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.

Electroacupuncture inhibits dendritic spine remodeling through the srGAP3-Rac1 signaling pathway in rats with SNL

Previous studies have shown that peripheral nerve injury can lead to abnormal dendritic spine remodeling in spinal dorsal horn neurons. Inhibition of abnormal dendritic spine remodeling can relieve neuropathic pain. Electroacupuncture (EA) has a beneficial effect on the treatment of neuropathic pain, but the specific mechanism remains unclear. Evidence has shown that slit-robo GTPase activating protein 3 (srGAP3) and Rho GTPase (Rac1) play very important roles in dendritic spine remodeling. Here, we used srGAP3 siRNA and Rac1 activator CN04 to confirm the relationship between SrGAP3 and Rac1 and their roles in improving neuropathic pain with EA. Spinal nerve ligation (SNL) was used as the experimental model, and thermal withdrawal latency (TWL), mechanical withdrawal threshold (MWT), Western blotting, immunohistochemistry and Golgi-Cox staining were used to examine changes in behavioral performance, protein expression and dendritic spines. More dendritic spines and higher expression levels of srGAP3 were found in the initial phase of neuropathic pain. During the maintenance phase, dendritic spines were more mature, which was consistent with lower expression levels of srGAP3 and higher expression levels of Rac1-GTP. EA during the maintenance phase reduced the density and maturity of dendritic spines of rats with SNL, increased the levels of srGAP3 and reduced the levels of Rac1-GTP, while srGAP3 siRNA and CN04 reversed the therapeutic effects of EA. These results suggest that dendritic spines have different manifestations in different stages of neuropathic pain and that EA may inhibit the abnormal dendritic spine remodeling by regulating the srGAP3/Rac1 signaling pathway to alleviate neuropathic pain.

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.

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.

Neuropathy in multiple sclerosis patients treated with teriflunomide

SUMMARY OBJECTIVE: Teriflunomide is an oral medication approved for the treatment of patients with multiple sclerosis. The primary effect of teriflunomide is to reduce de novo pyrimidine synthesis by inhibiting mitochondrial dihydroorotate dehydrogenase, thereby causing cell-cycle arrest. We aimed to investigate the occurrence of peripheral neuropathy, a rare side effect of teriflunomide, in patients receiving teriflunomide. METHODS: Multiple sclerosis patients receiving teriflunomide (n=42) or other disease modifying therapies (n=18) and healthy controls (n=25) were enrolled in this cross-sectional study between January 2020 and 2021. The mean duration of teriflunomide treatment was 26 months (ranging from 6 to 54 months). All participants underwent neurological examination and nerve conduction studies of tibial, peroneal, sural, superficial peroneal, median, and ulnar nerves by using surface recording bar and bipolar stimulating electrodes. RESULTS: The mean superficial peroneal nerve distal latency and conduction velocity were significantly slower, and the mean superficial peroneal nerve action potential amplitude was lower in patients using teriflunomide (2.50 ms, p<0.001; 47.35 m/s, p=0.030; and 11.05 μV, p<0.001, respectively). The mean peroneal motor nerve distal latency was significantly longer and amplitude was lower in teriflunomide patients (3.68 ms, p<0.001, and 5.25 mV, p=0.009, respectively). During the study period, treatment switching to another disease-modifying therapy was planned in 10 patients, and all neuropathic complaints were reversed after switching. CONCLUSION: Teriflunomide has the potential to cause peripheral neuropathy. The awareness of peripheral neuropathy, questioning the symptoms, and if suspected, evaluation with electromyography and switching the therapy in patients under teriflunomide treatment are crucial.

