Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients....Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients.During the processing of pain,the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation.Furthermore,the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies.Here,we will review the complex interplay between cells(satellite glial cells and inflammatory cells)and factors(cytokines,neurotrophic factors and genetic factors)that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain.More importantly,we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.展开更多
Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR3...Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.展开更多
Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays...Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.展开更多
Neuropathic pain(NPP)is a kind of pain caused by disease or damage impacting the somatosensory system.Ion channel drugs are the main treatment for NPP;however,their irregular usage leads to unsatisfactory pain relief....Neuropathic pain(NPP)is a kind of pain caused by disease or damage impacting the somatosensory system.Ion channel drugs are the main treatment for NPP;however,their irregular usage leads to unsatisfactory pain relief.To regulate the treatment of NPP with ion channel drugs in clinical practice,the Chinese Association for the Study of Pain organized first-line pain management experts from China to write an expert consensus as the reference for the use of ion channels drugs.Here,we reviewed the mechanism and characteristics of sodium and calcium channel drugs,and developed recommendations for the therapeutic principles and clinical practice for carbamazepine,oxcarbazepine,lidocaine,bulleyaconitine A,pregabalin,and gabapentin.We hope this guideline provides guidance to clinicians and patients on the use of ion channel drugs for the management of NPP.展开更多
Peripheral nerve injury often causes neuropathic pain and is associated with changes in the expression of numerous proteins in the dorsal horn of the spinal cord. To date, proteomic analysis method has been used to si...Peripheral nerve injury often causes neuropathic pain and is associated with changes in the expression of numerous proteins in the dorsal horn of the spinal cord. To date, proteomic analysis method has been used to simultaneously analyze hundreds or thousands of proteins differentially expressed in the dorsal horn of the spinal cord in rats or dorsal root ganglion of rats with certain type of peripheral nerve injury. However, a proteomic study using a mouse model of neuropathic pain could be attempted because of abundant protein database and the availability of transgenic mice. In this study, whole proteins were extracted from the ipsilateral dorsal half of the 4^(th)-6^(th) lumbar spinal cord in a mouse model of spared nerve injury(SNI)-induced neuropathic pain. In-gel digests of the proteins size-separated on a polyacrylamide gel were subjected to reverse-phase liquid-chromatography coupled with electrospray ionization ion trap tandem mass spectrometry(MS/MS). After identifying proteins, the data were analyzed with subtractive proteomics using ProtAn, an in-house analytic program. Consequently, 15 downregulated and 35 upregulated proteins were identified in SNI mice. The identified proteins may contribute to the maintenance of neuropathic pain,and may provide new or valuable information in the discovery of new therapeutic targets for neuropathic pain.展开更多
Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been w...Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase(PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neuronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the involvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.展开更多
Objective:Pain from herniated disc is a common type of neuropathic pain.This study investigated whether electroacupuncture (EA) stimulation at distal-proximal combinations of acupoints in the rat model of neuropathic ...Objective:Pain from herniated disc is a common type of neuropathic pain.This study investigated whether electroacupuncture (EA) stimulation at distal-proximal combinations of acupoints in the rat model of neuropathic pain modulates spinal interleukin-1 beta (IL-1β) to induce acupuncture analgesia and possibly serve as a pain-relief modality for herniated disc.Methods:A rat model of neuropathic pain was established.Rats were randomly divided into normal,model,sham,EA 1,EA 2,and EA 3 groups.EA 1 rats were needled at bilateral ExB2,BL25,BL40,and BL60 acupoints.EA 2 rats Were needled at bilateral BL40 and BL60.EA 3 rats were needled at bilateral L5 Ex-B2 and BL25.EA stimulation was administered once daily over 7 days.Mechanical withdrawal threshold from noxious mechanical stimulation was measured 1 day preoperatively and at 3,5,and7 days postoperatively.After 7 days of intervention,enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-1β in the spinal cord.Results:Mechanical withdrawal threshold of rats in the model group decreased at 3 days postoperatively when compared with the normal group (P < 0.01),lasting 7 days postoperatively.Mechanical withdrawal thresholds in the EA 1,EA 2,and EA 3 groups were elevated over the model group (P < 0.05;P < 0.01).No obvious differences were found between EA 1,EA 2,and EA 3 groups.ELISA demonstrated an increase in IL-1β in the spinal cord of rats in the model group compared with the normal group (P < 0.01).EA treatment attenuated the increase in spinal IL-1β in the model group.Expression of spinal IL-1β was significantly lower in EA 1,EA 2,and EA 3 groups.Conclusion:EA at distal + proximal acupoints,distal points,as well as proximal points attenuated upregulation of spinal IL-1β,alleviated the extent of neuropathic pain hypersensitivity,and promoted mechanical withdrawal threshold,resulting in EA analgesia.展开更多
OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sci...OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.展开更多
