Generation Of Neuropathic Pain Research Articles

Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.

CBP Expression Contributes to Neuropathic Pain via CREB and MeCP2 Regulation in the Spared Nerve Injury Rat Model.

Background and Objectives: This study aimed to investigate the relationship between neuropathic pain and CREB-binding protein (CBP) and methyl-CpG-binding protein 2 (MeCP2) expression levels in a rat model with spared nerve injury (SNI). Materials and Methods: Rat (male Sprague-Dawley white rats) models with surgical SNI (n = 6) were prepared, and naive rats (n = 5) were used as controls. The expression levels of CBP and MeCP2 in the spinal cord and dorsal root ganglion (DRG) were compared through immunohistochemistry at 7 and 14 days after surgery. The relationship between neuropathic pain and CBP/MeCP2 was also analyzed through intrathecal siRNA administration. Results: SNI induced a significant increase in the number of CBPs in L4 compared with contralateral DRG as well as with naive rats. The number of MeCP2 cells in the dorsal horn on the ipsilateral side decreased significantly compared with the contralateral dorsal horn and the control group. SNI induced a significant decrease in the number of MeCP2 neurons in the L4 ipsilateral DRG compared with the contralateral DRG and naive rats. The intrathecal injection of CBP siRNA significantly inhibited mechanical allodynia induced by SNI compared with non-targeting siRNA treatment. MeCP2 siRNA injection showed no significant effect on mechanical allodynia. Conclusions: The results suggest that CBP and MeCP2 may play an important role in the generation of neuropathic pain following peripheral nerve injury.

Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance

Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting.

Decoding gene expression signatures in mice trigeminal ganglion across trigeminal neuropathic pain stages via high-throughput sequencing

Trigeminal neuropathic pain (TNP) arises due to peripheral nerve injury, the mechanisms underlying which are little known. The altered gene expression profile in sensory ganglia is critical for neuropathic pain generation and maintenance. We, therefore, assessed the transcriptome of the trigeminal ganglion (TG) from mice at different periods of pain progression. Trigeminal neuropathic pain was established by partial infraorbital nerve transection (pIONT). High-throughput RNA sequencing was applied to detect the mRNA profiles of TG collected at 3 and 10 days after modeling. Injured TG displayed dramatically altered mRNA expression profiles compared to Sham. Different gene expression profiles were obtained at 3 and 10 days after pIONT. Moreover, 314 genes were significantly upregulated, and 81 were significantly downregulated at both 3 and 10 days post-pIONT. Meanwhile, enrichment analysis of these persistent differentially expressed genes (DEGs) showed that the MAPK pathway was the most significantly enriched pathway for upregulated DEGs, validated by immunostaining. In addition, TG cell populations defined by single-nuclei RNA sequencing displayed cellular localization of DEGs at a single-cell resolution. Protein-protein interaction (PPI) and sub-PPI network analyses constructed networks and identified the top 10 hub genes for DEGs at different time points. The present data provide novel information on the gene expression signatures of TG during the development and maintenance phases of TNP, and the identified hub genes and pathways may serve as potential targets for treatment.

Genetics meets function in sodium channel-related pain disorders

Abstract Voltage-gated sodium channels are crucial for pain perception. This is illustrated by several human genetic conditions that lead to either chronic pain or, vice versa, to congenital painlessness. The type of mutation, its impact on neuron excitability as well as the affected sodium channel subtype delineates a complex picture of the disorders. Genetic variants in sodium channels may affect the complex biophysical gating and also their trafficking, association with other proteins and more complex regulations of the channel protein and function, thus allowing us to explore the subtle but impactful effects of their dysregulation for human nociception. A detailed understanding of these pain disorders provides a unique chance to understand the detailed intricacies of nociception and pathological conditions such as neuropathic pain. With increasing awareness of the importance of sodium channel variants in neuropathic pain, more patients are genetically screened, sometimes identifying variants of unclear significance (VUS). Bioinformatic tools help to assess their potential disease causing impact, but functional studies using patch-clamp experiments in cell lines are needed to allow for reliable conclusions. Often cell lines are not sufficient to show a physiologically relevant phenotype and more complex, time intensive models, such as induced pluripotent stem cells (iPS-cells) are employed. A challenge remains to identify the role of each sodium channel VUS in the context of the detailed cellular genetic and functional context. To lay the grounds for such a detailed interpretation, we need a correlation of cellular function and genetic transcription on a single cell basis, as it is possible with the Patch-Seq technique. The more detailed our knowledge becomes on functional and genetic sensory neurons subtypes and their role in the generation of neuropathic pain, the more targeted the personal or population-based treatment can be.

