Eukaryotic initiation factor 4 gamma 2 contributes to neuropathic pain through down-regulation of Kv1.2 and the mu opioid receptor in mouse primary sensory neurones.

BACKGROUND: Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to neuropathic pain genesis. Eukaryotic initiation factor 4 gamma 2 (eIF4G2) is a general repressor of cap-dependent mRNA translation. Whether DRG eIF4G2 participates in nerve injury-induced alternations in gene expression and nociceptive hypersensitivity is unknown. METHODS: The expression and distribution of eIF4G2 mRNA and protein in mouse DRG after spinal nerve ligation (SNL) were assessed. Effects of eIF4G2 siRNA microinjected through a glass micropipette into the injured DRG on the SNL-induced DRG mu opioid receptor (MOR) and Kv1.2 downregulation and nociceptive hypersensitivity were examined. In addition, effects of DRG microinjection of adeno-associated virus 5-expressing eIF4G2 (AAV5-eIF4G2) on basal DRG MOR and Kv1.2 expression and nociceptive thresholds were analysed. RESULTS: eIF4G2 protein co-expressed with Kv1.2 and MOR in DRG neurones. Levels of eIF4G2 mRNA (1.7 [0.24] to 2.3 [0.14]-fold of sham, P<0.01) and protein (1.6 [0.14] to 2.5 [0.22]-fold of sham, P<0.01) in injured DRG were time-dependently increased on days 3-14 after SNL. Blocking increased eIF4G2 through microinjection of eIF4G2 siRNA into the injured DRG attenuated SNL-induced downregulation of DRG MOR and Kv1.2 and development and maintenance of nociceptive hypersensitivities. DRG microinjection of AAV5-eIF4G2 reduced DRG MOR and Kv1.2 expression and elicited hypersensitivities to mechanical, heat and cold stimuli in naïve mice. CONCLUSIONS: eIF4G2 contributes to neuropathic pain through participation in downregulation of Kv1.2 and MOR in injured DRG and is a potential target for treatment of this disorder.

Altered Cortical Reorganization and Brain Functional Connectivity in Phantom Limb Pain: A Functional MRI Study.

OBJECTIVES: Functional neuroimaging studies have shown that amputees have altered cortical reorganization and functional connectivity (FC). This study aimed to investigate whether patients with phantom limb pain (PLP) and PLP-free lower limb amputees exhibit changes in corresponding primary cortical motor area/somatosensory cortex (M1/S1) cortical reorganization and supplementary motor area (SMA) network FC. The association between functional magnetic resonance imaging (fMRI) changes and clinical parameters is also explored. METHODS: A total of 10 PLP patients were matched with 10 PLP-free amputees and 10 healthy controls (HCs). Before undergoing fMRI, all participants completed questionnaires evaluating pain, anxiety, depression, and health-related quality of life. Task-related activation and regions of interest (ROI)-wise connectivity analysis were applied to differentiate the brain regions of amputees from those of HCs. Linear correlation analysis was used to evaluate the correlation between altered FC and clinical manifestations. RESULTS: As compared with HCs, PLP patients showed increased cortical activation in M1/S1 when moving the intact foot, imagining phantom big toe movement, or having the corresponding thumb stimulated. The increased FC in the SMA network included the SMA-caudate nucleus, SMA-bilateral insula, and SMA-anterior cingulate cortex. Furthermore, results of the linear correlation analysis demonstrated that this increased FC was positively correlated with VAS scores, negatively correlated with Medical Outcomes Study 36-item Short-Form (SF-36) scores, and not correlated with anxiety or depression scores. CONCLUSIONS: Phantom limb pain in lower limb amputees is associated with M1/S1 cortical reorganization and altered SMA network FC in different areas of the brain, which could help to support our understanding of the central mechanism of PLP.

Case report: safety and efficacy of lidocaine infusion for the treatment of intractable zoster-associated neuralgia in solid organ transplant recipients.

Introduction: Solid organ transplant recipients are at high risk for developing severe zoster-associated neuralgia, and the pharmaceutic therapies of pain management for these patients with limited organ function are challenging. Intravenous lidocaine infusion showed positive analgesic effects and is used for the management of neuropathic pain. This case series reports the safety and effectiveness of intravenous lidocaine infusion in the treatment of intractable zoster-associated neuralgia in solid organ transplant recipients. Case series presentation: Five solid organ transplant recipients suffering from refractory zoster-associated neuralgia (numeric rating scale 8-10, despite using high doses of antiepileptic drugs or combined with opioids) were enrolled. Intravenous lidocaine (5 mg/kg ideal bodyweight) was administered over 1.5 h with the monitoring of vital signs. Pain intensity, patient satisfaction, adverse events, typical liver, and kidney function were evaluated. All subjects reported high satisfaction with their treatment and effective pain relief at the 6-month follow-up. One patient experienced short and mild numbness in the mouth and dizziness after the therapy, but no major adverse reactions were reported. Conclusion: This case series provides evidence that intravenous lidocaine infusion provided effective pain relief as an analgesic treatment option for transplant patients with intractable zoster-associated neuralgia.