Objective:To investigate the effect of aloin against chronic constriction injury(CCI)-induced neuropathic pain in rats.Methods:Rats were randomly divided into 7 groups:GroupⅠ(normal control),GroupⅡ(sham-operated),Gr...Objective:To investigate the effect of aloin against chronic constriction injury(CCI)-induced neuropathic pain in rats.Methods:Rats were randomly divided into 7 groups:GroupⅠ(normal control),GroupⅡ(sham-operated),GroupⅢ(CCI control)and GroupⅣ,Ⅴ,Ⅵ,andⅦ,which underwent CCI surgery and then were administered with aloin(5 mg/kg,p.o.;25 mg/kg,p.o.;125 mg/kg,p.o.)and gabapentin(50 mg/kg,p.o.),respectively for 14 days.Peripheral neuropathy was induced by silk ligatures(4-0)loosely placed around the sciatic nerve.Nociceptive thresholds against mechanical stimuli(Von-Frey filaments)and thermal stimuli(12℃and 40℃)were measured at midplantar paw region ipsilateral to the compressed nerve on day-3,7,11,and 14.The concentration of cytokines including tumor necrosis factor-α(TNF-α),interleukin-6,and interleukin-1βwas estimated at day-7.At day 14,motor nerve conduction velocity was determined under urethane anesthesia(1.25 g/kg).Oxidative stress parameters(malondiadehyde,glutathione,catalase,and superoxide dismutase)were estimated in sciatic nerve homogenates at day 14.Representative nerve samples were processed for histological investigations.Results:Aloin significantly reduced CCI-induced mechanical and thermal allodynia.It also improved motor nerve conduction velocity and decreased oxidative stress in nerve tissues.In addition,it decreased pro-inflammatory cytokine levels and restored the histoarchitecture of compressed sciatic nerve.Conclusions:Aloin mitigates CCI-induced neuropathic pain in rats by inhibiting oxidative stress and pro-inflammatory cytokines in the afflicted sciatic nerve.展开更多
Objective:Prostate cancer is the most frequent cancer in men and radical retropubic prostatectomy(RRP)is one of the first-line treatment.However,RRP has some side effects and can lead to chronic perineal pain.The obje...Objective:Prostate cancer is the most frequent cancer in men and radical retropubic prostatectomy(RRP)is one of the first-line treatment.However,RRP has some side effects and can lead to chronic perineal pain.The objective of the study was to determine in patients suffering from perineal pain after RRP the possibility of a neurogenic damage by means of a specific questionnaire dedicated to track down neuropathic pain.Methods:Forty patients were explored by a specific and validated questionnaire,the Neuropathic Pain Symptom Inventory(NPSI).Patients were divided into two groups:Group A with an NSPI score≥4 was considered as suffering from neuropathic pain,and Group B was considered as a control group without neuropathic pain(NSPI score<4).All patients had a perineal electrophysiological testing to confirm the possibility of a neurogenic damage.Results:Group A was composed by 13 men and Group B by 27 men,with mean age 72.45 years and mean duration of pain 2.7 years.In Group A,the most frequent symptoms were burning sensation,electrical shock and numbness.Location of the pain was global perineal area(8/13),anus(10/13),penis(5/13)and glans penis(2/13).Electromyography(EMG)findings confirmed the presence of denervation and neurogenic damages compared with controls(p<0.001).Conclusion:One third of the patients consulting for chronic pain following RRP had probably a neuropathic lesion leading to a chronic perineal pain as suggested by an NSPI score≥4 and EMG alterations.展开更多
<strong>Introduction: </strong>Pain with neuropathic characteristics is one of the most limiting as a consequence of injury or disease that affects the somatosensory system. <strong>Objective: </s...<strong>Introduction: </strong>Pain with neuropathic characteristics is one of the most limiting as a consequence of injury or disease that affects the somatosensory system. <strong>Objective: </strong>An assessment protocol is proposed to quantify the impact of neuropathic pain integrating personal, clinical, work and social aspects and to establish guidelines in its management and evolutionary control. <strong>Method:</strong> The medical literature on neuropathic pain and its impact is reviewed as a basis for including the variables that must be part of the protocol. <strong>Results:</strong> The variables are quantified individually and by groups of factors. The final result is stratified into four grades (mild, moderate, severe, extreme), which will serve for the subsequent control, monitoring and prevention of risks. <strong>Conclusion:</strong> The proposed protocol evaluates the impact of neuropathic pain in all aspects of the person who suffers it and quantifies the results establishing degrees for its control, follow-up and clinical, social and occupational intervention.展开更多
Objective The aim of the study was to investigate the efficacy and adverse effects of olanzapine in the treatment of moderate to severe refractory neuropathic pain.Methods Forty patients with digestive system cancer w...Objective The aim of the study was to investigate the efficacy and adverse effects of olanzapine in the treatment of moderate to severe refractory neuropathic pain.Methods Forty patients with digestive system cancer were enrolled,who had moderate to severe refractory neuropathic pain;the patients were treated with olanzapine for 2 weeks at a daily dosage of 5 mg to 10 mg per night according to patients’response and tolerability,combined with conventional analgesic therapy.Pain intensity was evaluated by using a Numeral Rating Scale(NRS)at baseline,3 days,and 2 weeks after therapy.The Pittsburg Sleep Quality Index(PSQI)was evaluated at baseline and 2 weeks after therapy.Data on adverse events were recorded.The dosage of conventional analgesics was adjusted over time based on the severity of pain.Results The mean pain score decreased by 2.575±1.318(P<0.000)at 3 days and by 3.400±1.614(P<0.000)at 2 weeks;30%of the patients experienced significant pain relief at 3 days and 50%at 2 weeks.The PSQI decreased by 4.725±2.828(P<0.000)at 2 weeks.The adverse events induced by olanzapine included sleepiness,weight gain,dizziness,fatigue,dry mouth,and constipation;all the side effects were mild.Conclusion When combined with conventional analgesic therapy,olanzapine was effective in relieving pain and sleep disturbance,and was well-tolerated among patients with refractory neuropathic pain.展开更多