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

TDZD-8 alleviates oxaliplatin induced neuropathic pain / 中国药理学通报

Aim To explore the effect of GSK-3β (glycogen synthase kinase-3 beta) inhibitor TDZD-8 on the neuropathic pain induced by side effects of chemotherapeutic drug oxaliplatin and the underlying mechanism. Methods The rat model of oxaliplatin-induced neuropathic pain was established by intraperitoneal injection of oxaliplatin for five consecutive days; the anti-nociception effect was detected by intrathecal injection of TDZD-8. The spontaneous flinches and mechanical pain threshold were used to detect the changes of pain behavior of rats; immunofluorescence and Western blot analysis were used to detect the changes of spinal inflammation and protein levels of rats. Results Intrathecally injection of TDZD-8 significantly alleviated oxaliplatin induced hyperalgesia in rats. TDZD-8 injection obviously inhibited the activation spinal microglia and the inflammatory reaction. TDZD-8 administration significantly inhibited GSK-3β activation. Conclusion TDZD-8 blocks GSK-3β activation, decreases NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome mediated spinal inflammation and alleviates neuropathic pain.

Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.

Peripheral BDNF Regulates Somatosensory-Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain / 神经科学通报·英文版

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.

Activation of Cannabinoid Receptor 1 in GABAergic Neurons in the Rostral Anterior Insular Cortex Contributes to the Analgesia Following Common Peroneal Nerve Ligation / 神经科学通报·英文版

The rostral agranular insular cortex (RAIC) has been associated with pain modulation. Although the endogenous cannabinoid system (eCB) has been shown to regulate chronic pain, the roles of eCBs in the RAIC remain elusive under the neuropathic pain state. Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve (CPN) ligation. The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice, glutamatergic, or GABAergic neuron cannabinoid receptor 1 (CB1R) knockdown mice with the whole-cell patch-clamp and pain behavioral methods. The E/I ratio (amplitude ratio between mEPSCs and mIPSCs) was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice. Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice. The analgesic effect of ACEA (a CB1R agonist) was alleviated along with bilateral dorsolateral funiculus lesions, with the administration of AM251 (a CB1R antagonist), and in CB1R knockdown mice in GABAergic neurons, but not glutamatergic neurons of the RAIC. Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.

Treating chronic pain: Current and future status of treatments and aftercare / 全日本鍼灸学会雑誌

The definition of pain by the International Association for the Study of Pain (IASP), as revised in 2020, states that it is "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," suggesting that pain or similar unpleasant sensory experiences may arise even if the cause of such sensations cannot be clearly identified. Pain, on the other hand, has been classified chronologically as acute, subacute or chronic pain such as those directly caused by cancer and non-cancer diseases and by the mechanisms involved. These are divided into nociceptive, neuropathic, and nociplastic pain, the last one of which is a recent addition to the classification. WHO created an independent category dedicated to chronic pain in its latest version of the International Classification of Diseases (ICD-11) defining it as pain that continues or reiterates over a period of three months or longer. As prolonged pain causes both physical and mental damage resulting in degradation of quality of life, it has been stressed that such pain must be approached from both the physical and mental perspectives. For this reason, multi-faceted evaluation is useful in treating chronic pain. In Japan, there are a number of guidelines for the treatment of chronic pain that have been published by different scientific societies as well as by a study group of the MHLW's Chronic Pain Policy Project. These serve as guides for providing evidence-based treatments to affected patients. Chronic pain remains a major challenge since they not only lower the quality of life of affected patients but also cause considerable damage to Japanese society as a whole.

Survey on the Utilization of In-Hospital Formulation 10% Lidocaine Gel for Neuropathic Pain / 医薬品情報学