Predictors of a Favorable Response to Transforaminal Epidural Steroid Injections for Lumbar Radiculopathy in the Elderly.

BACKGROUND: The efficacy and its associated predictors of transforaminal epidural steroid injection (TFESI) in elderly patients with lumbar radiculopathy are unknown. OBJECTIVE: The purpose of this retrospective study was to identify the efficacy of TFESI in elderly patients with lumbar radiculopathy and its associated predictors of long-term outcomes. STUDY DESIGN: Retrospective study. SETTING: Interventional pain clinics in West China Hospital of Sichuan University. METHODS: In total, 294 elderly patients who were diagnosed with lumbar radiculopathy and underwent transforaminal epidural steroid injections from January 2019 through January 2022 were retrospectively analyzed. Demographic, clinical, magnetic resonance imaging, and TFESI-related information was collected to assess the predictive factors of long-term outcomes of the TFESI. Pain scores were assessed using the Numeric Rating Scale. Treatment success was defined as a >= 50% reduction in pain scores at 6 months. RESULTS: Multivariate logistic regression analysis revealed that the duration of symptoms, immediate postoperative response, and neutrophilic granulocyte percentage were independently associated with a favorable response to TFESI. In addition, the level of pain at the initial visit and the number of TFESI performed were also associated with a good response in the multivariate regression analysis, even though the association was not statistically significant. LIMITATIONS: Approximately 6% of the patients were lost to follow-up; therefore, selection bias may have slightly influenced our findings. In addition, our patients were not compared with a control population, and consequently, a placebo effect could not be assessed. CONCLUSION: This study revealed that a short duration of symptoms, good immediate postoperative response and high neutrophilic granulocyte percentage were long-term predictors of a good response to TFESI in elderly patients with lumbar radiculopathy.

TET1 overexpression attenuates paclitaxel-induced neuropathic pain through rescuing K2p1.1 expression in primary sensory neurons of male rats.

AIMS: Paclitaxel-induced downregulation of two-pore domain K+ channel 1.1 (K2p1.1) caused by increasing DNA methylation within its gene promoter in the dorsal root ganglion (DRG) contributes to neuropathic pain. Given that ten-eleven translocation methylcytosine dioxygenase 1 (TET1) promotes DNA demethylation and gene transcription, the present study investigated whether DRG overexpression of TET1 produces an antinociceptive effect on the paclitaxel-induced nociceptive hypersensitivity. MAIN METHODS: TET1 was overexpressed in the DRG through unilateral microinjection of the herpes simplex virus expressing full-length Tet1 mRNA into the fourth and fifth lumbar DRGs of male rats. Behavioral tests were carried out to examine the effect of this overexpression on the paclitaxel-induced nociceptive hypersensitivity. Western blot analysis, chromatin immunoprecipitation assay and 5-hydroxymethylcytosine detection assay were performed to assess the levels of TET1/K2p1.1, 5-methylcytosine and 5-hydroxymethylcytosine, respectively. KEY FINDINGS: DRG overexpression of TET1 mitigated the paclitaxel-induced mechanical allodynia, heat hyperalgesia and cold hyperalgesia on the ipsilateral side during the development and maintenance periods. Locomotor function or basal (acute) responses to mechanical, heat or cold stimuli were not affected. Mechanistically, DRG overexpression of TET1 rescued the expression of K2p1.1 by blocking the paclitaxel-induced increase in the level of 5-methylcytosine and correspondingly reversing the paclitaxel-induced decreases in the amount of 5-hydroxymethylcytosine within the K2p1.1 promoter region in the microinjected DRGs of male rats. SIGNIFICANCE: Our findings suggest that DRG overexpression of TET1 alleviated chemotherapy-induced neuropathic pain likely through rescuing DRG K2p1.1 expression. Our findings may provide a potential avenue for the management of this disorder.

Effect of Pharmacological Inhibition of Fat-Mass and Obesity-Associated Protein on Nerve Trauma-Induced Pain Hypersensitivities.