Objective: When nerve injury or inflammatory injury, different miRNA-mediated signal pathways are activated or inactivated, causing pain or hyperalgesia. Therefore, miRNA has become a new direction of pain mechanism r...Objective: When nerve injury or inflammatory injury, different miRNA-mediated signal pathways are activated or inactivated, causing pain or hyperalgesia. Therefore, miRNA has become a new direction of pain mechanism research. We aimed to investigate the effect and mechanism of miR-362-3p on neuropathic pain in rats with chronic sciatic nerve injury (CCI). Methods: Neuropathic pain CCI rat model was established. Real-time-quantitative polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, intrathecal injection, Enzyme-linked immunosorbent assay (ELISA), and dual luciferase reporter gene assays were used to explore the role of miR-362-3p in neuropathic pain development and the relationship between miR-362-3p and JMJD1A (Jumonji domain-containing 1A). Results: In the CCI group, the miR-362-3p level was increased and JMJD1A level was reduced in spinal cords and isolated microglia. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) values were increased, the secretion of inflammatory factors was reduced, and the microglial marker Iba1 expression was decreased after intrathecal administration of miR-362-3p. miR-362-3p was observed to target JMJD1A. JMJD1A elevation abolished the inhibitory effects of miR-362-3p on neuropathic pain development. Conclusion: Intrathecal administration of miR-362-3p significantly relieved neuropathic pain in CCI rats and inhibited neuroinflammation possibly through regulating JMJD1A.展开更多
BACKGROUND: The clinical treatment of neuropathic pain is very troublesome ,and the physical method of radiofrequency thermocoagulation is a good choice for its treatment.OBJECTIVE: To observe the curative effact of p...BACKGROUND: The clinical treatment of neuropathic pain is very troublesome ,and the physical method of radiofrequency thermocoagulation is a good choice for its treatment.OBJECTIVE: To observe the curative effact of percutaneous radiofrequency thermocoagulation on neuropathic neuralgia.DESIGN:A case follow-up analysis.SETTING: Minimally Invasive Surgery Room,Department of Neurosurgery,Urumqi General Hospital of Lanzhou Military Area Command of Chinese PLA.PARTICIPANTS: Totally 131 patients were selected from the Department of Neurosurgery,Urumqi General Hospital of Lanzhou Military Area Command of Chinese PLA from December 2000 to June 2006,including 73 males and 58 females,aging 37-72 years old,AND the disease course was 2-15 years.①Drug treatment failed to alleviate the pain or induced obvious side the pain or induced obvious side effects; ②With the same pathological changes as pain and effective in the nerve block test; Had signed the informed consents before treatment.Distribution of the neuropathic pain:①Trigeminal neuralgia,which were lighting attack,located at V2 in 28 cases,V3 in 46 cases,V1+V2 in 3 cases,V2+V3 in 28 cases,and V1+V2+V3 in 1 cases;②Migraine located at(except the frontal branch of trigeminal nerve)greater and lesser occipital nerves in 6 cases,auriculotemporal nerve in 3 cases,temporal and zygomatic nerves in 3 cases;③Unilateral neuralgia of C2 and C3 following herpes zoster in 1 case,and chest intercostals neuralgia in 2 cases;④Lasting burning pain in the operative area after thoracotomy was in 1 case of lung cancer.METHODS: ①All the enrolled patients were treated with percutaneous puncture at trigeminal ganglion or peripheral nerve,then nerve block was performed firstly for anesthesia,and the pain disappeared immediately at this moment,there was hypoesthesia or numbness in the area of innervation,which manifested the puncture apposition was correct.then electrostimulation of 50 Hz with the current of 0.1-0.5 V was given for further functional localization.②The RFG-3C radiofrequency therapeutic instrument(Radionics,USA)was used,the tip of the radiofrequency electrode was exposed for 5 mm,the temperature was kept at 80-85℃,30-60 for each time, and treated for 3 or 4 times.The neuralgia following herpes zoster could also be treated by thermocoagulation at several points.③Evaluation standards for the therapeutic efficacy:Excellent meant the pain disappeared completely without taking any anodyne. Good referred to the pain was alleviated as compared with the preoperative one, and it could be effectively controlled by anodyne at relapse, but radiofrequency therapy was unnecessary.MAIN OUTCOME MEASURES:Therapeutic efficacy of neuropathic neuralgia of different types after treatment of percutaneous radiofrequency thermocoagulation.RESULTS:All the 131 patients were involved in the final analysis of results,no one missed.④Therapeutic efficacy:In the 24-month follow-up,the therapeutic efficacy was excellent in 106 cases(80,9%),good in 21 cases(16.0%)and had no change in 4 cases(3.1%).For 13 of the patients with trigeminal neuralgia,the pain relapsed after the lesion of peripheral branches,and it disappeared after the second treatment.The treatment was invalid for 1 patient with lung cancer suffering from pain in the operative area after thoracotomy,and the pain was alleviated by spinal cord stimulation.The pain disappeared after treated for 3 times in the patients with cervical neuralgia following herpes zoster.②The pain relapsed in 28 cases(21.4%)at 12 months of the follow-up.③Adverse events and side effects:Except the hypoesthesia of different severity at the site of pain,there was no other complication after treatment.CONCLUSION:The follow-up results showed that percutaneous radiofrequency thermocoagulation is one of the effective methods for treating neuropathic neuralgias of various types.展开更多