Role of Specialized Pro-Resolving Mediators in Neuropathic Pain.

Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)—i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the “resolution of inflammation”–has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.

Peripheral Mechanisms of Neuropathic Pain-the Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain.

Neuropathic pain in humans arises as a consequence of injury or disease of somatosensory nervous system at peripheral or central level. Peripheral neuropathic pain is more common than central neuropathic pain, and is supposed to result from peripheral mechanisms, following nerve injury. The animal models of neuropathic pain show extensive functional and structural changes occurring in neuronal and non-neuronal cells in response to peripheral nerve injury. These pathological changes following damage lead to peripheral sensitization development, and subsequently to central sensitization initiation with spinal and supraspinal mechanism involved. The aim of this narrative review paper is to discuss the mechanisms engaged in peripheral neuropathic pain generation and maintenance, with special focus on the role of glial, immune, and epithelial cells in peripheral nociception. Based on the preclinical and clinical studies, interactions between neuronal and non-neuronal cells have been described, pointing out at the molecular/cellular underlying mechanisms of neuropathic pain, which might be potentially targeted by topical treatments in clinical practice. The modulation of the complex neuro-immuno-cutaneous interactions in the periphery represents a strategy for the development of new topical analgesics and their utilization in clinical settings.

Contribution of colony-stimulating factor 1 to neuropathic pain.

Molecular and cellular interactions among spinal dorsal horn neurons and microglia, the resident macrophages of the central nervous system, contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. Emerging evidence also demonstrates that reciprocal interactions between macrophages and nociceptive sensory neurons in the dorsal root ganglion contribute to the initiation and persistence of nerve injury-induced mechanical hypersensitivity (allodynia). We previously reported that sensory neuron-derived colony-stimulating factor 1 (CSF1), by engaging the CSF1 receptor (CSF1R) that is expressed by both microglia and macrophages, triggers the nerve injury-induced expansion of both resident microglia in the spinal cord and macrophages in the dorsal root ganglion and induces their respective contributions to the neuropathic pain phenotype. Here, we review recent research and discuss unanswered questions regarding CSF1/CSF1R-mediated microglial and macrophage signaling in the generation of neuropathic pain.

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain.

A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up-regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin-1β (IL-1β), IL-6 and IL-18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.

P2Y receptors in neuropathic pain

This review summarizes and evaluates the relationship between neuropathic pain and P2Y receptors from inception to 2019. Purinergic receptors have been well studied in recent years using various molecular biological methods. The main research objective of this review is to determine the association of P2Y1, P2Y2, P2Y6, P2Y12 and P2Y13 receptors with neuropathic pain. This review includes the most comprehensive subtypes of P2Y that related to neuropathic pain and the current therapeutic method of neuropathic pain. G protein-coupled P2Y receptors are located on neurons, astrocytes, oligodendrocytes and microglial cells and regulate neurotransmission. Nerve injury is the prime reason for abnormal regulation of P2Y receptor mRNA expression, subsequently, inducing neuropathic pain. Neuropathic pain is a type of chronic pain that is divided into peripheral, central and mixed. Numerous studies demonstrated a positive correlation between the expression level of P2Y receptors and neuropathic pain generation. Also, several reports showed that P2Y short hairpin RNA (shRNA) and P2Y antagonist can be used as an analgesic to relieve neuropathic pain via decreasing P2Y receptor expression level and neural cell activation. However, the transformation process from basic experiments to clinical applications is a long process. Current deficiencies and future research directions are discussed at the end of this review.

