Primary sensory neurons in dorsal root ganglia (DRG) have long axons and a high demand for mitochondria, and mitochondrial dysfunction has been implicated in peripheral neuropathy after diabetes and chemotherapy1,2. However, the mechanisms by which primary sensory neurons maintain their mitochondrial supply remain unclear. Satellite glial cells (SGCs) in DRG encircle sensory neurons and regulate neuronal activity and pain3. Here we show that SGCs are capable of transferring mitochondria to DRG sensory neurons in vitro, ex vivo and in vivo by the formation of tunnelling nanotubes with SGC-derived myosin 10 (MYO10). Scanning and transmission electron microscopy revealed tunnelling nanotube-like ultrastructures between SGCs and sensory neurons in mouse and human DRG. Blockade of mitochondrial transfer in naive mice leads to nerve degeneration and neuropathic pain. Single-nucleus RNA sequencing and in situ hybridization revealed that MYO10 is highly expressed in human SGCs. Furthermore, SGCs from DRG of people with diabetes exhibit reduced MYO10 expression and mitochondrial transfer to neurons. Adoptive transfer of human SGCs into the mouse DRG provides MYO10-dependent protection against peripheral neuropathy. This study uncovers a previously unrecognized role of peripheral glia and provides insights into small fibre neuropathy in diabetes, offering new therapeutic strategies for the management of neuropathic pain.
Postoperative cognitive dysfunction (POCD) is common in the aged population and associated with poor clinical outcomes. Irisin, an endogenous molecule that mediates the beneficial effects of exercise, has shown neuroprotective potential in several models of neurological diseases. Here we show that preoperative serum level of irisin is reduced in dementia patients over the age of 70. Comprehensive proteomics analysis reveals that deletion of irisin affects the nervous and immune systems, and reduces the expression of complement proteins. Systemically administered irisin penetrates the blood-brain barrier in mice, targets the microglial integrin αVβ5 receptor, activates signal transducer and activator of transcription 6 (STAT6), induces microglia reprogramming to the M2 phenotype, and improves immune microenvironment in LPS-induced neuroinflammatory mice. Finally, prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction. Our findings provide new insights into the direct regulation of the immune microenvironment by irisin, and reveal that recombinant irisin holds great promise as a novel therapy for preventing POCD and other neuroinflammatory disorders. SUMMARY: Our findings reveal molecular and cellular mechanisms of irisin on neuroinflammation, and show that prophylactic administration of irisin prevents POCD-like behavior, particularly early cognitive dysfunction.
Classical migraine patients experience aura, which is transient neurological deficits associated with cortical spreading depression (CSD), preceding headache attacks. It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons. In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing nonsynaptic signaling between brain and trigeminal cells. After CSD, ~11% of the CSF proteome is altered, with up-regulation of proteins that directly activate receptors in the trigeminal ganglion. CSF collected from animals exposed to CSD activates trigeminal neurons in naïve mice in part by CSF-borne calcitonin gene–related peptide (CGRP). We identify a communication pathway between the central and peripheral nervous system that might explain the relationship between migrainous aura and headache.