Objective: the objective of this study was to evaluate the efficacy of the lidocaine patch 5% in different types of neuropathic pain. Methods: a prospective, longitudinal, observational study on a sample of 16 patient...Objective: the objective of this study was to evaluate the efficacy of the lidocaine patch 5% in different types of neuropathic pain. Methods: a prospective, longitudinal, observational study on a sample of 16 patients who consulted for neuropathic pain. A lidocaine patch 5% was applied to the painful area and as primary endpoint, the severity of the pain was studied using the Verbal Numeric Rating Scale (VNRS). Secondary quality of life-related endpoints were sleep during the night, mood and patient global impression of the treatment. Results: demographic data: 62.5% female and 37.5% male;mean age 55.31 ± 13.9 years;time since onset of the pain 8.4 months;and classified into 4 diagnosis groups: post-herpetic neuralgia 18.8%;complex regional pain syndrome 25%;surgical wound 50%;and others 6.3%. There was a reduction of more than 2 points in pain on the VNRS (median 6.5 to 3.5;p = 0.001), an improvement in sleep during the night, mood and relief (p < 0.05), less use of analgesics, no complications and over 30% of subjects reported improvement of over 50%. Conclusions: The lidocaine patch 5% could be a useful tool for the control of neuropathic pain, not only for post-herpetic neuralgia, and it has a good safety and tolerability profile.展开更多
Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice.Unfortunately,current pharmacological treatments for neuropathic pain lack clinical effic...Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice.Unfortunately,current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions.As G protein-coupled receptors(GPCRs)are widely distributed throughout the body,including the pain transmission pathway and descending inhibition pathway,the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum.Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects.This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain,and discuss the potential benefits and adverse factors of this treatment.We will also concentrate on the development of biased agonists of GPCRs,and based on important examples of biased agonist development in recent years,we will describe universal strategies for designing structure-based biased agonists.It is foreseeable that,with the continuous improvement of GPCRs allosteric modulation and biased agonist theory,effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.展开更多
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 neuropat...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.展开更多
tDiabetic neuropathic pain(DNP)is the most common disabling complication of diabetes.Emerging evi-dence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area;however,the...tDiabetic neuropathic pain(DNP)is the most common disabling complication of diabetes.Emerging evi-dence 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 con-clusion,our studies identified Ntn-3 as an important regula-tor of DNP pathogenesis by gating the aberrant sprouting of sensory axons,indicating that Ntn-3 is a potential druggable target for DNP treatment.展开更多
The thalamocortical(TC)circuit is closely asso-ciated with pain processing.The hyperpolarization-activated cyclic nucleotide-gated(HCN)2 channel is predominantly expressed in the ventral posterolateral thalamus(VPL)th...The thalamocortical(TC)circuit is closely asso-ciated 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 trac-ing,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 pharmaco-logical 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.展开更多
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 a...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.展开更多
基金under a contract of the“Nicolás Monardes”program(RC-0002-2021)from the Andalusian Health Service,Andalusian Regional Ministry of Health and Consumptionfunds from the Excellent Project from Andalusian Government(Proy Excel_00996)+8 种基金funded by the French Multiple Sclerosis Foundation(ARSEP,1259&1254)the National Multiple Sclerosis Society(NMSS,RG 5088-A-1)the program“Investissements d’Avenir”(ANR-10-IAIHU-06 and ANR-11-INBS-0011–Neur ATRIS)under a“Miguel Servet”contract(CP20-0049)from the Health Institute CarlosⅢ,Ministry of Science and Innovation,Spainreceived grants from Andalusian Government and the European Commission under the Seventh Framework Program of the European Union(agreement Num.291730,contract TAHUB-II-107)ARSEP 1254IBRO Return Home FellowshipAES2022 from Health Institute CarlosⅢ(PI22/01141)the Excellent Project from Andalusian Regional Ministry of University,Research and Innovation(Proy Excel_00996)。
文摘Neuropathic pain is a severe and chronic condition widely found in the general population.The reason for this is the extensive variety of damage or diseases that can spark this unpleasant constant feeling in patients.During the processing of pain,the dorsal root ganglia constitute an important region where dorsal root ganglion neurons play a crucial role in the transmission and propagation of sensory electrical stimulation.Furthermore,the dorsal root ganglia have recently exhibited a regenerative capacity that should not be neglected in the understanding of the development and resolution of neuropathic pain and in the elucidation of innovative therapies.Here,we will review the complex interplay between cells(satellite glial cells and inflammatory cells)and factors(cytokines,neurotrophic factors and genetic factors)that takes place within the dorsal root ganglia and accounts for the generation of the aberrant excitation of primary sensory neurons occurring in neuropathic pain.More importantly,we will summarize an updated view of the current pharmacologic and nonpharmacologic therapies targeting the dorsal root ganglia for the treatment of neuropathic pain.
基金supported by the National Notural Science Foundation of China,Nos.82071556 and 82271291 (both to WM)
文摘Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.
基金National Natural Science Foundation of China,No.819 73305 (to ZQ)Science and Technology Planning Project of Guangzhou of China,No.20190401 0487 (to ZQ)+1 种基金Natural Science Foundation of Guangdong Province,China,No.2021A1515010897 (to TT)Discipline Construction Fund of Cen tral Peoples Hospital of Zhanjiang,Nos.2020A01 (to TT) and 2020A02 (to TT)。
文摘Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.