A TLR\u2013CXCL1 pathway in DRG neurons induces neutrophil accumulation in the DRG and mechanical allodynia in EAE mice

Multiple sclerosis (MS) is a potentially disabling disease of the central nervous system. Approximately half of the patients with MS experience severe pain; however, currently available therapeutics provide only insufficient relief. The mechanisms underlying the generation of neuropathic pain in patients with MS are not fully understood. Recently, we found that neutrophil elastase from accumulated neutrophils in the dorsal root ganglion (DRG) sensitizes DRG neurons and induces mechanical allodynia in a mouse model of experimental autoimmune encephalomyelitis (EAE). However, the mechanism underlying neutrophil accumulation in the DRG after myelin oligodendrocyte glycoprotein (MOG35–55, immunogenic peptide) immunization remains unclear. Here, we found that C-X-C motif ligand 1 (CXCL1) was upregulated in DRG neurons after MOG35–55 immunization. Increased expression of CXCL1 protein was also observed in primary cultured DRG neurons treated with MOG35–55, which was mediated through toll-like receptor 4 (TLR4). Gene silencing of TLR4 or CXCL1 in DRG neurons significantly attenuated neutrophil accumulation in the DRG and mechanical allodynia during the preclinical phase of EAE (around day 5 after immunization). Our results thus suggest that a TLR4–CXCL1 pathway in DRG neurons triggers neutrophil recruitment in the DRG and subsequent mechanical allodynia in response to MOG35–55.

KCNMB3 in spinal microglia contributes to the generation and maintenance of neuropathic pain in mice.

Neuropathic pain is one of most intense types of chronic pain. Numerous studies investigating neuropathic pain have described the critical involvement of microglia in the spinal cord. Previous studies have indicated that activation of large conductance Ca2+‑activated K+(BK) channels contributes to microglial activation in the spinal dorsal horn(SDH) and the generation of neuropathic pain. However, the specific role of BK channels in spinal microglia in neuropathic pain has not been fully addressed in previous studies, as BK channel inhibitors were used to inhibit microglial BK channel based on their inhibitory kinetics. We previously identified that Ca2+‑activated K+ channel β3 auxiliary subunit(KCNMB3), which is an auxiliary subunit of BK channels and regulates gating properties of the channel, is exclusively expressed in microglia in the spinal cord. The present study analyzed the role of BK channels in spinal microglia in neuropathic pain using a spinal microglia‑specific BK channel knockdown method, with intrathecal injection of KCNMB3 small interfering RNA. Neuropathic pain was significantly attenuated in KCNMB3 knockdown mice. Increases in the number of microglia in the SDH following nerve injury were attenuated by KCNMB3 knockdown. Furthermore, increased levels of pain‑associated molecules in the SDH were attenuated in KCNMB3 knockdown mice. Attempts were also made to analyze the effects of KCNMB3 knockdown on chronic pain. KCNMB3 knockdown ameliorated chronic pain and inhibited the expression levels of pain‑associated molecules in the SDH. The results from the present study suggested that BK channels modulated the activation state of spinal microglia, and that KCNMB3 is a potential therapeutic target for neuropathic pain.

Cathepsin E in neutrophils contributes to the generation of neuropathic pain in experimental autoimmune encephalomyelitis.

Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.

Pain: Persistent postsurgery and bone cancer-related pain.

The generation of neuropathic pain is a complex dynamic process. Factors involved include one or more dysregulated sensory neural pathways; dysregulated activity of specific neurotransmitters, synapses, receptors and cognitive and emotional neural circuits; and the balance between degenerative and regenerative neural events. Risk factors include age, sex, cognition, emotions, genetic polymorphism, previous or ongoing chronic pain conditions and the use of certain drugs. Intense pain experienced before, during and after surgery is a risk factor for the development of central sensitization with consequent persistent postsurgery neuropathic pain. Blockade of N-methyl-D-aspartate receptors with appropriate drugs during and immediately after surgery may prevent persistent postsurgical pain. Most cancers, but particularly malignant metastases in bone, can induce persistent pain. Local factors including direct damage to sensory nerve fibres, infiltration of nerve roots by cancer cells and algogenic biological agents within the microenvironment of the tumour bring about central sensitization of dorsal horn neurons, characterized by neurochemical reorganization with persistent cancer pain. In this article, the clinical features, pathogenesis and principles of management of persistent postsurgery pain and cancer pain are briefly discussed.

Neuropathic pain modulation after spinal cord injury by breathing-controlled electrical stimulation (BreEStim) is associated with restoration of autonomic dysfunction.

