Effect of high-frequency repetitive transcranial magnetic stimulation in M1 region combined with dorsolateral prefrontal cortex on electroencephalogram θ frequency band amplitude of patients with neuropathic pain after spinal cord injury / 中国康复理论与实践

ObjectiveTo explore the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) in M1 region combined with dorsolateral prefrontal cortex (DLPFC) on electroencephalogram (EEG) θ frequency band amplitude of patients with neuropathic pain (NP) after spinal cord injury. MethodsFrom June, 2022 to June, 2023, 50 NP patients after SCI in Qingdao University Affiliated Hospital were included and divided into M1 region stimulation group (n = 25) and M1 region combined with DLPFC stimulation group (the combined stimulation group, n = 25). M1 region stimulation group received 10 Hz rTMS in the left M1 region, while the combined stimulation group received same stimulation in left M1 region combined with DLPFC, for three weeks. Before and after intervention, the pain was assessed with Short Form of McGill Pain Questionnaire (SF-MPQ), the depression and anxiety status were evaluated using Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), and the EEG θ frequency band amplitude was recorded to detect the changes of brain electrophysiological activity. ResultsFour cases in M1 region stimulation group, and two cases in the combined stimulation group were dropped. After intervention, the total score of SF-MPQ and the scores of the subscales, the scores of HMMD and HAMA decreased in both groups (|t| > 2.523, P < 0.05). The EEG θ frequency band amplitude significantly reduced in the prefrontal and frontal regions in M1 region stimulation group (|t| > 5.243, P < 0.001), and it also significantly reduced in the prefrontal, frontal regions, central and parietal regions in the combined stimulation group (|t| > 4.630, P < 0.001). All the scores were lower (|t| > 2.270, Z = -1.973, P < 0.05), and the EEG θ frequency band amplitude in the prefrontal, frontal regions, central and parietal regions were lower (P < 0.05) in the combined stimulation group than in M1 region stimulation group. ConclusionHigh frequency rTMS is an effective analgesic method on NP after SCI, which can improve their depression and anxiety symptoms and reduce the EEG θ frequency band amplitude. Compared with M1 region rTMS stimulation, the combination of M1 region and DLPFC rTMS is more effective.

Manejo racional de las neuropatías diabéticas: consenso multidisciplinario de expertos / Rational management of the diabetic neuropathies: a multidisciplinary expert group consensus

Resumen: La diabetes mellitus, un padecimiento crónico y progresivo, ocupó el tercer lugar en defunciones durante el período comprendido de enero a junio de 2021 en México. Su complicación crónica más frecuente es la neuropatía diabética que tiene un impacto importante en el sistema nervioso. En la Ciudad de México se reunió un grupo multidisciplinario de expertos para establecer un algoritmo de tratamiento que considere los aspectos sintomáticos y etiopatogénicos de la neuropatía diabética. Se utilizó un método Delphi en tiempo real con dos rondas de preguntas interactivas. La implementación del algoritmo propuesto permitirá abordar de manera integral al paciente diabético con neuropatía dolorosa y no dolorosa, tanto en el terreno de los síntomas como en la etiopatogenia. Este abordaje brinda la oportunidad de mejorar la calidad de vida y lograr la reinserción a la vida familiar y laboral. El panel de expertos recomienda al ácido tióctico como tratamiento etiopatogénico de primera línea en la neuropatía diabética.

Abstract: Diabetes mellitus, a chronic and progressive condition, was the third most common cause of death in Mexico between January and June 2021. Its most frequent chronic complication is diabetic neuropathy, which has a major impact on the nervous system. A multidisciplinary group of experts met in Mexico City to establish a treatment algorithm considering the symptomatic and etiopathogenic aspects of diabetic neuropathy. A real-time Delphi method with two rounds of interative questions was used. The implementation of the proposed algorithm will allow a comprehensive approach to the diabetic patient with painful and non-painful neuropathy, both in terms of symptoms and etiopathogenesis. This approach provides the opportunity to improve quality of life and achieve reintegration into family and work life. The expert panel recommends thioctic acid as the first line etiopathogenic treatment for diabetic neuropathy.