Genetic knockout or knockdown of fat-mass and obesity-associated protein (FTO), a demethylase that participates in RNA N6-methyladenosine modification in injured dorsal root ganglion (DRG), has been demonstrated to alleviate nerve trauma-induced nociceptive hypersensitivities. However, these genetic strategies are still impractical in clinical neuropathic pain management. The present study sought to examine the effect of intrathecal administration of two specific FTO inhibitors, meclofenamic acid (MA) and N-CDPCB, on the development and maintenance of nociceptive hypersensitivities caused by unilateral L5 spinal nerve ligation (SNL) in rats. Intrathecal injection of either MA or N-CDPCB diminished dose-dependently the SNL-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneous ongoing nociceptive responses in both development and maintenance periods, without altering acute/basal pain and locomotor function. Intrathecal MA also reduced the SNL-induced neuronal and astrocyte hyperactivities in the ipsilateral L5 dorsal horn. Mechanistically, intrathecal injection of these two inhibitors blocked the SNL-induced increase in the histone methyltransferase G9a expression and rescued the G9a-controlled downregulation of mu opioid receptor and Kv1.2 proteins in the ipsilateral L5 DRG. These findings further indicate the role of DRG FTO in neuropathic pain and suggest potential clinical application of the FTO inhibitors for management of this disorder.

Nerve trauma-caused downregulation of opioid receptors in primary afferent neurons: Molecular mechanisms and potential managements.

Neuropathic pain is the most common clinical disorder destroying the quality of patient life and leading to a marked economic and social burden. Opioids are still last option for pharmacological treatment of this disorder, but their antinociceptive effects are limited in part due to the downregulation of opioid receptors in the primary afferent neurons after peripheral nerve trauma. How this downregulation occurs is not completely understood, but recent studies have demonstrated that peripheral nerve trauma drives the alterations in epigenetic modifications (including DNA methylation, histone methylation and mciroRNAs), expression of transcription factors, post-transcriptional modifications (e.g., RNA methylation) and protein translation initiation in the neurons of nerve trauma-related dorsal root ganglion (DRG) and that these alternations may be associated with nerve trauma-caused downregulation of DRG opioid receptors. This review presents how opioid receptors are downregulated in the DRG after peripheral nerve trauma, specifically focusing on distinct molecular mechanisms underlying transcriptional and translational processes. This review also discusses how this downregulation contributes to the induction and maintenance of neuropathic pain. A deeper understanding of these molecular mechanisms likely provides a novel avenue for prevention and/or treatment of neuropathic pain.

CREB Participates in Paclitaxel-Induced Neuropathic Pain Genesis Through Transcriptional Activation of Dnmt3a in Primary Sensory Neurons.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) often occurs in cancer patients treated with antineoplastic drugs. Therapeutic management of CIPNP is very limited, at least in part due to the largely unknown mechanisms that underlie CIPNP genesis. Here, we showed that systemic administration of the chemotherapeutic drug paclitaxel significantly and time-dependently increased the levels of cyclic AMP response element-binding protein (CREB) in dorsal root ganglion (DRG) neurons. Blocking this increase through DRG microinjection of Creb siRNA attenuated paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of the adeno-associated virus 5 expressing full-length Creb mRNA led to enhanced responses to basal mechanical, heat, and cold stimuli in mice in absence of paclitaxel treatment. Mechanically, paclitaxel-induced increase of DRG CREB protein augmented Dnmt3a promoter activity and participated in the paclitaxel-induced upregulation of DNMT3a protein in the DRG. CREB overexpression also elevated the expression of DNMT3a in in vivo and in vitro DRG neurons of naïve mice. Given that DNMT3a is an endogenous instigator of CIPNP and that CREB co-expresses with DNMT3a in DRG neurons, CREB may be a key player in CIPNP through transcriptional activation of the Dnmt3a gene in primary sensory neurons. CREB is thus a likely potential target for the therapeutic management of this disorder.

The Trend of Labor Analgesia in the World and China: A Bibliometric Analysis of Publications in Recent 30 Years.

PURPOSE: Labor analgesia is part of the most important tasks an anesthesiologist needs to deal with. With the "two-child policy" in China, the number of parturients has increased significantly, labor analgesia more should be valued. There has been a tremendous change on labor analgesia research in China and around the world; however, broader trends in the prevalence and scope of labor analgesia research remain underexplored. The current study quantitatively analyzes trends in labor analgesia research publications in the past 30 years. METHODS: A bibliometric approach was used to search Scopus, PubMed, Web of Science and the China National Knowledge Infrastructure for all labor analgesia-related research articles. The research progress and growing trend were quantitatively analyzed by total publications, research types, research institutions, journal impact factors, and author's contribution. Total citations frequency, average citations per item and h-index were used for evaluating literature quantity. RESULTS: From 1988 to 2018, over 8000 documents in labor analgesia research field were published worldwide. According to Scopus, 68.2% papers of all documents were articles. The USA published the largest number of articles (2204, 27.45%). China had published 175 articles (2.18%), ranking the 11th. According to WOS, there were 221 research categories for labor analgesia articles all over the world. The total citations were 76,207, average 9.086 citations per item, and the h-index was 114, average 14 citations per item worldwide. The total citations and h-index of papers published in China were as follows: 353 total citations, 7.06 citations per item, and 10 h-index. High contribution journals, authors, institutions and the top 10 most cited articles on labor analgesia in the world and China were also listed. CONCLUSION: Labor analgesia research has grown markedly during the 1988-2018 period. Although China had made remarkable achievements, there was a gap in the high-quality studies between China and other leading countries.

