderly Patients Undergoing Hip Joint Replacement Surgery: A Prospective Observational Cohort Study.

Background: Although major joint replacement surgery has a high overall success rate, postoperative cognitive dysfunction (POCD) is a common complication after anesthesia and surgery, increasing morbidity and mortality. Identifying POCD risk factors would be helpful to prevent and decrease the occurrence of POCD. We hypothesized that preoperative chronic pain increases the risk of POCD. Methods: A single-center, observational, prospective cohort study was conducted from January 2018 to March 2020. All consecutive elderly patients (>65 years) who underwent elective total hip arthroplasty or hemiarthroplasty with general anesthesia by the same surgeon were enrolled. The patients underwent neuropsychological testing preoperatively and at 7 days and 2 months after surgery. To determine POCD, a nonsurgical control group was recruited from the general community. Results: Of the 141 patients who finished the neuropsychological testing 7 days after surgery, 61 (43.2%) had preoperative chronic pain. Of the 61 patients, 17 (27.9%) developed POCD; of the 79 patients with no chronic pain, 10 (12.7%) had developed POCD by 7 days after surgery. Multivariate logistic regression analysis identified preoperative chronic pain as a risk factor of POCD assessed 7 days after surgery (odds ratio 6.527; P = 0.009). There was no significant difference in the POCD incidence 2 months after surgery between patients with and without preoperative chronic pain. Conclusion: Preoperative chronic pain was a risk factor of developing POCD within 7 days after surgery in elderly patients following hip joint replacement surgery. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03393676].

Effects of transcutaneous electrical acupuncture point stimulation on peripheral capillary oxygen saturation in elderly patients undergoing colonoscopy with sedation: a prospective randomized controlled trial.

INTRODUCTION: This study investigated whether transcutaneous electrical acupuncture point stimulation (TEAS) at PC6 can reduce the proportion of elderly patients experiencing a drop of ⩾4% in peripheral capillary oxygen saturation (SpO2) while undergoing colonoscopy under sedation. METHODS: A total of 32 elderly patients (aged ⩾ 65 years) scheduled for colonoscopy were randomly assigned in a 1:1 ratio to receive either real or sham TEAS (treatment or control groups, respectively). Each patient received oxygen (2 L/min) delivered routinely via nasal cannula. The treatment group was given TEAS at PC6 for 20 min at 2 Hz frequency and 6 mA intensity; the control group underwent the same procedures but with zero frequency/intensity. SpO2 and other physiological parameters were measured prior to sedation and colonoscopy (baseline) and at seven other timepoints through departure from recovery. Depth of anesthesia was measured using a Narcotrend monitor. RESULTS: Significantly fewer patients in the treatment group experienced a ⩾4% decrease from baseline SpO2 (2/16) than patients in the control group (10/16; p = 0.004). The two groups were comparable with regard to respiratory rate, systolic and diastolic blood pressures, mean arterial pressure, and heart rate. CONCLUSION: TEAS applied at PC6 with 2 Hz frequency was feasible and may be helpful in reducing the rate of hypoxia in elderly patients during colonoscopy.Trial registration number: NCT03775122 (ClinicalTrials.gov).

Author Correction: DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Molecular Transport through a Biomimetic DNA Channel on Live Cell Membranes.

Biological membrane channels, considered as molecular gatekeepers, control the transportation of molecules and ions across live cell membranes. Developing synthetic passable channels with predictable structures, high transport efficiency, and low cytotoxicity on live cells is of great interest for replicating the functions of endogenous protein channels, but remains challenging. The development of DNA nanotechnology provides possible solutions for making synthetic channels with precise structures and controllable functionalization. Therefore, in this work, we constructed a phosphorothioate-modified DNA nanopore able to structurally mimic biological channels for molecular transport across live cell membranes. With its stable structure with small hollow size (<2 nm) and the ability to interact with the lipid molecules, this DNA nanopore could show stable insertion into the plasma membrane. We further proved that this membrane-spanning channel could transport ions and antitumor drugs to neurons and cancer cells, respectively, and do so within a certain time window. We expect that this live cell membrane-spanning synthetic DNA nanopore will provide a tool for studying cellular communication, building synthetic cells, and achieving controlled transmembrane transport to cells.

Neuropeptide Y1 Receptor Antagonist Alters Gut Microbiota and Alleviates the Ovariectomy-Induced Osteoporosis in Rats.

A plethora of evidence has suggested that gut microbiota is involved in the occurrence and development of postmenopausal osteoporosis (PMO). It has been suggested that neuropeptide Y (NPY) modulates the bone metabolism through Y1 receptor (Y1R), and might be associated with gut microbiota. The present study aims to evaluate the anti-osteoporotic effects of Y1R antagonist and to investigate the potential mechanism by which Y1R antagonist regulates gut microbiota. In this study, eighteen female rats were randomly divided into three groups: the sham surgery (SHAM) group, the ovariectomized (OVX) group, and OVX+BIBO3304 group. After 6 weeks following surgery, Y1R antagonist BIBO3304 was administered to the rats in OVX+BIBO3304 group for 7 days. The bone microstructure and serum biochemical parameters were measured at 12 weeks after operation. The differences in the gut microbiota were analyzed by 16S rDNA gene sequencing. Heat-map and Spearman's correlation analyses were constructed to investigate the correlations between microbiota and bone metabolism-related parameters. The results indicated that OVX+BIBO3304 group showed significantly higher BMD, BV/TV, Tb.Th, Tb.N, Conn.D, and serum Ca2+ level than those in OVX group. Additionally, Y1R antagonist changed the gut microbiota composition with lower Firmicutes/Bacteroidetes ratio and higher proportions of some probiotics, including Lactobacillus. The correlation analysis showed that the changes of gut microbiota were closely associated with bone microstructure and serum Ca2+ levels. Our results suggested that Y1R antagonist played an anti-osteoporotic effect and regulated gut microbiota in OVX rats, indicating the potential to utilize Y1R antagonist as a novel treatment for PMO.