Lidocaine 5% patch in the treatment of localized neuropathic pain due to nerve compression. Case reports / Emplastro de lidocaína a 5% no tratamento da dor neuropática localizada por compressão nervosa. Relato de casos

ABSTRACT BACKGROUND AND OBJECTIVES: Neuropathic pain is a chronic condition with a significant burden for patients, society, and healthcare systems. Due to neuropathic complexity, its management must be different than the one for nociceptive pain. First-line systemic treatments may be associated with dose-dependent adverse events and drug-drug interactions. On the other hand, topical treatments have less systemic adverse events, with the 5% lidocaine transdermal patch being recommended for firstor second line of treatment for neuropathic pain according to various international guidelines. The aim of this study is to present three cases of localized neuropathic pain due to nerve compression managed with 5% lidocaine transdermal patch. CASE REPORTS: The cases of three adult patients (>40 years old) with pain or tingling for a long period of time and their outcomes with treatment with 5% lidocaine transdermal patch for a prolonged duration were investigated. All three cases report a significant improvement in pain. CONCLUSION: The results of the reported cases revealed that a 5% lidocaine transdermal patch represents an effective, safe and tolerable and noninvasive option for the management of localized neuropathic pain due to peripheric nerve compression.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor neuropática é uma condição crônica com impactos significativos para o paciente, a sociedade e o sistema de saúde. Pela sua complexidade neuropática, a sua abordagem deve ser diferente da dor nociceptiva. Os tratamentos sistêmicos de primeira linha para a dor neuropática podem estar associados à incidência de eventos adversos dose-dependentes e interações farmacológicas. Por outro lado, os fármacos tópicos apresentam menor incidência de eventos adversos sistêmicos, sendo o emplastro de lidocaína a 5% recomendado como primeira ou segunda linha de tratamento para essa condição em diversos guidelines internacionais. O objetivo deste estudo foi apresentar três casos clínicos de dor neuropática localizada por compressão nervosa manejados com o emplastro de lidocaína a 5%. RELATO DOS CASOS: Três pacientes com idade superior a 40 anos e queixas de dor ou parestesia de longa duração foram manejados com emplastro de lidocaína a 5% em tratamento prolongado, com melhora da intensidade de dor expressiva. CONCLUSÃO: Os resultados dos casos reportados revelaram que o emplastro de lidocaína a 5% se apresentou como uma opção terapêutica eficaz, segura, bem tolerada e não invasiva no manejo da dor neuropática localizada por compressão nervosa periférica.

Can chronic spontaneous urticarial produce symptoms of neuropathic pain?

Abstract Background Chronic spontaneous urticaria (CSU) is a condition that is associated with recurrent pruritic hives and/or angioedema lasting for more than 6 weeks and is known to affect 1% of the population. Neuropathic pain can be defined as abnormal pain in the peripheral or central nervous system following injury and results from dysfunctions in the peripheral or central nervous system without peripheral nociceptor stimulation. Histamine appears in the pathogenesis of both the CSU and diseases of the neuropathic pain spectrum. Objective To evaluate the symptoms of neuropathic pain in patients with CSU using scales. Method Fifty-one patients with CSU and 47 sex- and age-matched healthy controls were included in the study. Results The results of the short-form McGill Pain Questionnaire revealed the scores in the sensory and affective domains, Visual Analogue Scale (VAS) scores and pain indices to be significantly higher in the patient group (p < 0.05 for all cases), while the overall pain assessment and sensory assessment based on the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale were also significantly higher in the patient group. Based on the assumption that scores of > 12 indicated neuropathy, 27 (53%) of the patients in the patient group and 8 (17%) in the control group were found to have neuropathy (p < 0.05). Study limitations Cross-sectional study, small patient sample and use of self-reported scales. Conclusion In addition to itching, patients with CSU should be aware of the potential for the association of neuropathic pain. In this chronic disease that is known to affect the quality of life, using an integrated approach with the patients and identifying accompanying problems are as important as treating the dermatological disorder.