Ultrasound for predicting difficult airway in obstetric anesthesia: Protocol and methods for a prospective observational clinical study.

BACKGROUND: Failed intubation and ventilation during cesarean deliveries are important causes of anesthetic-related maternal mortality. Due to the physiological changes in airway anatomy, parturient had higher incidences of difficult airway than non-obstetric population. Accurate airway assessment is the first step and the most important in airway management. However, the common clinical screening tests, shown low sensitivity and specificity with a limited predictive value. Ultrasound is a quick, noninvasive, inexpensive tool, with the advancement of ultrasound technology, modern ultrasound machine is more portable with better resolution and enhanced tissue penetration, provide better imaging in tissues like epiglottis, vocal cords, ring-shaped membrane, and can be used in airway assessment. Here, the aim of the current study was to find whether preoperative ultrasound assessment of neck anatomy can predict difficult airway in parturient, and provide new ideas and a theoretical basis in the airway management of obstetric anesthesia. METHODS: This is a prospective, observational single-blinded study in a single-center. Subjects will be recruited from patients aged from 18 to 60 years, gestational age ≥ 36 weeks, scheduled for cesarean section under general anesthesia and tracheal intubation. Ultrasound measurement will be performed to detect anterior cervical soft tissue thickness at five anatomical levels (hyoid bone, epiglottis, cricothyroid membrane, thyroid isthmus and suprasternal notch) in the upper airway. The thickness of the soft tissue in the front of the neck and clinical airway measurements will be compared between the "easy intubation" and "difficult intubation" group divided by Cormack-Lehane grade. Receiver-operating characteristic curves were used to determine the sensitivity and specificity of "difficulty prediction capability" of each sonographic and physical measurements. Clinical factors associated with difficult intubation will be determined by univariate analyses. Multiple logistic regression analysis performed to determine independent predictors of difficult intubation. CONCLUSIONS: The study outlined in this protocol will explore the possibility of ultrasound for predicting difficult airway in obstetric anesthesia. This may provide new insight into the practice of airway management. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800018949.

Gasserian ganglion injected with Adriamycin successfully relieves intractable trigeminal nerve postherpetic neuralgia for an elderly patient: A case report.

RATIONALE: Effective treatments for trigeminal nerve postherpetic neuralgia (PHN) are limited. Adriamycin (doxorubicin) has been applied to the treatment of neuropathic pain. This study reports a new treatment: Adriamycin injected to Gasserian ganglion for an elderly patient with the intractable trigeminal nerve PHN. PATIENT CONCERNS: A 75-year-old man complained of lancing, burning pain in the right mandibular branch of the trigeminal nerve (V3) for 3 months after rash eruption. DIAGNOSES: Trigeminal nerve PHN. INTERVENTIONS: Approximately 0.5 mL of 0.25% Adriamycin and 20 mg methylprednisolone injected to Gasserian ganglion through the foramen ovale with computer tomography guidance. OUTCOMES: The visual analog scale was 10 of 100 throughout the 1-month follow-up, and oxcarbazepine had also been tapered. The patient remained free of pain at the 12-month follow-up. LESSONS: The treatment of Adriamycin injection to Gasserian ganglion is effective and safe, and may be considered as an alternative treatment for trigeminal nerve PHN. However, more research is needed to verify the validity.

Pulsed radiofrequency of brachial plexus under ultrasound guidance for refractory stump pain: a case report.

The post-amputation (pain) syndrome, including stump pain, phantom limb sensation, and phantom limb pain is common but difficult to treat. Refractory stump pain in the syndrome is an extremely challenging and troublesome clinical condition. Patients respond poorly to drugs, nerve blocks, and other effective treatments like spinal cord stimulation and surgery. Pulsed radiofrequency (PRF) technique has been shown to be effective in reducing neuropathic pain. This report describes a patient with persistent and refractory upper limb stump pain being successfully relieved with PRF of brachial plexus under ultrasound guidance after a 6-month follow-up period, suggesting that PRF may be considered as an alternative treatment for refractory stump-neuroma pain.