BackgroundRecent findings have implicated supraspinal origins from the pain neuromatrix– central autonomic network (PNM–CAN) in the generation of neuropathic pain (NP) after spinal cord injury (SCI). The aim of this study was to further investigate the theorized PNM–CAN mechanisms in persons with SCI by using a centrally directed pain intervention, provided by breathing-controlled electrical stimulation (BreEStim), to measure resultant autonomic changes measured by time and frequency domain heart rate variability (HRV) analysis.MethodsNull and active BreEStim interventions were administered to SCI+NP subjects (n=10) in a random order. HRV data and VAS pain scores were collected at resting pre-test and 30 minutes post-test time points. Resting HRV data were also collected from SCI–NP subjects (n=11).ResultsSCI+NP subjects demonstrated a lower baseline HRV and parasympathetic tone, via SD of the normal-to-normal intervals (SDNN) and low frequency (LF) parameters, compared with SCI–NP subjects. However, following active BreEStim, SCI+NP subjects exhibited an increase in HRV and parasympathetic tone, most notably via pairs of successive R–R beat lengths varying by greater than 50 ms (NN50) and proportion of NN50 for total number of beats (pNN50) parameters along with lower VAS scores. Additionally, the post-test SCI+NP group was found to have a statistically comparable autonomic profile to the SCI–NP group across all HRV variables, including SDNN and LF parameters.ConclusionThe analgesic effects of active BreEStim in SCI+NP subjects were associated with restoration of autonomic dysfunction in this population.

Analyses of gene expression profiles in the rat dorsal horn of the spinal cord using RNA sequencing in chronic constriction injury rats

BackgroundNeuropathic pain is caused by damage to the nervous system, resulting in aberrant pain, which is associated with gene expression changes in the sensory pathway. However, the molecular mechanisms are not fully understood.MethodsWistar rats were employed for the establishment of the chronic constriction injury (CCI) models. Using the Illumina HiSeq 4000 platform, we examined differentially expressed genes (DEGs) in the rat dorsal horn by RNA sequencing (RNA-seq) between CCI and control groups. Then, enrichment analyses were performed for these DEGs using Gene Ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Hierarchical Cluster, and protein-protein interaction (PPI) network.ResultsA total of 63 DEGs were found significantly changed with 56 upregulated (e.g., Cxcl13, C1qc, Fcgr3a) and 7 downregulated (e.g., Dusp1) at 14 days after CCI. Quantitative reverse-transcribed PCR (qRT-PCR) verified changes in 13 randomly selected DEGs. GO and KEGG biological pathway analyses showed that the upregulated DEGs were mostly enriched in immune response-related biological processes, as well as 14 immune- and inflammation-related pathways. The downregulated DEGs were enriched in inactivation of mitogen-activated protein kinase (MAPK) activity. PPI network analysis showed that Cd68, C1qc, C1qa, Laptm5, and Fcgr3a were crucial nodes with high connectivity degrees. Most of these genes which have previously been linked to immune and inflammation-related pathways have not been reported in neuropathic pain (e.g., Laptm5, Fcgr3a).ConclusionsOur results revealed that immune and defense pathways may contribute to the generation of neuropathic pain after CCI. These mRNAs may represent new therapeutic targets for the treatment of neuropathic pain.

Paralogs of the Calcium-Dependent Activator Protein for Secretion Differentially Regulate Synaptic Transmission and Peptide Secretion in Sensory Neurons.

The two paralogs of the calcium-dependent activator protein for secretion (CAPS) are priming factors for synaptic vesicles (SVs) and neuropeptide containing large dense-core vesicles (LDCVs). Yet, it is unclear whether CAPS1 and CAPS2 regulate exocytosis of these two vesicle types differentially in dorsal root ganglion (DRG) neurons, wherein synaptic transmission and neuropeptide release are of equal importance. These sensory neurons transfer information from the periphery to the spinal cord (SC), releasing glutamate as the primary neurotransmitter, with co-transmission via neuropeptides in a subset of so called peptidergic neurons. Neuropeptides are key components of the information-processing machinery of pain perception and neuropathic pain generation. Here, we compared the ability of CAPS1 and CAPS2 to support priming of both vesicle types in single and double knock-out mouse (DRG) neurons using a variety of high-resolution live cell imaging methods. While CAPS1 was localized to synapses of all DRG neurons and promoted synaptic transmission, CAPS2 was found exclusively in peptidergic neurons and mediated LDCV exocytosis. Intriguingly, ectopic expression of CAPS2 empowered non-peptidergic neurons to drive LDCV fusion, thereby identifying CAPS2 as an essential molecular determinant for peptidergic signaling. Our results reveal that these distinct functions of both CAPS paralogs are based on their differential subcellular localization in DRG neurons. Our data suggest a major role for CAPS2 in neuropathic pain via control of neuropeptide release.