Practical aspects of the use of medicinal cannabis in chronic pain / Aspectos práticos do uso da cannabis medicinal em dor crônica

ABSTRACT BACKGROUND AND OBJECTIVES: Evidence has revealed an important role in the use of medical cannabis, and the interaction of the endocannabinoid system with other drugs for the treatment of chronic neuropathic and nociplastic pain. The objective of this review is to bring an update on published data on doses and care with the use of cannabinoids that demonstrate the interaction in the pathophysiology of chronic pain and its treatment. CONTENTS: A research-based review was carried out in the MEDLINE, PUBMED database using the keywords "cannabis and pain", "endocannabinoid"; "neuropathic pain"; "nociplastic pain"; "drug interactions". CONCLUSION: Drug interaction with cannabinoids requires further scientific knowledge and doses are individual, which makes it difficult to create a protocol for treatment.

RESUMO JUSTIFICATIVA E OBJETIVOS: As evidências têm revelado um papel importante sobre o uso da cannabis medicinal e da interação do sistema endocanabinoide com outros fármacos para o tratamento de dor crônica neuropática e nociplástica. O objetivo deste estudo foi prover atualização sobre os dados publicados quanto a doses e cuidados com o uso dos canabinoides que mostrem interação na fisiopatologia da dor crônica e seu tratamento. CONTEÚDO: Foi realizada uma revisão baseada em pesquisa na base de dados Medline, Pubmed com uso dos unitermos "cannabis e dor", "endocannabinoid", "neuropathic pain", "nociplastic pain" e "drug interactions". CONCLUSÃO: A interação farmacológica com os canabinoides requer aprofundamento do conhecimento científico e as doses são individuais, o que dificulta a criação de um protocolo para tratamento.

Prevalence and interference of neuropathic pain in the quality of life in patients with knee osteoarthritis

Abstract Objective: With the aging of the population, more patients have complained of pain due to knee Osteoarthritis (OA), and the number of arthroplasties has also increased. The objective of this study is to evaluate the prevalence of the neuropathic pain component in candidates for Total Knee Replacement and the effects of this component on their quality of life. Methods: In this cross-sectional study, patients with OA candidates for knee arthroplasty in the present institution were evaluated using the pain detection questionnaire and the Visual Analog Pain (VAS) scale to measure the pain index and the presence of associated neuropathic pain. In addition, evaluation of the quality of life and functionality using the EQ5D and SF12 questionnaires and their relationship with cases of neuropathic pain were performed. Results: One hundred twenty-six patients were evaluated, and 71.4 % were female. The age ranged from 46 to 85 years, and about 70 % of the patients had some associated clinical comorbidity. Neuropathic pain was present in 28.6 % of the patients evaluated. Patients with neuropathic pain presented worse results in the VAS evaluation, in the care, pain, and anxiety domains of the EQ5D, and in the physical and mental scores of the SF12. Conclusion: Neuropathic pain was present in 28.6 % of the patients with knee OA who are candidates for arthro-plasty. Patients with associated neuropathic pain present a higher level of pain and worse quality of life scores. Recognizing this type of pathology is extremely important in fully monitoring gonarthrosis.