基金Supported by Sichuan Science and Technology Program,No.2018SZ0386。
文摘Neuropathic pain(NPP)is a kind of pain caused by disease or damage impacting the somatosensory system.Ion channel drugs are the main treatment for NPP;however,their irregular usage leads to unsatisfactory pain relief.To regulate the treatment of NPP with ion channel drugs in clinical practice,the Chinese Association for the Study of Pain organized first-line pain management experts from China to write an expert consensus as the reference for the use of ion channels drugs.Here,we reviewed the mechanism and characteristics of sodium and calcium channel drugs,and developed recommendations for the therapeutic principles and clinical practice for carbamazepine,oxcarbazepine,lidocaine,bulleyaconitine A,pregabalin,and gabapentin.We hope this guideline provides guidance to clinicians and patients on the use of ion channel drugs for the management of NPP.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(2015RIDIAIA01059432)
文摘Peripheral nerve injury often causes neuropathic pain and is associated with changes in the expression of numerous proteins in the dorsal horn of the spinal cord. To date, proteomic analysis method has been used to simultaneously analyze hundreds or thousands of proteins differentially expressed in the dorsal horn of the spinal cord in rats or dorsal root ganglion of rats with certain type of peripheral nerve injury. However, a proteomic study using a mouse model of neuropathic pain could be attempted because of abundant protein database and the availability of transgenic mice. In this study, whole proteins were extracted from the ipsilateral dorsal half of the 4^(th)-6^(th) lumbar spinal cord in a mouse model of spared nerve injury(SNI)-induced neuropathic pain. In-gel digests of the proteins size-separated on a polyacrylamide gel were subjected to reverse-phase liquid-chromatography coupled with electrospray ionization ion trap tandem mass spectrometry(MS/MS). After identifying proteins, the data were analyzed with subtractive proteomics using ProtAn, an in-house analytic program. Consequently, 15 downregulated and 35 upregulated proteins were identified in SNI mice. The identified proteins may contribute to the maintenance of neuropathic pain,and may provide new or valuable information in the discovery of new therapeutic targets for neuropathic pain.
基金Department of Biotechnology Govt of India,for their financial support to Dr.Ashutosh Kumar via grant BT/527/NE/TBP/2013the financial support from Department of Pharmaceuticals,Ministry of Chemical and Fertilizers and NIPER Hyderabad for their support
文摘Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase(PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neuronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the involvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.
基金This study was supported by grants from the Project of Beijing University of Chinese Medicine in China(No.JYB22 e JS022).
文摘Objective:Pain from herniated disc is a common type of neuropathic pain.This study investigated whether electroacupuncture (EA) stimulation at distal-proximal combinations of acupoints in the rat model of neuropathic pain modulates spinal interleukin-1 beta (IL-1β) to induce acupuncture analgesia and possibly serve as a pain-relief modality for herniated disc.Methods:A rat model of neuropathic pain was established.Rats were randomly divided into normal,model,sham,EA 1,EA 2,and EA 3 groups.EA 1 rats were needled at bilateral ExB2,BL25,BL40,and BL60 acupoints.EA 2 rats Were needled at bilateral BL40 and BL60.EA 3 rats were needled at bilateral L5 Ex-B2 and BL25.EA stimulation was administered once daily over 7 days.Mechanical withdrawal threshold from noxious mechanical stimulation was measured 1 day preoperatively and at 3,5,and7 days postoperatively.After 7 days of intervention,enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-1β in the spinal cord.Results:Mechanical withdrawal threshold of rats in the model group decreased at 3 days postoperatively when compared with the normal group (P < 0.01),lasting 7 days postoperatively.Mechanical withdrawal thresholds in the EA 1,EA 2,and EA 3 groups were elevated over the model group (P < 0.05;P < 0.01).No obvious differences were found between EA 1,EA 2,and EA 3 groups.ELISA demonstrated an increase in IL-1β in the spinal cord of rats in the model group compared with the normal group (P < 0.01).EA treatment attenuated the increase in spinal IL-1β in the model group.Expression of spinal IL-1β was significantly lower in EA 1,EA 2,and EA 3 groups.Conclusion:EA at distal + proximal acupoints,distal points,as well as proximal points attenuated upregulation of spinal IL-1β,alleviated the extent of neuropathic pain hypersensitivity,and promoted mechanical withdrawal threshold,resulting in EA analgesia.
