Molecular Mechanisms Of Neuropathic Pain Research Articles

Methyltransferase METTL3 regulates neuropathic pain through m6A methylation modification of SOCS1

The mechanisms of neuropathic pain (NP) are considered multifactorial. Alterations in the suppressor of cytokine signaling 1 (SOCS1) play a critical role in neural damage and inflammation. Epigenetic RNA modifications, specifically N6-methyladenosine (m6A) methylation, have increasingly been observed to impact the nervous system. Nevertheless, there is a scarcity of studies investigating the connection between m6A methylation and SOCS1 in the molecular mechanisms of NP. This study investigates the roles and potential mechanisms of the m6A methyltransferase like 3 (METTL3) and SOCS1 in female rats with spinal nerve ligation (SNL)-induced NP. It was found that in NP, both METTL3 and overall m6A levels were downregulated, leading to the activation of pro-inflammatory cytokines, such as interleukin-1β, interleukin 6, and tumor necrosis factor-α. Notably, The SOCS1 mRNA is significantly enriched with m6A methylation modifications, with the most prevalent m6A methyltransferase METTL3 stabilizing the downregulation of SOCS1 by targeting m6A methylation modifications at positions 151, 164, and 966.Exogenous supplementation of METTL3 improved NP-related neuroinflammation and behavioral dysfunctions, but these effects could be reversed by the absence of SOCS1. Additionally, the depletion of endogenous SOCS1 promoted NP progression by inducing the toll-like receptor 4 (TLR4) signaling pathway. The dysregulation of METTL3 and the resulting m6A modification of SOCS1 form a crucial epigenetic regulatory loop that promotes the progression of NP. Targeting the METTL3/SOCS1 axis might offer new insights into potential therapeutic strategies for NP.

Transient Receptor Potential Channels: Multiple Modulators of Peripheral Neuropathic Pain in Several Rodent Models.

Neuropathic pain, a prevalent chronic condition in clinical settings, has attracted widespread societal attention. This condition is characterized by a persistent pain state accompanied by affective and cognitive disruptions, significantly impacting patients' quality of life. However, current clinical therapies fall short of addressing its complexity. Thus, exploring the underlying molecular mechanism of neuropathic pain and identifying potential targets for intervention is highly warranted. The transient receptor potential (TRP) receptors, a class of widely distributed channel proteins, in the nervous system, play a crucial role in sensory signaling, cellular calcium regulation, and developmental influences. TRP ion channels are also responsible for various sensory responses including heat, cold, pain, and stress. This review highlights recent advances in understanding TRPs in various rodent models of neuropathic pain, aiming to uncover potential therapeutic targets for clinical management.

Exploring the possibilities of using in vitro model for neuropathic pain studies

Establishing experimental models to study neuropathic pain has been challenging due to the complex mechanism underlying the condition. Although in vivo models have been useful in the observation of behavioural pain responses, it should be acknowledged that species-to-species variance can lead to differences in terms of molecular mechanism and genetic expression. The study of molecular and signal transduction of neuropathic pain using in vivo models faces limitations due to ethical considerations involving pain induction in animals and the intricacy of molecular interactions in the pathophysiology of the condition. Hence, developing relevant in vitro models to study neuropathic pain is important, as it considers the physiological microenvironment and reduces the use of experimental animals. Several considerations should be taken into account in developing an in vitro model of neuropathic pain, including the use of either primary culture of cell lines with considerations to their origins; human or animal, the method of neuropathic pain-like induction and the relevant assays to assess pain. This review recapitulates previous research employing in vitro models in investigating the molecular mechanism of neuropathic pain, intending to provide an alternative to the growing concerns on in vivo neuropathic pain models.