Mechanism of Honghua Oral Liquid in Alleviating Neuropathic Pain / 中国实验方剂学杂志

ObjectiveTo investigate the pharmacodynamic characteristics and explore the molecular mechanism of Honghua oral liquid （HOL） in relieving neuropathic pain （NP）. MethodHealthy male SD rats were randomly assigned into sham group， model group， low-， medium-， high-dose （0.5， 1.0， 2.0 mL·kg-1·d-1， respectively） HOL groups， and a positive drug （pregabalin， 25 mg·kg-1·d-1） group， with 6 rats in each group. Spinal nerve ligation （SNL） of L5 was conducted in other groups except the sham group. Drug administration was performed 3 days after the SNL surgery for 2 consecutive weeks， and samples were collected after the end of the administration. During the treatment period， the mechanical pain threshold and cold pain threshold were determined to measure the pain-relieving effect of HOL. Transcriptome sequencing was performed on hippocampal tissue samples from the sham， model， and high-dose HOL groups， and differentially expressed genes between the sham group and the model group as well as the model group and HOL high-dose group were obtained. After pathway enrichment analysis， we selected the targets which were closely related to neuroinflammation for validation， and predicted the specific binding sites of the major active components in HOL with the targets through molecular docking. In addition， the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-10 （IL-10） were determined by enzyme-linked immunosorbent assay （ELISA） to evaluate the effect of HOL on neuroinflammation in NP rats. ResultCompared with the sham group， SNL decreased the mechanical pain threshold and cold pain threshold （P<0.05）. Compared with the model group， HOL recovered the mechanical pain threshold and cold pain threshold （P<0.05）. The transcriptome data showed that 376 differentially expressed genes （DEGs） were identified between the model group and the sham group， including 124 upregulated genes and 252 downregulated genes， and 194 DEGs between the model group and the high-dose HOL group， including 33 upregulated genes and 161 downregulated genes. Among them， insulin-like growth factor 1（IGF1）， matrix metallopeptidase-2 （MMP-2）， matrix metallopeptidase-14 （MMP-14）， erb-B2 receptor tyrosine kinase 2 （ERBB2）， and integrin subunit alpha 5 （ITGA5） associated with NP were selected for further validation. The Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） results showed that compared with the sham group， the modeling up-gurelated the mRNA levels of the above five molecules in the hippocampus （P<0.01）. Compared with model group， HOL down-regulated the mRNA levels of these molecules （P<0.01）. The molecular docking results showed that the main active components of safflower， hydroxysafflor yellow A， kaempferol， and quercetin， formed stable hydrogen bonds with the amino acid residues of IGF1， MMP-2， MMP-14， ERBB2， and ITGA5. The enzyme-linked immunosorbent assay（ELISA） results showed that compared with those in the sham group， the serum levels of TNF-α and IL-10 were out of balance in the model rats （P<0.01）. Compared with the model group， HOL lowered the level of the pro-inflammatory cytokine TNF-α （P<0.01） and elevated that of the anti-inflammatory cytokine IL-10 （P<0.05）. ConclusionHOL exerts analgesic effect on SNL rats by inhibiting neuroinflammation.

Mechanism of Mongolian drug Naru-3 in initiation of neuroinflammation of neuropathic pain from MMP9/IL-1β signaling pathway / 中国中药杂志

Neuropathic pain(NP) has similar phenotypes but different sequential neuroinflammatory mechanisms in the pathological process. It is of great significance to inhibit the initiation of neuroinflammation, which has become a new direction of NP treatment and drug development in recent years. Mongolian drug Naru-3 is clinically effective in the treatment of trigeminal neuralgia, sciatica, and other NPs in a short time, but its pharmacodynamic characteristics and mechanism of analgesia are still unclear. In this study, a spinal nerve ligation(SNL) model simulating clinical peripheral nerve injury was established and the efficacy and mechanism of Naru-3 in the treatment of NPs was discussed by means of behavioral detection, side effect evaluation, network analysis, and experimental verification. Pharmacodynamic results showed that Naru-3 increased the basic pain sensitivity threshold(mechanical hyperalgesia and thermal radiation hyperalgesia) in the initiation of SNL in animals and relieved spontaneous pain, however, there was no significant effect on the basic pain sensitivity threshold and motor coordination function of normal animals under physiological and pathological conditions. Meanwhile, the results of primary screening of target tissues showed that Naru-3 inhibited the second phase of injury-induced nociceptive response of formalin test in mice and reduced the expression of inflammatory factors in the spinal cord. Network analysis discovered that Naru-3 had synergy in the treatment of NP, and its mechanism was associated with core targets such as matrix metalloproteinase-9(MMP9) and interleukin-1β(IL-1β). The experiment further took the dorsal root ganglion(DRG) and the stage of patho-logical spinal cord as the research objects, focusing on the core targets of inducing microglial neuroinflammation. By means of Western blot, immunofluorescence, agonists, antagonists, behavior, etc., the mechanism of Naru-3 in exerting NP analgesia may be related to the negative regulation of the MMP9/IL-1β signaling pathway-mediated microglia p38/IL-1β inflammatory loop in the activation phase. The relevant research enriches the biological connotation of Naru-3 in the treatment of NP and provides references for clinical rational drug use.