>丘脑底核深部脑刺激(deep brain stimulation targeting the subthalamic nucleus, STN-DBS)可有效缓解进展期帕金森病(Parkinson's disease, PD)运动障碍。DBS需要依赖高频（通常指≥100 Hz）电刺激才能发挥疗效，但其分子机制尚不明确。已有研究表明，音猬因子(sonic hedgehog, Shh)作为一种分泌蛋白，能够在高频刺激下从神经元中释放，并通过影响细胞膜上谷氨酸转运体表达调控胞外谷氨酸水平。在多巴胺能神经元中敲除Shh，可诱导PD样运动障碍。该研究旨在探讨Shh是否介导高频STN-DBS改善运动障碍。该研究采用单侧纹状体注射6-羟基多巴胺，建立PD啮齿类动物模型。以阿朴吗啡诱导的对侧旋转实验和平衡木实验，评估运动障碍。结果：（1）同侧高频STN-DBS (100 Hz)显著缓解运动障碍。腹腔注射Shh信号通路抑制剂环巴胺(cyclopamine, Cyc)阻断DBS对PD动物运动障碍的改善作用；侧脑室内注射Shh信号通路激动剂(SAG)，其作用与DBS类似，缓解运动障碍。这些结果表明，Shh在DBS改善PD运动障碍中发挥重要作用。（2）神经示踪结果显示，同侧STN可以投射到双侧丘脑前核(anterior thalamic nucleus, ANT)。然而，在PD模型中，同侧STN-DBS，只能增加对侧ANT的Shh含量。（3）干预对侧ANT中Shh信号通路，如
Chronic pain is a significant health problem worldwide. Recent evidence has suggested that the ventral hippocampus is dysfunctional in humans and rodents, with decreased neuronal excitability and connectivity with other brain regions, parallel pain chronicity, and persistent nociceptive hypersensitivity. But the molecular mechanisms underlying hippocampal modulation of pain remain poorly elucidated. In this study, we used ex vivo whole-cell patch-clamp recording, immunofluorescence staining, and behavioral tests to examine whether hyperpolarization-activated cyclic nucleotide-gated channels 2 (HCN2) in the ventral hippocampal CA1 (vCA1) were involved in regulating nociceptive perception and CFA-induced inflammatory pain in mice. Reduced sag potential and firing rate of action potentials were observed in vCA1 pyramidal neurons from CFA-injected mice. Moreover, the expression of HCN2, but not HCN1, in vCA1 decreased in mice injected with CFA. HCN2 knockdown in vCA1 pyramidal neurons induced thermal hypersensitivity, whereas overexpression of HCN2 alleviated thermal hyperalgesia induced by intraplantar injection of CFA in mice. Our findings suggest that HCN2 in the vCA1 plays an active role in pain modulation and could be a promising target for the treatment of chronic pain.
The prelimbic cortex (PL) is actively engaged in pain modulation. The infralimbic cortex (IL) has been reported to regulate the PL. However, how this regulation affects pain remains unclear. In the present study, we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli, but a temporary hypo-function of the IL by in vivo electrophysiological recording in rats with peripheral inflammation. Manipulation of the PL or IL had opposite effects on thermal hyperalgesia. Furthermore, the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL. Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia, whereas its inhibition exacerbated chronic pain. Overall, our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain: hypo-function of the IL leads to hyperactivity of the PL, which regulates thermal hyperalgesia, and thus contributes to the chronicity of pain.
A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: gamma-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.
An epidemic of sleep loss currently affects modern societies worldwide and is implicated in numerous physiological disorders, including pain sensitization, although few studies have explored the brain pathways affected by active sleep deprivation (ASD; e.g., due to recreation). Here, we describe a neural circuit responsible for pain sensitization in mice treated with 9-h non-stress ASD. Using a combination of advanced neuroscience methods, we found that ASD stimulates noradrenergic inputs from locus coeruleus (LCNA) to glutamatergic neurons of the hindlimb primary somatosensory cortex (S1HLGlu). Moreover, artificial inhibition of this LCNA→S1HLGlu pathway alleviates ASD-induced pain sensitization in mice, while chemogenetic activation of this pathway recapitulates the pain sensitization observed following ASD. Our study thus implicates activation of the LCNA→S1HLGlu pathway in ASD-induced pain sensitization, expanding our fundamental understanding of the multisystem interplay involved in pain processing.
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca2+ and peroxisome proliferator-activated receptor a (PPAR ⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChRmediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
As a main structure of the limbic system, the hippocampus plays a critical role in pain perception and chronicity. The ventral hippocampal CA1 (vCA1) is closely associated with negative emotions such as anxiety, stress, and fear, yet how vCA1 neurons encode nociceptive information remains unclear. Using in vivo electrophysiological recording, we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats. Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions: the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli, whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties. Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors. Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats, whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain. These results provide direct evidence for the representations of nociceptive information in vCA1.