Investigating Post-transcriptional Mechanism of Neuropathic Pain

Neuropathic pain is a chronic condition which can arise following damage to the somatosensory system and often involves both hyperalgesia and allodynia. The molecular mechanisms of neuropathic pain remain incompletely understood but require enduring alterations in specific gene programs and protein synthesis affecting neuronal signaling and excitability. We investigate non-coding RNA and RNA-binding protein regulatory pathways in impacting hyperalgesia and neuropathic pain using the mouse spared nerve injury model. Nerve injury alters the expression of many miRNAs, including the highly conserved let-7 family miRNAs, which repress pro-growth mRNAs and are implicated in axon growth, neuronal plasticity, and brain circuit development. The Lin28 RNA binding protein can prevent maturation of let-7 precursor RNAs; consequently, increased Lin28 signaling promotes pro-growth gene expression. The regulation and potential roles of Lin28/let-7 pathway in neuropathic pain remain largely unexplored. In preliminary data, we find that Lin28a loss of function in some, but not other, sensory neuron populations can result in a deficit in mechanical hypersensitivity post-injury. In the SNI mouse model, we evaluate molecular mechanisms underlying pain using single molecule detection. A specific RNA imaging assay, RNAscope in situ hybridization (ISH), is used to amplify single RNA target signals in fixed tissues to allow mapping of the spatiotemporal patterns and cell type specificity of changes. We find that Lin28 mRNAs are elevated in classes of injured neurons relative to uninjured neurons in dorsal route ganglia (DRG) which are ipsilateral at early, 3 day, timepoints post-SNI surgery. In contrast, Lin28 mRNAs are highly elevated following a more protracted time courses post-surgery in the compartment of injured neuronal processes. The spatiotemporal differences in Lin28 mRNA levels across compartments of the nervous system following nerve injury could indicate potential trafficking or local stabilization of Lin28 mRNAs and are the subject of ongoing investigations. Grant support from NIH NS103974.

Investigating post-transcriptional mechanisms of neuropathic pain

Neuropathic pain is a chronic condition which can arise following damage to the somatosensory system and often involves both hyperalgesia and allodynia. The molecular mechanisms of neuropathic pain remain incompletely understood but require enduring alterations in specific gene program expression and protein synthesis affecting neuronal signaling and excitability. We investigate the roles of non-coding RNA regulatory pathways in impacting hyperalgesia and determining the mRNA complement recruited during the protein synthesis response in neuropathic pain. Nerve injury alters the expression of many miRNAs, including the highly conserved let-7 family miRNAs, which repress pro-growth mRNAs and are implicated in axon growth, neuronal plasticity, and brain circuit development. The Lin28 RNA binding protein can prevent maturation of let-7 precursor RNAs; consequently, increased Lin28 signaling promotes pro-growth gene expression. The regulation and potential roles role of Lin28/let-7 pathway in neuropathic pain remain largely unexplored. Using spared nerve injury (SNI) mouse models of neuropathic pain, we find in preliminary data that Lin28a loss of function in sensory neuron populations can result in a deficit in mechanical hypersensitivity post-surgery. In SNI and sciatic nerve transection (SNT) mouse models, we evaluate molecular mechanisms underlying pain using single molecule detection and genetic manipulation. A sensitive RNA imaging assays, RNAScope in situ hybridization (ISH), is used to amplify single RNA target signals in fixed tissues to allow mapping of the spatiotemporal patterns and cell type specificity of changes in non-coding RNA regulatory pathways. Digital PCR is used to provide sensitive and quantitative validation. We find lin28 mRNA level are elevated in injured dorsal root ganglion cells, injured sciatic nerves and their surrounding Schwann cells at 3 days post SNI and SNT surgery accordingly. Neuropathic pain is a chronic condition which can arise following damage to the somatosensory system and often involves both hyperalgesia and allodynia. The molecular mechanisms of neuropathic pain remain incompletely understood but require enduring alterations in specific gene program expression and protein synthesis affecting neuronal signaling and excitability. We investigate the roles of non-coding RNA regulatory pathways in impacting hyperalgesia and determining the mRNA complement recruited during the protein synthesis response in neuropathic pain. Nerve injury alters the expression of many miRNAs, including the highly conserved let-7 family miRNAs, which repress pro-growth mRNAs and are implicated in axon growth, neuronal plasticity, and brain circuit development. The Lin28 RNA binding protein can prevent maturation of let-7 precursor RNAs; consequently, increased Lin28 signaling promotes pro-growth gene expression. The regulation and potential roles role of Lin28/let-7 pathway in neuropathic pain remain largely unexplored. Using spared nerve injury (SNI) mouse models of neuropathic pain, we find in preliminary data that Lin28a loss of function in sensory neuron populations can result in a deficit in mechanical hypersensitivity post-surgery. In SNI and sciatic nerve transection (SNT) mouse models, we evaluate molecular mechanisms underlying pain using single molecule detection and genetic manipulation. A sensitive RNA imaging assays, RNAScope in situ hybridization (ISH), is used to amplify single RNA target signals in fixed tissues to allow mapping of the spatiotemporal patterns and cell type specificity of changes in non-coding RNA regulatory pathways. Digital PCR is used to provide sensitive and quantitative validation. We find lin28 mRNA level are elevated in injured dorsal root ganglion cells, injured sciatic nerves and their surrounding Schwann cells at 3 days post SNI and SNT surgery accordingly.