Traditional Chinese Medicine Diagnosis and Treatment of Neuropathic Pain from Theory of Chronic Pain Entering Collaterals / 中国实验方剂学杂志

Neuropathic pain is a clinical symptom with complex mechanisms and high incidence. The commonly used analgesics have limited efficacy and can cause serious side effects. The theory of chronic pain entering collaterals was proposed by YE Tianshi， a famous physician focusing on warm diseases in the Qing dynasty， on the basis of the ancient therapies for pain. This theory is particularly suitable for the diagnosis and treatment of neuropathic pain in view of the clinical course and manifestations. The chronic neuropathic pain can enter the Yin collateral in deeper sites. The pathogenesis of neuropathic pain is summarized as a deficiency in origin and excess in superficiality. The root cause is the dysfunction of Zang-Fu organs， mainly the liver, kidney and heart， while the superficial causes are phlegm and stasis caused by the obstructed Qi and blood movement due to the consumption of Qi and blood in collaterals. Accordingly， the therapies such as dispelling blood stasis， resolving phlegm， and dredging collaterals should be adopted. This paper expounds the traditional Chinese medicine （TCM） pathogenesis and treatment of neuropathic pain， enriching the knowledge and providing new ideas for the TCM prevention and treatment of this disease as a collateral disease.

Rhodojaponin VI indirectly targets Cav2.2 channels via N-ethylmaleimide-sensitive fusion protein to alleviate neuropathic pain

Neuropathic pain is a chronic disease that severely afflicts the life and emotional status of patients, but currently available treatments are often ineffective. Novel therapeutic targets for the alleviation of neuropathic pain are urgently needed. Rhodojaponin VI, a grayanotoxin from Rhododendron molle, showed remarkable antinociceptive efficacy in models of neuropathic pain, but its biotargets and mechanisms are unknown. Given the reversible action of rhodojaponin VI and the narrow range over which its structure can be modified, we perforwmed thermal proteome profiling of the rat dorsal root ganglion to determine the protein target of rhodojaponin VI. N-Ethylmaleimide-sensitive fusion (NSF) was confirmed as the key target of rhodojaponin VI through biological and biophysical experiments. Functional validation showed for the first time that NSF facilitated trafficking of the Cav2.2 channel to induce an increase in Ca2+ current intensity, whereas rhodojaponin VI reversed the effects of NSF. In conclusion, rhodojaponin VI represents a unique class of analgesic natural products targeting Cav2.2 channels via NSF.

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

Analgesic Effect of Intrathecal 2R， 6R-HNK on Neuropathic Pain in Female Mice / 中山大学学报(医学科学版)

ObjectiveTo investigate the analgesic action and mechanism of intrathecal 2R， 6R-hydroxynorketamine （2R， 6R-HNK） on spared nerve injury （SNI）-induced chronic neuropathic pain （CNP） in female mice. MethodsSNI was used to establish acute and chronic CNP models in female mice. The mice were randomly divided into different groups with administration of vehicle， 2R， 6R-HNK or S-ketamine （10 mg/kg intraperitoneal injection/i.p. or 7， 21 μmol/L intrathecal injection/i.t.） at 3 weeks after or 30 min/1 d before operation （n = 3 - 7 mice/group）. The curative or preventive effect of 2R， 6R-HNK was evaluated by mechanical paw withdrawal threshold （PWT） and the analgesic efficiency. Finally， immunofluorescence and RT-PCR of dorsal root ganglion （DRG） and spinal dorsal horn （SDH） were used to explore the possible mechanisms. ResultsCompared with vehicle， intrathecal injection of 2R， 6R-HNK largely reversed SNI-induced bilateral mechanical allodynia in a delayed-and-dose-dependent way. Among them， 21 μmol/L 2R， 6R-HNK reached its maximum analgesic efficiency （75.32±7.69） % at 2 d. Pre-intrathecal delivery of 2R， 6R-HNK also delayed the development of bilateral mechanical hypersensitivity 2 - 3 d induced by SNI. Mechanically， 2R， 6R-HNK reversed not only the abnormal excitability of neurons in bilateral DRG and superficial SDH， but also the upregulation of calcitonin gene-related peptide （CGRP） and brain-derived nerve growth factor （BDNF） in DRG. ConclusionIntrathecal administration of 2R， 6R-HNK exerts an analgesic effect against CNP， probably via suppressing abnormal neuronal excitability in ascending pain pathway as well as down-regulating CGRP and BDNF expression in DRG neurons.