It is well known that affective and pleasant touch promotes individual well-being and facilitates affiliative social communication, although the neural circuit that mediates this process is largely unknown. Here, we show that social-touch-like tactile stimulation (ST) enhances firing of oxytocin neurons in the mouse paraventricular hypothalamus (PVH) and promotes social interactions and positively reinforcing place preference. These results link pleasant somatosensory stimulation to increased social interactions and positive affective valence. We further show that tachykinin 1 (Tac1+) neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) send monosynaptic excitatory projections to PVH oxytocin neurons. Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing. Together, these results identify a dipeptidergic pathway from l/vlPAG Tac1+ neurons to PVH oxytocin neurons, through which pleasant sensory experience promotes social behavior.
Objective:This retrospective study compared the clinical efficacy and safety of knee nerve multi-mode radiofrequency vs knee joint injection medical chitosan in the treatment of refractory knee osteoarthritis(KOA).Methods:From February 2020 to March 2021 66 patients with refractory KOA who received treatment at the Pain Department of China-Japan Friendship Hospital were divided into the surgery group(n = 35)and the injection group(n = 31).The patients'numerical rating scale(NRS)scores,the Western Ontario and McMaster Universities(WOMAC)osteoarthritis index scores,the proportion of nonsteroidal antiinflammatory drugs(NSAIDs)and/or opioid drugs used,surgical related complications and patient satisfaction were evaluated and analyzed at the time of before surgery and 2 weeks,1,3,6 and 12 months after surgery.Results:Compared with pre-operation,the patients in surgical group had better efficacy than the injection group.The NRS scores and WOMAC scores,as well as the postoperative drug use rate,decreased significantly at the times of 2 weeks,1,3,6 and 12 months follow-up after surgery.No serious adverse reactions,such as lower limb numbness,lower limb weakness,hypoesthesia,paresthesia,and neuralgia,were observed after surgery.82.9%of the patients in surgery group,38.7%of the patients in injection group were satisfied with the post-operative results at the time of 12 months follow-up after surgery.Conclusion:The combination of knee nerve radiofrequency and low-temperature plasma radiofrequency ablation can effectively alleviate knee joint pain,improve joint function,and have no serious adverse reactions,which can be used as an alternative treatment mode for refractory KOA other than total knee arthroplasty.
疼痛是癌症病人最常见的症状之一.研究显示, 40％癌症病人伴有中重度疼痛 [1].癌痛可导致病人无法耐受相关的抗肿瘤治疗 [2],故癌痛治疗至关重要.鞘内药物输注系统 (implantable drug delivery system, IDDS) 用于癌痛治疗的有效性和安全性已被多个研究证实 [3,4].
There are many kinds of analgesic drugs.Management of narcotic analgesics need to be strengthened.There is a phenomenon of irrational use of opioid in China,while the problem of opioid abuse in the United States has led to a series of serious social crises,which should be prevented.With reference to the outstanding achievements of the grading management system of antibiotics and the actual situation of clinical pain management,this study creatively puts forward the hierarchical management model of analgesics in medical institutions.The study aims to explore the standardization and individualized diagnosis and treatment of clinical pain,to standardize the clinical use of analgesics in medical institutions,and to provide homogeneous,efficient and safe pain management for all kinds of pain patients.
1.一般资料 病例,男性,70 岁,因"右侧胸背部疼痛 2天"于 2021-08-05 在外院行胸部CT示:右侧第 6肋骨弥漫性骨质破坏伴邻近胸壁软组织增厚,考虑恶性肿瘤.
骨关节炎(osteoarthritis,OA)是一种常见的退行性关节疾病,其发病原因和病理机制尚不明确.目前,在临床上仍然缺乏有效的治疗方法,当务之急是寻找潜在的治疗靶点.瞬时受体电位锚蛋白1(transient receptor potential ankyrin-1,TRPA1)和瞬时受体电位香草素受体 4(transient receptor potential vanilloid-4,TRPV4)属于瞬时受体电位阳离子通道(transient receptor potential cation channel,TRP)家族的成员,在初级感觉神经元以及各种细胞中广泛表达,参与热、机械和化学物质等刺激的信号转导.越来越多的研究表明,TRPA1和TRPV4在OA的软骨退化、炎症反应和疼痛中起着重要作用.本文综述了TRPA1和TRPV4通道的生理功能,并概述了它们在OA发展和疼痛中最新的研究进展.同时,总结了TRPA1和TRPV4通道药物在治疗OA中的作用以及讨论未来的研究方向,为OA的治疗提供新思路.