基金The project supported by National Natural Science Foundation of China(81473234,U1303221)
文摘OBJECTIVE To investigated the effects of INI-0602 on nociceptive reflex,depression-associated andanxiety-related behaviors caused by neuropathic pain in sciatic nerve injury rats.METHODS Male rat were subjected to sciatic nerve injury(SNI)or sham surgery.Rat received daily treatment with INI-0602 intrathecally,at a dose of 0.25μg/10μL.The response frequency to mechanical allodynia in animals was measured with von Frey hairs on day 1,3,5,7,14,21.Rats were evaluated in the forced swimming test(FST)test,tail suspension test(TST),sucrose preference test(SPT)for depression-like behavior.We performed open field test(OFT)and elevated plus-maze test(EPM)to evaluate anxiety-associated behaviors.Besides,we investigated the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF)and also the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.RESULTS The SNI procedure produced mechanical allodynia and accompanied with depressive-like and anxiety-like behavior.Treatment with INI-0602 produced a significant analgesic effect in SNI rats at day 7(model+NS:11.017±1.506 g;model+INI-0602:31.157±1.532 g,P<0.01),and still obviously on the 21th day(31.067±1.787,P<0.01).INI-0602 could also improve the performance of sciatic nerve injury rats among program behavior tests related to depression and anxiety.In parallel with relief of pain,the alterations of NMDA receptor and the brain-derived neurotrophic factor(BDNF),involved in central sensitization and synaptic plasticity,were investigated.INI-0602 not only could inhibited spared nerve injury induced up-regulated of NR2B and phosphorylation NR2B in early and late neuropathic pain(early phase:Nr2b:2.897±0.228,P<0.01;p-Nr2b:2.984±0.236,P<0.01;late phase:Nr2b:2.594±0.187,P<0.01;p-Nr2b:3.124±0.330,P<0.01),but also could inhibit the increased of BDNF in the early(model+NS:3.637±0.381,model+INI-0602:1.148±0.372,P<0.01)and upregulate the BDNF in late stage(model+NS:0.438±0.103,model+INI-0602:1.222±0.092,P<0.01).Meanwhile,INI-0602 significantly decreased the expression of connexin43 and connexin32,structure protein of gap junction channel,on the protein level and the number of activated astrocyte showed by immunohistochemical.CONCLUSION INI-0602 blocked behavioral changes induced by neuropathic pain,suggesting that it might be a promising pharmacological approach of painemotion diseases.
文摘Objective:To investigate the effect of aloin against chronic constriction injury(CCI)-induced neuropathic pain in rats.Methods:Rats were randomly divided into 7 groups:GroupⅠ(normal control),GroupⅡ(sham-operated),GroupⅢ(CCI control)and GroupⅣ,Ⅴ,Ⅵ,andⅦ,which underwent CCI surgery and then were administered with aloin(5 mg/kg,p.o.;25 mg/kg,p.o.;125 mg/kg,p.o.)and gabapentin(50 mg/kg,p.o.),respectively for 14 days.Peripheral neuropathy was induced by silk ligatures(4-0)loosely placed around the sciatic nerve.Nociceptive thresholds against mechanical stimuli(Von-Frey filaments)and thermal stimuli(12℃and 40℃)were measured at midplantar paw region ipsilateral to the compressed nerve on day-3,7,11,and 14.The concentration of cytokines including tumor necrosis factor-α(TNF-α),interleukin-6,and interleukin-1βwas estimated at day-7.At day 14,motor nerve conduction velocity was determined under urethane anesthesia(1.25 g/kg).Oxidative stress parameters(malondiadehyde,glutathione,catalase,and superoxide dismutase)were estimated in sciatic nerve homogenates at day 14.Representative nerve samples were processed for histological investigations.Results:Aloin significantly reduced CCI-induced mechanical and thermal allodynia.It also improved motor nerve conduction velocity and decreased oxidative stress in nerve tissues.In addition,it decreased pro-inflammatory cytokine levels and restored the histoarchitecture of compressed sciatic nerve.Conclusions:Aloin mitigates CCI-induced neuropathic pain in rats by inhibiting oxidative stress and pro-inflammatory cytokines in the afflicted sciatic nerve.
文摘Objective:Prostate cancer is the most frequent cancer in men and radical retropubic prostatectomy(RRP)is one of the first-line treatment.However,RRP has some side effects and can lead to chronic perineal pain.The objective of the study was to determine in patients suffering from perineal pain after RRP the possibility of a neurogenic damage by means of a specific questionnaire dedicated to track down neuropathic pain.Methods:Forty patients were explored by a specific and validated questionnaire,the Neuropathic Pain Symptom Inventory(NPSI).Patients were divided into two groups:Group A with an NSPI score≥4 was considered as suffering from neuropathic pain,and Group B was considered as a control group without neuropathic pain(NSPI score<4).All patients had a perineal electrophysiological testing to confirm the possibility of a neurogenic damage.Results:Group A was composed by 13 men and Group B by 27 men,with mean age 72.45 years and mean duration of pain 2.7 years.In Group A,the most frequent symptoms were burning sensation,electrical shock and numbness.Location of the pain was global perineal area(8/13),anus(10/13),penis(5/13)and glans penis(2/13).Electromyography(EMG)findings confirmed the presence of denervation and neurogenic damages compared with controls(p<0.001).Conclusion:One third of the patients consulting for chronic pain following RRP had probably a neuropathic lesion leading to a chronic perineal pain as suggested by an NSPI score≥4 and EMG alterations.
文摘<strong>Introduction: </strong>Pain with neuropathic characteristics is one of the most limiting as a consequence of injury or disease that affects the somatosensory system. <strong>Objective: </strong>An assessment protocol is proposed to quantify the impact of neuropathic pain integrating personal, clinical, work and social aspects and to establish guidelines in its management and evolutionary control. <strong>Method:</strong> The medical literature on neuropathic pain and its impact is reviewed as a basis for including the variables that must be part of the protocol. <strong>Results:</strong> The variables are quantified individually and by groups of factors. The final result is stratified into four grades (mild, moderate, severe, extreme), which will serve for the subsequent control, monitoring and prevention of risks. <strong>Conclusion:</strong> The proposed protocol evaluates the impact of neuropathic pain in all aspects of the person who suffers it and quantifies the results establishing degrees for its control, follow-up and clinical, social and occupational intervention.