Dihydroartemisinin Regulates Neuro-microglia to Relieve Neuropathic Pain / 中国实验方剂学杂志

ObjectiveTo evaluate the intervention effect of dihydroartemisinin （DHA） on hippocampal nerve injury in L5 spinal nerve ligation （SNL） model and tumor necrosis factor-α （TNF-α） hippocampal continuous injection model. In primary cultured microglia-hippocampal neurons， the regulatory pattern of DHA on microglia-hippocampal neuronal interactions was confirmed. MethodThe experimental animals were divided into Sham group， SNL group， and DHA group （16 mg·kg-1）， with 3 mice in each group. The hippocampal CA3 glutamatergic neurons were labeled with adeno-associated virus ［Calmodulin-dependent protein kinase Ⅱ（CaMKⅡ） dTomato AAV］， and their contributions to the hippocampal CA1， prefrontal cortex （Frc）， anterior cortex （ACC）， projections of nucleus accumbens （Nac）， and Basolateral Amygdala （BLA） were traced by immunofluorescence staining. The experimental animals were divided into a Sham group， a TNF-α hippocampus continuous injection model group， DHA-L， DHA-M， and DHA-H groups （4， 8， 16 mg·kg-1）， and pregabalin group （25 mg·kg-1）， with 4 mice in each group. The morphology of pyramidal neurons in the hippocampal CA1 and CA3 regions was counted by Golgi staining. The continuous activation of hippocampal primary neurons and microglia was induced， DHA intervention was given by co-culture， and the cell soma area and the expression of postsynaptic density protein 95 （PSD95） inside and outside the primary and secondary dendritic spines of neurons were counted by immunofluorescence. ResultCompared with the Sham group， the projection of CA3 glutamatergic neurons to CA1 region， Frc， and ACC in the SNL group was significantly reduced （P<0.01）， while the projection to Nac and BLA was significantly increased （P<0.01）. As compared with the SNL group， the projection of hippocampal CA3 glutamatergic neurons to CA1 region， Frc， and ACC was significantly increased in the DHA group （P<0.01）， while the projection to Nac and BLA was significantly reduced （P<0.01）. Golgi staining results showed that as compared with the Sham group， the density of dendritic spines and the number of dendritic branches in the CA1 and CA3 pyramidal neurons in the TNF-α hippocampal continuous injection model group were significantly reduced （P<0.01）. As compared with the TNF-α hippocampal continuous injection model， the density of dendritic spines and the number of dendritic branches in hippocampal CA1 and CA3 pyramidal neurons in the DHA-M and DHA-H groups were significantly increased （P<0.05， P<0.01）. Compared with DHA-M group， the total dendrite length of CA1 pyramidal neurons in hippocampus in DHA-H group was significantly increased （P<0.01）， while the total dendrite length of CA1 neurons and the total dendrite base length of CA3 neurons in DHA-L group was significantly decreased （P<0.01）. Compared with the blank control group， the cell soma area of the glycine group and glutamate group increased significantly （P<0.01）. As compared with the glycine group and glutamate group， the cell area of the glycine + glutamate group was significantly increased （P<0.01）， and as compared with the glutamate group， the cell soma area of the glutamate + DHA group was significantly reduced （P<0.01）. As compared with the glycine acid + glutamate group， the cell soma area of the glycine + glutamate + DHA group was significantly reduced （P<0.01）， and as compared with the glutamate + DHA group， the cell soma area of the glycine + glutamate + DHA group was also significantly reduced （P<0.05）. Compared with the blank control group， the cell soma area of the glutamate group was significantly increased （P<0.01）. As compared with the glutamate group， the cell soma area of the glutamate + DHA-L， glutamate + DHA-M， and glutamate + DHA-H groups was significantly reduced （P<0.01）. As compared with the blank control group， the expression of the resting primary microglia + glycine group in primary and secondary dendritic internal and external postsynaptic density protein 95 （PSD95） was significantly increased （P<0.01）. As compared with the resting primary microglia + glycine group， the expression of PSD95 in the primary and secondary dendritic spinous and external neurons of the activated primary microglia + glycine group was significantly reduced （P<0.01）. As compared with the activated primary microglia + glycine group， the expression of PSD95 in the primary and secondary dendritic spinous and external neurons in the activated primary microglia + glycine + DHA group was significantly increased （P<0.01）. As compared with the activated primary microglia + DHA group， the expression of PSD95 in the primary and secondary dendritic spines and outside neurons in the activated primary microglia + glycine + DHA group was significantly increased （P<0.01）. ConclusionDHA has a significant repair effect on vertebral neuronal damage caused by hippocampal microglia and TNF-α overexpression in NP pathology， and this repair is closely related to the dual inhibition of neuronal-microglia by DHA.

CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain / 神经科学通报·英文版

Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms. The circRNAs are mainly enriched in the central nervous system. However, their function in various physiological and pathological conditions have yet to be determined. Here, we identified circFhit, an exon-intron circRNA expressed in GABAergic neurons, which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain. Moreover, we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R+ neurons by promoting the expression of its parental gene Fhit in cis. Mechanistically, circFhit was directly bound to the intronic region of Fhit, and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron. In summary, we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R+ neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory Axons / 神经科学通报·英文版

Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.

Thalamocortical Circuit Controls Neuropathic Pain via Up-regulation of HCN2 in the Ventral Posterolateral Thalamus / 神经科学通报·英文版

The thalamocortical (TC) circuit is closely associated with pain processing. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is predominantly expressed in the ventral posterolateral thalamus (VPL) that has been shown to mediate neuropathic pain. However, the role of VPL HCN2 in modulating TC circuit activity is largely unknown. Here, by using optogenetics, neuronal tracing, electrophysiological recordings, and virus knockdown strategies, we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex (S1HL) as well as mechanical hypersensitivity following spared nerve injury (SNI)-induced neuropathic pain in mice. Either pharmacological blockade or virus knockdown of HCN2 (shRNA-Hcn2) in the VPL was sufficient to alleviate SNI-induced hyperalgesia. Moreover, shRNA-Hcn2 decreased the excitability of TC neurons and synaptic transmission of the VPL-S1HL circuit. Together, our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain.

Analgesic Effect and Mechanism of Osteoking on Dorsal Root Ganglion Compression Model Rats / 中国实验方剂学杂志

ObjectiveTo investigate the analgesic effect and mechanism of Osteoking （OK） on nerve compression in lumbar disc herniation. MethodThe rat model of chronic compression of dorsal root ganglion （CCD） was established to simulate clinical lumbar disc herniation. The CCD rats were randomly divided into model group， low， medium， and high dose OK groups （1.31， 2.63， 5.25 mL·kg-1·d-1）， and pregabalin group （5 mg·kg-1）， with eight rats in each group. Another eight SD rats were taken as the blank group， and the same volume of normal saline was given by gavage. Behavioral tests， side effect evaluation， network analysis， Western blot， immunofluorescence， and antagonist application were used to explore the effect. ResultCompared with the blank group， the mechanical hyperalgesia threshold， thermal hyperalgesia threshold， and the expression of inflammatory factors in the spinal dorsal horn of the model group are significantly increased （P<0.01）， and the related indicators of the affected foot footprints are significantly down-regulated （P<0.01）. The expression of signal transducer and activator of transcription 3 （STAT3）， vascular endothelial growth factor A （VEGFA）， and phosphorylated extracellular regulated protein kinase （p-ERK） in microglia in the spinal dorsal horn is significantly increased in the model group （P<0.01）. Compared with the model group， low， medium， and high dose OK groups can increase the mechanical hyperalgesia and thermal hyperalgesia thresholds of CCD rats （P<0.05， P<0.01） in a dose-dependent manner， improve the gait of CCD rats （P<0.05， P<0.01）， and reduce the expression of inflammatory factors in the spinal dorsal horn （P<0.05， P<0.01）. The expression of STAT3， VEGFA， and p-ERK in the spinal dorsal horn microglia of CCD rats is significantly decreased （P<0.05， P<0.01）， and the acetic acid-induced nociceptive response in rats is effectively reduced （P<0.05， P<0.01）. In addition， there is no tolerance. The results of the body mass test， organ index， forced swimming， and rotation show that OK has no obvious toxic or side effects. Further antagonist experiments show that MRS1523 and RS127445 can reverse the transient analgesic effect of OK compared with the high dose OK group （P<0.01）. ConclusionOK has a good analgesic effect on the CCD model without obvious toxic side effects， and its mechanism may be related to the activation of ADORA3 and HTR2B and the inhibition of STAT3， VEGFA， p-ERK， and other elements in microglia.