Objective: In many medical institutions in Japan, 10% lidocaine gel is prepared as an in-hospital formulation to treat intractable neuropathic pain. Clinical studies have reported the short-term efficacy of topical lidocaine therapy for neuropathic pain, while there are few reports in real-world practice. To clarify the clinical usage and its usefulness, in this study, we investigated the duration of use, amount, effectiveness, and safety of 10% lidocaine gel.Design: We conducted a retrospective study investigating the actual usage of 10% lidocaine gel using electronic medical records.Methods: This study included 74 patients treated with 10% lidocaine gel in Kyoto University Hospital between July 2019 and January 2022. Information about disease (purpose of use), concomitant medications and other background information of the patients were collected. In addition, the duration of use, amount, adverse events, and discontinuation of 10% lidocaine gel were investigated. Effectiveness was determined by physician interviews and the pain visual analogue scale (VAS).Results: Ten percent lidocaine gel was used primarily to treat postherpetic neuralgia and, in some cases, other types of chronic pain for a median duration of use of 3.2 months (0.03-118.5). Pain relief was achieved in 73.3% of patients according to physician interviews, with a significant decrease in the VAS score. Although adverse events were observed in 12 patients (16.2%), including skin problems (12.2%), paralysis (4.1%), and somnolence (1.4%), eight patients continued to use 10% lidocaine gel after their occurrence. Three patients discontinued it due to adverse events, and their symptoms subsequently improved thereafter.Conclusion: The present results suggest that 10% lidocaine gel is effective and safe even when used for a long-time. Although this is a single-center study, it is the first systematic investigation of real-world usage of an in-hospital formulation of 10% lidocaine gel and is expected to assist clinical practice and drug development.

Efficacy evaluation of radiofrequency thermocoagulation and pulse radiofrequency for the ganglion impar in treating primary perineal pain / 西安交通大学学报(医学版)

【Objective】 To compare the efficacy of radiofrequency thermocoagulation and pulsed radiofrequency for the ganglion impar in treating primary perineal pain. 【Methods】 We analyzed 79 patients with primary perineal pain who underwent radiofrequency thermocoagulation (group A) and pulsed radiofrequency (group B) in the ganglion impar from January 2020 to March 2022. VAS, excellent and good rates, sleep quality, postoperative medication usage, complications, and recurrence were evaluated before and 24 h, 1 W, 1 M, 3 M and 6 M after operation. The differences between the two groups were compared. 【Results】 The VAS score of group A gradually decreased at each level after operation, and the VAS score of group B gradually increased after 24 hours of operation. The differences between the two groups began to appear 1 week after operation, and the differences further increased with the extension of time (P<0.001). In six months after follow-up, the excellent and good rates of group A (86%) was significantly higher than that of group B (22%). In addition to postoperative perineal skin numbness, group A was superior to group B in improving sleep, postoperative oral medication (pregabalin and opioids), and disease recurrence (P<0.05). 【Conclusion】 Radiofrequency thermocoagulation for the ganglion impar can improve the quality of life by reducing pain, improving the excellent and good rates, improving sleep, and reducing recurrence a medication. The effect is better than that of pulsed radiofrequency.

Effects of neuropathic pain induced by selective nerve injury model on intestinal microflora diversity in mice / 西安交通大学学报(医学版)

【Objective】 To investigate the effects of neuropathic pain induced by selective nerve injury (SNI) on intestinal microflora diversity in C57 mice. 【Methods】 36 C57 mice were randomly divided into SNI model group (n=18), sham-operation group (n=8), and control group (n=10). At day 0,1, 3, 7, and 14 after modeling, mechanical pain threshold and thermal pain sensitivity tests were carried out. At day 14 after modeling, colon content (fresh feces) from all the mice were collected for intestinal microflora diversity analysis. 【Results】 One day after modeling, the mechanical pain threshold in SNI group decreased significantly (more than 70%) due to nerve injury, and the thermal pain threshold decreased by 40%, while sham group and control group had no significant decrease. SNI group showed foot hyperalgesia, and the difference was statistically significant compared with sham group and control group (P<0.001). Compared with control group, sham-operation group had a transient decrease in thermal pain threshold on the first day after modeling (P=0.006), but there was no difference in pain threshold between the two groups on the third day after modeling. The α-diversity analysis showed that the abundance of Observed, Chao1, ACE and Simpson in SNI group was significantly lower than that in control group (P<0.05). That is, SNI group had flora disorder due to pain stimulation. Observed, Chao1, ACE, and Simpson were less abundant in sham group than in control group (P<0.05) and the change was between SNI group and control group. 【Conclusion】 Neuropathic pain induced by SNI model resulted in the decrease of mechanical pain threshold and thermal pain threshold, which leads to the reduction of intestinal flora diversity in C57 mice.