基金grants from double top independent innovation physician funded projects of Huazhong University of Science and Technology(No.3011540024,5001540074,5001540095)Wuhan young and middle-age medical backbone training project(No.2016whzqnyxggrcl).
文摘Objective The aim of the study was to investigate the efficacy and adverse effects of olanzapine in the treatment of moderate to severe refractory neuropathic pain.Methods Forty patients with digestive system cancer were enrolled,who had moderate to severe refractory neuropathic pain;the patients were treated with olanzapine for 2 weeks at a daily dosage of 5 mg to 10 mg per night according to patients’response and tolerability,combined with conventional analgesic therapy.Pain intensity was evaluated by using a Numeral Rating Scale(NRS)at baseline,3 days,and 2 weeks after therapy.The Pittsburg Sleep Quality Index(PSQI)was evaluated at baseline and 2 weeks after therapy.Data on adverse events were recorded.The dosage of conventional analgesics was adjusted over time based on the severity of pain.Results The mean pain score decreased by 2.575±1.318(P<0.000)at 3 days and by 3.400±1.614(P<0.000)at 2 weeks;30%of the patients experienced significant pain relief at 3 days and 50%at 2 weeks.The PSQI decreased by 4.725±2.828(P<0.000)at 2 weeks.The adverse events induced by olanzapine included sleepiness,weight gain,dizziness,fatigue,dry mouth,and constipation;all the side effects were mild.Conclusion When combined with conventional analgesic therapy,olanzapine was effective in relieving pain and sleep disturbance,and was well-tolerated among patients with refractory neuropathic pain.
文摘Objective: When nerve injury or inflammatory injury, different miRNA-mediated signal pathways are activated or inactivated, causing pain or hyperalgesia. Therefore, miRNA has become a new direction of pain mechanism research. We aimed to investigate the effect and mechanism of miR-362-3p on neuropathic pain in rats with chronic sciatic nerve injury (CCI). Methods: Neuropathic pain CCI rat model was established. Real-time-quantitative polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, intrathecal injection, Enzyme-linked immunosorbent assay (ELISA), and dual luciferase reporter gene assays were used to explore the role of miR-362-3p in neuropathic pain development and the relationship between miR-362-3p and JMJD1A (Jumonji domain-containing 1A). Results: In the CCI group, the miR-362-3p level was increased and JMJD1A level was reduced in spinal cords and isolated microglia. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) values were increased, the secretion of inflammatory factors was reduced, and the microglial marker Iba1 expression was decreased after intrathecal administration of miR-362-3p. miR-362-3p was observed to target JMJD1A. JMJD1A elevation abolished the inhibitory effects of miR-362-3p on neuropathic pain development. Conclusion: Intrathecal administration of miR-362-3p significantly relieved neuropathic pain in CCI rats and inhibited neuroinflammation possibly through regulating JMJD1A.
文摘BACKGROUND: The clinical treatment of neuropathic pain is very troublesome ,and the physical method of radiofrequency thermocoagulation is a good choice for its treatment.OBJECTIVE: To observe the curative effact of percutaneous radiofrequency thermocoagulation on neuropathic neuralgia.DESIGN:A case follow-up analysis.SETTING: Minimally Invasive Surgery Room,Department of Neurosurgery,Urumqi General Hospital of Lanzhou Military Area Command of Chinese PLA.PARTICIPANTS: Totally 131 patients were selected from the Department of Neurosurgery,Urumqi General Hospital of Lanzhou Military Area Command of Chinese PLA from December 2000 to June 2006,including 73 males and 58 females,aging 37-72 years old,AND the disease course was 2-15 years.①Drug treatment failed to alleviate the pain or induced obvious side the pain or induced obvious side effects; ②With the same pathological changes as pain and effective in the nerve block test; Had signed the informed consents before treatment.Distribution of the neuropathic pain:①Trigeminal neuralgia,which were lighting attack,located at V2 in 28 cases,V3 in 46 cases,V1+V2 in 3 cases,V2+V3 in 28 cases,and V1+V2+V3 in 1 cases;②Migraine located at(except the frontal branch of trigeminal nerve)greater and lesser occipital nerves in 6 cases,auriculotemporal nerve in 3 cases,temporal and zygomatic nerves in 3 cases;③Unilateral neuralgia of C2 and C3 following herpes zoster in 1 case,and chest intercostals neuralgia in 2 cases;④Lasting burning pain in the operative area after thoracotomy was in 1 case of lung cancer.METHODS: ①All the enrolled patients were treated with percutaneous puncture at trigeminal ganglion or peripheral nerve,then nerve block was performed firstly for anesthesia,and the pain disappeared immediately at this moment,there was hypoesthesia or numbness in the area of innervation,which manifested the puncture apposition was correct.then electrostimulation of 50 Hz with the current of 0.1-0.5 V was given for further functional localization.②The RFG-3C radiofrequency therapeutic instrument(Radionics,USA)was used,the tip of the radiofrequency electrode was exposed for 5 mm,the temperature was kept at 80-85℃,30-60 for each time, and treated for 3 or 4 times.The neuralgia following herpes zoster could also be treated by thermocoagulation at several points.③Evaluation standards for the therapeutic efficacy:Excellent meant the pain disappeared completely without taking any anodyne. Good referred to the pain was alleviated as compared with the preoperative one, and it could be effectively controlled by anodyne at relapse, but radiofrequency therapy was unnecessary.MAIN OUTCOME MEASURES:Therapeutic efficacy of neuropathic neuralgia of different types after treatment of percutaneous radiofrequency thermocoagulation.RESULTS:All the 131 patients were involved in the final analysis of results,no one missed.④Therapeutic efficacy:In the 24-month follow-up,the therapeutic efficacy was excellent in 106 cases(80,9%),good in 21 cases(16.0%)and had no change in 4 cases(3.1%).For 13 of the patients with trigeminal neuralgia,the pain relapsed after the lesion of peripheral branches,and it disappeared after the second treatment.The treatment was invalid for 1 patient with lung cancer suffering from pain in the operative area after thoracotomy,and the pain was alleviated by spinal cord stimulation.The pain disappeared after treated for 3 times in the patients with cervical neuralgia following herpes zoster.②The pain relapsed in 28 cases(21.4%)at 12 months of the follow-up.③Adverse events and side effects:Except the hypoesthesia of different severity at the site of pain,there was no other complication after treatment.CONCLUSION:The follow-up results showed that percutaneous radiofrequency thermocoagulation is one of the effective methods for treating neuropathic neuralgias of various types.