Yiqi Huoxue Tongluo Prescription Inhibits Activation of Astrocytes to Relieve Diabetic Neuropathic Pain in Rats via ERK Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Yiqi Huoxue Tongluo prescription （YHTP） in the treatment of diabetic neuropathic pain （DNP）. MethodNinety SPF-grade SD male rats were randomized into blank， model， low- （2.25 g·kg-1）， medium- （4.5 g·kg-1）， and high-dose （9 g·kg-1） YHTP， and mecobalamin （0.175 mg·kg-1） groups. Except those in the blank group， the rats in the remaining 5 groups were fed with a high-fat and high-glucose diet and subjected to intraperitoneal injection of low-dose （35 mg·kg-1） streptozotocin （STZ） to establish the model of DNP. The sciatic nerve conduction velocity in DNP rats was measured by the neurophysiological method， and the levels of interleukin-6 （IL-6）， IL-1β， and tumor necrosis factor-α （TNF-α） were measured by enzyme-linked immunosorbent assay （ELISA）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was employed to measure the mRNA levels of glial fibrillary acidic protein （GFAP） and extracellular signal-regulated kinase （ERK） in the spinal cord. Western blot was employed to measure the protein levels of GFAP and phosphorylated ERK （p-ERK）， and immunofluorescence staining to measure the fluorescence intensity of GFAP and p-ERK in the spinal cord. In the cell experiments， 100 mmol·L-1 high glucose was used to induce the activation of astrocytes （CTX-TNA2） for the modeling of nerve cell injury. The cells were randomized into the normal， model， drug-containing serum （10% YQHT）， inhibitor ［10 mol·L-1 corynoxeine （COR）］， drug-containing serum + inhibitor （10% YHTP + 10 mol·L-1 COR） groups. The levels of pro-inflammatory factors （TNF-α and IL-1β） and the anti-inflammatory factor IL-10 in CTX-TNA2 cells were determined by ELISA， and the protein levels of GFAP and p-ERK in CTX-TNA2 cells by Western blot. ResultThe animal experiments showed that compared with the blank group， the model group presented reduced mechanical withdrawal threshold （MWT）， thermal work limit （TWL）， and nerve conduction velocity， elevated levels of fasting blood glucose， IL-1β， TNF-α， and IL-6， and up-regulated protein levels of GFAP and p-ERK， and mRNA levels of ERK1， ERK2， GFAP （P<0.01）. Compared with model group， YHTP increased the MWT， TWL， and sciatic nerve conduction velocity （P<0.01）， lowered the levels of IL-1β， TNF-α， and IL-6 （P<0.01）， and down-regulated the protein levels of GFAP and p-ERK， and mRNA levels of ERK1， ERK2， GFAP in the spinal cord （P<0.05， P<0.01）. The cell experiments showed that compared with the blank group， the model group had decreased survival rate， elevated levels of pro-inflammatory factors， and up-regulated protein levels of ERK and GFAP （P<0.01）. Compared with the model group， the YHTP-containing serum lowered the levels of IL-1β and TNF-α （P<0.05， P<0.01）， elevated the level of IL-10 （P<0.01）， and down-regulated the protein levels of ERK and GFAP （P<0.01）. ConclusionYHTP may inhibit the activation of astrocytes by inhibiting the ERK signaling pathway to reduce inflammation and thus relieve DNP.

The Role of Post-Translational Modifications of Cav3. 2 in Neuropathic Pain / 中国生物化学与分子生物学报

Neuropathic pain is a common chronic pain that affects human health worldwide. As an important mediator of excitatory conduction in neurons, ion channels are important targets for mechanism research and drug research in this field. T-type calcium channel(Cav3) can be activated transiently when neurons are close to the resting potential of -70 mV, resulting in a transient Ca