国际疼痛学会(International Association for the Study of Pain, IASP)将慢性癌症相关性疼痛(chronic cancer-related pain, CCRP)定义为由癌症原发或转移,或癌症治疗所引起的疼痛(以下简称癌痛).不同癌症病人、癌症的不同阶段,其疼痛的病因、病理机制和临床表现均有所不同.疼痛评估是治疗癌痛的首要环节,准确全面的疼痛评估对制订个体化治疗方案和获得满意的治疗效果至关重要.目前因规范化癌痛评估体系的缺乏,影响了癌痛病人的治疗效果.为进一步完善癌痛的规范化管理,为临床医师提供规范的评估标准,中国医师协会疼痛科医师分会、中华医学会疼痛学分会、国家疼痛专业医疗质量控制中心、北京市疼痛治疗质量控制和改进中心组织相关领域专家,借鉴国内外相关指南,并结合临床实践经验,撰写本共识.本共识采用推荐意见分级的评估、制订和评价(grade of recommendations assessment, development and evaluation, GRADE) 分级体系,将证据质量等级分为高 (A)、中 (B)、低 (C)、极低 (D) 4 级;推荐级别分为强推荐和弱推荐(见附录).
神经病理性疼痛是一种常见的、致残的慢性疼痛,是由躯体感觉神经系统的损伤或疾病引起的.了解神经病理性疼痛的发病机制对于开发慢性疼痛新的有效治疗策略至关重要.Tiam1是一种Rac1鸟嘌呤核苷酸交换因子,在海马发育过程中通过诱导细胞骨架重构促进树突和突触的生长.该研究使用多种神经病理性疼痛动物模型,发现Tiam1通过促进细胞骨架重构和突触NMDAR稳定性来协调脊髓背角的突触结构和功能可塑性,这些作用对于神经病理性疼痛的开始、过渡和维持至关重要.此外,针对脊髓Tiam1的反义寡核苷酸能持续缓解对神经病理性疼痛的敏感性.该研究表明Tiam1协调突触功能和结构可塑性是神经病理性疼痛病理生理学的基础.干预Tiam1介导的突触可塑性异常在神经病理性疼痛治疗中有长期影响.
Objective:This study aimed to assess the effects of different concentrations of gaseous ozone and ozonated water injection around gasserian ganglion on the patient with trigeminal neuralgia.Methods:Collected the data of patients who suffered from trigeminal neuralgia from November 2016 to November 2021 in the Aviation General Hospital and the Affiliated Hospital of Shandong Second Medical University,then divided into 3 groups 23 μg/ml ozonated water injection group(23 patients),30 μg/ml gaseous ozone injection group(31 patients),40 μg/ml gaseous ozone injection group(17 patients).The therapeutic efficacy was evaluated via visual analogue scale(VAS),Barrow neurological institute(BNI)pain score and tactile sensation at pre-treatment and 1 week,6 months,1 year,post-treatment.Results:The VAS and BNI scores in the three groups at different time points were significantly lower than pre-treatment.Compared with 23 μg/ml ozonated water injection and 40 μg/ml gaseous ozone injection groups,the VAS,and BNI scores of the 30 μg/ml gaseous ozone injection group were lower 1 week after treatment.Similarly,the tactile sensation was significantly decreased at post-treatment compared to pre-treatment(P<0.05).However,there was no statistical difference among the three groups,and no significant complications were observed after 23 μg/ml ozonated water injection.Conclusion:23 μg/ml ozonated water injection,30 μg/ml gaseous ozone injection and 40 μg/ml gaseous ozone injection are effective therapies for treating TN.23 μg/ml ozonated water injection has a lower risk of potential complications and is safer in clinical applications.
神经根型颈椎病(cervical spondylotic radiculop-athy, CSR)是指颈神经根受压或刺激而引起的颈肩背部疼痛、上肢及手指的疼痛或运动感觉异常的临床疾病,是颈椎病中常见的一种类型,其发病率约占颈椎病病人的60％～70％ [1,2].临床上该病起病急、症状重,严重影响病人日常生活质量,因此探究CSR安全有效的治疗方法具有重要的社会意义.