TNF signal, ROS, and caspase-11 play important role in HIV gp120 with morphine-Induced Neuropathic Pain.

Recent clinical evidence suggests that repeated use of opioid medications increases chronic pain in individuals living with HIV. It is important to elucidate the exact molecular mechanisms of neuropathic pain (NP) in opioid users living with HIV. HIV-related neuron damage is induced by activating glial cells releasing neurotoxic factors (such as, TNFα). Chronic morphine use also induces TNFα product. Spinal mitochondrial superoxide (mtO2●-) plays important role in neuropathic pain. Non-canonical inflammasome, caspase-11 signal pathway is involved in methamphetamine-induced neuron apoptosis. Increased ROS enhances caspase-11 expression during enteric pathogen infection. In the present study, we investigated the role of TNFRI, mtO2●- and caspase-11 in a HIV coat glycoprotein gp120 with morphine (gp120/M)-induced neuropathic pain state. HIV-gp120 with morphine induced mechanical allodynia lasting for 3 weeks. HIV-gp120/M upregulated the expression of TNFRI, mitochondrial superoxide, with caspase-11, and down-regulated Sirt3 in the spinal dorsal horn. TNFRI-/- knockout mice were higher mechanical threshold and longer thermal latency than that in wildtype mice. Intrathecal administration of antisense oligonucleotides against TNFRI, Mito-Temple (mitochondrial scavenger of mtO2●-), or siRNA agonist caspase-11 mRNA reduced mechanical allodynia in the gp120/M neuropathic pain model. Antisense oligonucleotides against TNFRI reduced the number of MitoSox (a marker of mtO2●-) positive cells in the SCDH in gp120/M group. The rat neuronal neuroblast (B35) cell line (ATCC) were treated with rTNFα (10 ng/mL, Peprotech) increased expression of mtO2●- and caspase-11, and caspase-11 related inflammatory factors such as, caspase-1, and IL-1β. In conclusions, spinal TNFRI signal plays a significant role in the HIV gp120-related neuropathic pain state, and provide evidence for a novel approach to treating chronic pain in opioid users living with HIV. NIH R01DA34749, R01DA047089, and R01DA047157, and R01DA047157-03S1.

The gene regulatory network in different brain regions of neuropathic pain mouse models.

Neuropathic pain is directly developed from lesions or somatosensory nervous system diseases that are associated with emotion regulation. In general population, the incidence of neuropathic pain ranges from 7% to 10%, but the underlying mechanism remains largely unknown. Neuropathic pain is often associated with structural and functional abnormalities in multiple brain regions, and its regulation has been shown to correspond with the forebrain, including nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and periaqueductal gray (PAG). To investigate the molecular mechanism of neuropathic pain across different brain regions, we identified the differentially expressed genes (DEGs) between the spared nerve injury model (SNI) mice suffering neuropathic pain and the control Sham mice in NAc, mPFC and PAG three brain regions, and mapped these genes onto a comprehensively functional association network. Thereafter, novel neuropathic pain genes in these three regions were identified using With Random Walk with Restart (RWR) analysis, such as Asic3, Cd200r1 and MT2, besides well-known Capn11 and CYP2E1. Interactions or cross talks among DEGs in NAc, mPFC and PAG three brain regions were discovered. Our results provide novel insights into neuropathic pain and help to explore therapeutic targets in the treatment.

Weighted gene co-expression network analysis reveals specific modules and hub genes related to neuropathic pain in dorsal root ganglions

Neuropathic pain is a common, debilitating clinical issue. Here, the weighted gene co-expression network analysis (WGCNA) was used to identify the specific modules and hub genes that are related to neuropathic pain. The microarray dataset of a neuropathic rat model induced by tibial nerve transection (TNT), including dorsal root ganglion (DRG) tissues from TNT model (n=7) and sham (n=8) rats, was downloaded from the ArrayExpress database (E-MTAB-2260). The co-expression network modules were identified by the WGCNA package. The protein–protein interaction (PPI) network was constructed, and the node with highest level of connectivity in the network were identified as the hub gene. A total of 1739 genes and seven modules were identified. The most significant module was the brown module, which contained 215 genes that were primarily associated with the biological process (BP) of the defense response and molecular function of calcium ion binding. Furthermore, C–C motif chemokine ligand 2 (Ccl2), Fos and tissue inhibitor of metalloproteinase 1 (Timp1) which were identified as the hub genes in the PPI network and two subnetworks separately. The in vivo studies validated that mRNA and protein levels of Ccl2, Fos and Timp1 were up-regulated in DRG and spinal cord tissues after TNT. The present study offers novel insights into the molecular mechanisms of neuropathic pain in the context of peripheral nerve injury.