Sleep deprivation of rats increases postsurgical expression and activity of L-type calcium channel in the dorsal root ganglion and slows recovery from postsurgical pain.

Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain.

Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing Kcna2 in Primary Afferent Neurons.

Expressional changes of pain-associated genes in primary sensory neurons of DRG are critical for neuropathic pain genesis. DNA methyltransferase (DNMT)-triggered DNA methylation silences gene expression. We show here that DNMT1, a canonical maintenance methyltransferase, acts as the de novo DNMT and is required for neuropathic pain genesis likely through repressing at least DRG Kcna2 gene expression in male mice. Peripheral nerve injury upregulated DNMT1 expression in the injured DRG through the transcription factor cAMP response element binding protein-triggered transcriptional activation of Dnmt1 gene. Blocking this upregulation prevented nerve injury-induced DNA methylation within the promoter and 5'-untranslated region of Kcna2 gene, rescued Kcna2 expression and total Kv current, attenuated hyperexcitability in the injured DRG neurons, and alleviated nerve injury-induced pain hypersensitivities. Given that Kcna2 is a key player in neuropathic pain, our findings suggest that DRG DNMT1 may be a potential target for neuropathic pain management.SIGNIFICANCE STATEMENT In the present study, we reported that DNMT1, a canonical DNA maintenance methyltransferase, is upregulated via the activation of the transcription factor CREB in the injured DRG after peripheral nerve injury. This upregulation was responsible for nerve injury-induced de novo DNA methylation within the promoter and 5'-untranslated region of the Kcna2 gene, reductions in Kcna2 expression and Kv current and increases in neuronal excitability in the injured DRG. Since pharmacological inhibition or genetic knockdown of DRG DNMT1 alleviated nerve injury-induced pain hypersensitivities, DRG DNMT1 contributes to neuropathic pain genesis partially through repression of DRG Kcna2 gene expression.

High-Voltage-Activated Calcium Channel in the Afferent Pain Pathway: An Important Target of Pain Therapies.

High-voltage-activated (HVA) Ca2+ channels are widely expressed in the nervous system. They play an important role in pain conduction by participating in various physiological processes such as synaptic transmission, changes in synaptic plasticity, and neuronal excitability. Available evidence suggests that the HVA channel is an important therapeutic target for pain management. In this review, we summarize the changes in different subtypes of HVA channel during pain and present the currently available evidence from the clinical application of HVA channel blockers. We also review novel drugs in various phases of development. Moreover, we discuss the future prospects of HVA channel blockers in order to promote "bench-to-bedside" translation.

DNMT3a-triggered downregulation of K2p 1.1 gene in primary sensory neurons contributes to paclitaxel-induced neuropathic pain.

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K2p 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 2p 1.1 mRNA and its coding K2p 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K2p 1.1 and mimicking this increase reduces DRG K2p 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K2p 1.1 may contribute to chemotherapy-induced neuropathic pain.

MBD1 Contributes to the Genesis of Acute Pain and Neuropathic Pain by Epigenetic Silencing of Oprm1 and Kcna2 Genes in Primary Sensory Neurons.

The transmission of normal sensory and/or acute noxious information requires intact expression of pain-associated genes within the pain pathways of nervous system. Expressional changes of these genes after peripheral nerve injury are also critical for neuropathic pain induction and maintenance. Methyl-CpG-binding domain protein 1 (MBD1), an epigenetic repressor, regulates gene transcriptional activity. We report here that MBD1 in the primary sensory neurons of DRG is critical for the genesis of acute pain and neuropathic pain as DRG MBD1-deficient mice exhibit the reduced responses to acute mechanical, heat, cold, and capsaicin stimuli and the blunted nerve injury-induced pain hypersensitivities. Furthermore, DRG overexpression of MBD1 leads to spontaneous pain and evoked pain hypersensitivities in the WT mice and restores acute pain sensitivities in the MBD1-deficient mice. Mechanistically, MDB1 represses Oprm1 and Kcna2 gene expression by recruiting DNA methyltransferase DNMT3a into these two gene promoters in the DRG neurons. DRG MBD1 is likely a key player under the conditions of acute pain and neuropathic pain.SIGNIFICANCE STATEMENT In the present study, we revealed that the mice with deficiency of methyl-CpG-binding domain protein 1 (MBD1), an epigenetic repressor, in the DRG displayed the reduced responses to acute noxious stimuli and the blunted neuropathic pain. We also showed that DRG overexpression of MBD1 produced the hypersensitivities to noxious stimuli in the WT mice and rescued acute pain sensitivities in the MBD1-deficient mice. We have also provided the evidence that MDB1 represses Oprm1 and Kcna2 gene expression by recruiting DNA methyltransferase DNMT3a into these two gene promoters in the DRG neurons. DRG MBD1 may participate in the genesis of acute pain and neuropathic pain likely through regulating DNMT3a-controlled Oprm1 and Kcna2 gene expression in the DRG neurons.