文摘Objective: the objective of this study was to evaluate the efficacy of the lidocaine patch 5% in different types of neuropathic pain. Methods: a prospective, longitudinal, observational study on a sample of 16 patients who consulted for neuropathic pain. A lidocaine patch 5% was applied to the painful area and as primary endpoint, the severity of the pain was studied using the Verbal Numeric Rating Scale (VNRS). Secondary quality of life-related endpoints were sleep during the night, mood and patient global impression of the treatment. Results: demographic data: 62.5% female and 37.5% male;mean age 55.31 ± 13.9 years;time since onset of the pain 8.4 months;and classified into 4 diagnosis groups: post-herpetic neuralgia 18.8%;complex regional pain syndrome 25%;surgical wound 50%;and others 6.3%. There was a reduction of more than 2 points in pain on the VNRS (median 6.5 to 3.5;p = 0.001), an improvement in sleep during the night, mood and relief (p < 0.05), less use of analgesics, no complications and over 30% of subjects reported improvement of over 50%. Conclusions: The lidocaine patch 5% could be a useful tool for the control of neuropathic pain, not only for post-herpetic neuralgia, and it has a good safety and tolerability profile.
基金This work was supported in part by the National Natural Science Foundation of China(No.81925034 and No.22237005)the Innovation Program of Shanghai Municipal Education Commission(No.2019-01-07-00-01-E00036,China)+4 种基金the Key Research and Development Program of Ningxia Hui Autonomous Region(No.2022CMG01002,China)the innovative research team of high-level local universities in Shanghai(Nos.SSMUZLCX20180702 and SHSMU-ZDCX20212700,China)the Natural Science Foundation of Ningxia(Nos.2022AAC02029 and 2021AAC03139,China)the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(No.SNZJU-SIAS-007,China)the open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University(No.KF-202204,China).
文摘Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice.Unfortunately,current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions.As G protein-coupled receptors(GPCRs)are widely distributed throughout the body,including the pain transmission pathway and descending inhibition pathway,the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum.Extensive research has shown that allosteric modulators targeting GPCRs on the pain pathway can effectively alleviate symptoms of neuropathic pain while reducing or eliminating adverse effects.This review aims to provide a comprehensive summary of the progress made in GPCRs allosteric modulators in the treatment of neuropathic pain,and discuss the potential benefits and adverse factors of this treatment.We will also concentrate on the development of biased agonists of GPCRs,and based on important examples of biased agonist development in recent years,we will describe universal strategies for designing structure-based biased agonists.It is foreseeable that,with the continuous improvement of GPCRs allosteric modulation and biased agonist theory,effective GPCRs allosteric drugs will eventually be available for the treatment of neuropathic pain with acceptable safety.
基金The Natural Science Foundation of China (Nos.21732008,and 81771205)CAMS Innovation Fund for Medical Sciences (CIFMS,Nos.CIFMS-2022-I2M-JB-009,China)The National Postdoctoral Program for Innovative Talents (No.BX20180053,China)
文摘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.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(LY19H090030)the Science and Technology Innovation 2030-Major Project of Brain Science and Brain-like Research(2021ZD0202501)the Excellent Innovation Program of Hangzhou Municipal University in 2019,and the National Natural Science Foundation of China(82150003,91949104,and 31871022).
文摘tDiabetic neuropathic pain(DNP)is the most common disabling complication of diabetes.Emerging evi-dence 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 con-clusion,our studies identified Ntn-3 as an important regula-tor of DNP pathogenesis by gating the aberrant sprouting of sensory axons,indicating that Ntn-3 is a potential druggable target for DNP treatment.
基金This work was supported by the National Natural Science Foundation of China(81960216,81903595,81860216,and 32060186)and the Natural Science Foundation of Jiangxi Province(20202BABL206049 and 20202BAB216043).
文摘The thalamocortical(TC)circuit is closely asso-ciated 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 trac-ing,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 pharmaco-logical 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.
基金supported by the National Natural Science Foundation of China(319700936,81801103,81901127,and 82101307)the Science and Technology Program of Guangdong(2018B030334001)+3 种基金the Natural Science Foundation of Guangdong(2019A1515010871,2019A1515010645,and 2022A1515010414)the Guangzhou Science and Technology Plan Project(201803010006)the Natural Science Foundation of Jiangsu(BK20210904)the Fundamental Research Funds for the Central Universities(19ykpy44).
文摘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.