Lysophosphatidic Acid Receptor Signaling Underlying Chronic Pain and Neuroprotective Mechanisms through Prothymosin α

For my Ph.D. research topic, I isolated endogenous morphine-like analgesic dipeptide, kyotorphin, which mediates Met-enkephalin release, and discovered kyotorphin synthetase, a putative receptor and antagonist. Furthermore, I succeeded in purifying μ-opioid receptor and functional reconstitution with purified G proteins. After receiving my full professor position at Nagasaki University in 1996, I worked on two topics of research, molecular mechanisms of chronic pain through lysophosphatidic acid (LPA) and identification and characterization of neuroprotective protein, prothymosin α. In a series of studies, we have shown that LPA signaling defines the molecular mechanisms of neuropathic pain and fibromyalgia in terms of development and maintenance. Above all, the discovery of feed-forward system in LPA production and pain memory may contribute to better understanding of chronic pain and future analgesic drug discovery. Regarding prothymosin α, we first discovered it as neuronal necrosis-inhibitory molecule through two independent mechanisms, such as toll-like receptor and F0/F1 ATPase, both which protect neurons through indirect mechanisms. Prothymosin α is released by non-classical and non-vesicular mechanisms on various stresses, such as ischemia, starvation, and heat-shock. Thus it may be called a new type of neuroprotective damage-associated molecular patterns (DAMPs)/Alarmins. Heterozygotic mice showed a defect in memory-learning and neurogenesis as well as anxiogenic behaviors. Small peptide, P6Q derived from prothymosin α retains neuroprotective actions, which include blockade of cerebral hemorrhage caused by late treatment with tissue plasminogen activator in the stroke model in mice.

Lysozyme over‐expression during nerve injury excites Aδ & C fibres in a fibre specific manner to incite neuropathic pain

Human lysozyme is one of the most extensively studied proteins yet its exact physiological functions still remain a mystery. Here, we highlight a hitherto unrecognized role of lysozyme in neuropathic pain and neuronal excitability. Injection of lysozyme alone in healthy rats leads to heightened sensitivity in them towards both mechanical and thermal pain stimuli. Also, in rat models of neuropathic pain, lysozyme is over – expressed and its down – regulation by siRNA or inhibition of its activity by its disaccharide inhibitor ‐ chitobiose relieves pain confirming a causal role of lysozyme in neuropathic pain. Moreover, as the catalytically incompetent lysozyme or its chemically inhibited counterparts fail to provoke pain indicate that it deploys its catalytic site for eliciting pain. Bath application of lysozyme remarkably increased both the spontaneous excitatory potentials and currents (sEPSPs & sEPSCs) and the amplitudes of afferent mediated evoked excitatory synaptic inputs (eFPSPs & eEPSCs) in Aδ fibres in a fibre specific manner in the dorsal horn neurons. It also increased paired pulsed ratio only in the C‐fibres. When complexed with chitobiose it does not lead to any change in neuronal excitability. Thus, lysozyme excites neurons by deploying its catalytic region in a fibre specific manner. Further, we show that it deploys its catalytic site to recruit Annexin A2 to transduce TLR4→NFkβ signaling pathway which may culminate in the fusion of neurotransmitter vesicles at the synapse to manifest neuronal excitability and eventually pain. Thus, glycan inhibitors of lysozyme and antagonists of the pathway recruited by it to inflict pain pave not only the way for novel approaches for dissecting the molecular mechanism of neuropathic pain but also for treating this unmet medical need efficaciously.Support or Funding InformationCouncil of Scientific and Industrial Research, India to ASThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Jun, Gal, Cd74, and C1qb as potential indicator for neuropathic pain.