Membrane potential synchrony of neurons in anterior cingulate cortex plays a pivotal role in generation of neuropathic pain

The pathophysiology of neuropathic pain generation has not been fully investigated. Previous studies have primarily focused on changes in the properties of single neurons in the brain after nerve injury; however, little is known concerning the role of neuron-to-neuron connections in neuropathic pain pathogenesis. Synaptic transmission potentiation in anterior cingulate cortex (ACC) has been confirmed to be responsible for the formation of neuropathic pain. Thus, analysis of interneuronal connections in the ACC is an important approach for understanding the mechanism of neuropathic pain since it provides information on the potency of synaptic transmission. Here, we recorded membrane potentials from pairs of ACC neurons in anaesthetised rats and found that cross-correlations between pairs of ACC neurons significantly increased after surgery for chronic constriction injury (CCI). Moreover, CCI surgery could also enhance the power spectrum density of lower and higher-frequency membrane oscillations while having no effect on middle-frequency oscillations. The activation of membrane potential synchrony and power spectrum was reversed by the electrical synapse blocker mefloquine and pain behaviour was simultaneously alleviated. Our results may indicate that activation of membrane potential synchrony contributes to generation of neuropathic pain.

Leptin is essential for microglial activation and neuropathic pain after preganglionic cervical root avulsion

AimsPreganglionic cervical root avulsion (PCRA) affects both the peripheral and central nervous systems and is often associated with neuropathic pain. Unlike peripheral nerve injuries (PNI), central lesions caused by disruption of cervical roots from the spinal cord following PCRA contribute to the generation of neuropathic pain. Leptin is involved in the development of neuropathic pain after PNI by affecting neurons. However, whether leptin is involved in microglial activation leading to neuropathic pain after PCRA is unknown. Main methodsPreganglionic avulsion of the left 6th–8th cervical roots was performed in C57B/6J mice and leptin-deficient mice. A leptin antagonist or leptin was administered to C57B/6J mice and leptin-deficient mice after injury, respectively. The expression pattern of spinal and supraspinal microglia was examined by immunofluorescent staining. Von Frey filaments were used to test pain sensitivity. Key findingsLeptin is essential for the development of neuropathic pain after PCRA. Allodynia was absent in the leptin-deficient mice and the mice administered the leptin antagonist. We also found that leptin deficiency or the administration of its antagonist inhibited the development of microgliosis in the dorsal horn and brainstem. Furthermore, increase in the expression of CD86 and iNOS, and Wallerian degeneration were noted in the spinal cord. The administration of exogenous leptin to leptin-deficient mice reversed these effects. SignificanceWe concluded that leptin is involved in the proliferation and activation of microglia, which in turn enhances the development of neuropathic pain. Blocking the effects of leptin might be a target for the treatment of neuropathic pain after PCRA.

Pain-related evoked potentials after intraepidermal electrical stimulation to Aδ and C fibers in patients with neuropathic pain

Neuropathic pain can result from neuronal hyperexcitability and complex interactions of the nociceptive pathways. Intraepidermal electrical stimulation (IES) is a novel technique that can selectively activate Aδ and C fibers. To investigate patterns of changes in Aδ- and C-mediated brain responses in patients with neuropathic pain using IES, we recorded pain-related evoked potential (PREP) after IES of Aδ and C fibers in 20 patients with neuropathic pain and 15 age-matched healthy volunteers. We evaluated PREP latencies, amplitudes, and amplitude ratios of PREPs after C/Aδ-fiber stimulation. PREP amplitudes after Aδ-fiber stimulation tended to be smaller in the patient group, whereas there were no significant differences in amplitudes after C-fiber stimulation between the patient and normal control groups. PREP amplitude ratios after C/Aδ-fiber stimulation were significantly greater in the patient group than in the control group, and the higher ratio tended to be associated with a greater visual analog scale score. Patients with neuropathic pain had a tendency towards decreased Aδ amplitudes and significantly increased C/Aδ PREP amplitude ratios and this ratio appeared to be associated with the intensity of pain. Our findings suggest that decreased inhibition of the Aδ to C nociceptive systems is associated with generation of neuropathic pain.