Neuropathic pain is a kind of pain caused by primary or secondary impairment or dysfunction of peripheral or central nervous system. Patients with neuropathic pain were often with poor clinical outcome. We screened the differentially expressed genes between sciatic nerve injury and dorsal root ganglion gene in the sham operation model. Microarray and the spared nerve injury module were used to explore the molecular mechanism of neuropathic pain by injuries and the differentially expressed genes (DEGs) were identified out. Besides, the bioinformatics methods were used to figure out the signaling pathways and expression regulation pattern these DEGs were enriched in, which may provide a basis for the molecular research and medicine target of therapy. Besides, protein-protein interaction network analysis was performed on these selected intersection genes. A total of 40 DEGs were screened out and only pctp gene was down-regulated, the left 39 genes were all up-regulated. Then, GO and KEGG enrichment analysis were performed on these intersection genes by DAVID software. Furthermore, protein-protein interaction network analysis was used to analyze the critical genes of neuropathic pain. Finally, four genes, that is, Jun, Gal, Cd74, and C1qb were identified to have strong interactions with other genes, which may function as the prognostic and predictive genes of neuropathic pain caused by peripheral injuries. Our results suggested that four differentially expressed genes, Jun, Gal, Cd74, and C1qb, had the potential to serve as prognostic or predictive markers for neuropathic pain, suggesting a potential application in the improvement of prognostic tools and treatments.

Chronic constriction injury of sciatic nerve changes circular RNA expression in rat spinal dorsal horn.

BackgroundMechanisms of neuropathic pain are still largely unknown. Molecular changes in spinal dorsal horn may contribute to the initiation and development of neuropathic pain. Circular RNAs (circRNAs) have been identified as microRNA sponges and involved in various biological processes, but whether their expression profile changes in neuropathic pain condition is not reported.MethodsTo test whether neuropathic pain influences circRNA expression, we developed a sciatic chronic constriction injury (CCI) model in rats. The CCI ipsilateral spinal dorsal horns of lumbar enlargement segments (L3–L5) were collected, and the total RNA was extracted and subjected to Arraystar Rat circRNA Microarray. Quantitative real-time polymerase chain reaction (qPCR) was used to confirm the circRNA expression profile. To estimate functions of differential circRNAs, bioinformatics analyses including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes Pathway analyses were performed for the top 100 circRNAs and circRNA–microRNA networks were constructed for the top 10 circRNAs.ResultscircRNA microarrays showed that 469 circRNAs were differentially expressed between CCI and sham-operated rats (fold change ≥2). In all, 363 of them were significantly upregulated, and the other 106 were downregulated in the CCI group. Three of them (circRNA_013779, circRNA_008008, and circRNA_003724) overexpressed >10 times after CCI insult. Expression levels of eight circRNAs were verified using qPCR. GO analysis revealed that thousands of predicted target genes were involved in the biological processes, cellular component, and molecular function; in addition, dozens of these genes were enriched in the Hippo signaling pathway, MAPK signaling pathway, and so on. Competing endogenous RNAs analysis showed that circRNA_008008 and circRNA_013779 are the two largest nodes in the circRNA–microRNA interaction network of the top 10 circRNAs.ConclusionCCI resulted in a comprehensive expression profile of circRNAs in the spinal dorsal horn in rats. CircRNAs in the dorsal horn could be helpful to reveal molecular mechanisms of neuropathic pain.

Flow cytometry analysis of inflammatory cells isolated from the sciatic nerve and DRG after chronic constriction injury in mice

BackgroundCellular responses to nerve injury play a central role in the pathogenesis of neuropathic pain. However, the analysis of site specific cellular responses to nerve injury and neuropathic pain is limited to immunohistochemistry staining with numerous limitations. New methodsWe proposed to apply flow cytometry to overcome some of the limitations and developed two protocols for isolation of cells from small specimens of the sciatic nerve and dorsal root ganglion (DRG) in mice. Results and comparasion with existingmethods We found that both the non-enzymatic and enzymatic approaches were highly effective in harvesting a sufficient number of cells for flow cytometry analysis in normal and pathological conditions. The total number of cells in the injury site of the sciatic and its DRGs increased significantly 14days after chronic constriction injury (CCI) of the sciatic nerve, compared to sham surgery control or the contralateral control. The enzymatic approach yielded a significantly higher total number of cells and CD45 negative cells, suggesting that this approach allows for harvest of more resident cells, compared to the non-enzymatic method. The percentage of CD45+/CD11b+ cells was significantly increased in the sciatic nerve but not in the DRG. These results were consistent with both protocols. ConclusionsWe thus offer two simple and effective protocols that allow for application of flow cytometry to the investigation of cellular and molecular mechanisms of neuropathic pain.

An Improved Rodent Model of Trigeminal Neuropathic Pain by Unilateral Chronic Constriction Injury of Distal Infraorbital Nerve.

The orofacial pain caused by trigeminal nerve damage is severe and perhaps more debilitating than other types of neuropathic pain. However, studies on trigeminal neuropathic pain remain limited. This is largely because of the lack of proper animal models because of the complexity of the existing surgical procedures required to induce trigeminal nerve injury. Our improved dIoN-CCI model is likely to make it more accessible to study the cellular and molecular mechanisms of neuropathic pain caused by trigeminal nerve damage.

Downregulation of Cdh1 signalling in spinal dorsal horn contributes to the maintenance of mechanical allodynia after nerve injury in rats.

BackgroundAnaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 are important ubiquitin-ligases in proliferating cells and terminally differentiated neurons. In recent years, APC/C-Cdh1 has been reported as an important complex contributing to synaptic development and transmission. Interestingly, cortical APC/C-Cdh1 is found to play a critical role in the maintenance of neuropathic pain, but it is not clear whether APC/C-Cdh1 in spinal dorsal cord is involved in molecular mechanisms of neuropathic pain conditions.ResultsImmunostaining showed that Cdh1 was mainly distributed in dorsal horn neurons of the spinal cord in rats. Its expression was downregulated in the ipsilateral dorsal horn at 14 days after spared nerve injury. Rescued expression of Cdh1 in spinal cord by intrathecal administration of recombinant lentivirus encoding Cdh1 (Lenti-Cdh1-GFP) significantly attenuated spared nerve injury-induced mechanical allodynia. Furthermore, rescued expression of spinal Cdh1 significantly reduced surface membrane expression of GluR1, but increased the expression of GluR1-related erythropoietin-producing human hepatocellular receptor A4 and its ligand EphrinA1 in dorsal horn of spared nerve injury-treated animals.ConclusionsThis study indicates that a downregulation of Cdh1 expression in spinal dorsal horn is involved in molecular mechanisms underlying the maintenance of neuropathic pain. Upregulation of spinal Cdh1 may be a promising approach to treat neuropathic pain.

Update on the pathobiology of neuropathic pain

Nerve injury or dysfunction in the peripheral and central nervous systems are the leading causes for the development of neuropathies, which are frequently associated with allodynia and hyperalgesia. Treatment of these disorders is often unsatisfactory due to side effects or insufficient analgesia of the currently available drugs. Therefore, elucidating the molecular mechanisms of neuropathic pain is an important prerequisite for the rational development of novel analgesic drugs for the therapy of neuropathic pain. Several proteomic approaches have been performed to explore protein modifications in the nervous system associated with neuropathies in different animal models, which might contribute to the detection of new drug targets. Furthermore, there are proteomic studies investigating human cerebrospinal fluid from patients suffering from neuropathies. The results of these studies and the potential clinical value of the proteomic data are summarized and discussed in this review.

Proteomics in Neuropathic Pain Research

Neuropathic pain is often caused by nerve injury or dysfunction in the peripheral and central nervous system and is frequently associated with allodynia and hyperalgesia. The underlying molecular mechanisms of neuropathic pain are largely unknown, and therefore, pharmacologic treatment is insufficient in many cases. To elucidate translational and posttranslational modifications in the nervous system that arise after nerve injury, a number of proteomic studies have been performed using different animal neuropathy models. The results of these proteomic approaches are summarized in this review to provide a better overview of proteins that are involved into the pathogenesis of nerve injury and neuropathic pain. This might allow a better understanding of the pathophysiologic signaling pathways in this impairment, facilitate the discovery of specific biomarkers, and thus promote the development of novel pain therapies.

Emerging Strategies for the Treatment of Neuropathic Pain.

Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. jmao@partners.orgEmerging Strategies for the Treatment of Neuropathic Pain. Edited by James N. Campbell, M.D., Allan I. Basaum, Ph.D., Andre Dray, Ph.D., Ronald Dubner, D.D.S., Robert H. Dworkin, Ph.D., and Christine N. Sang, M.D. Seattle, Washington, IASP Press, 2006. Pages: 514. Price: $80.00.For those of us who practice pain medicine, it is undeniably challenging to treat patients with neuropathic pain. Neuropathic pain is a unique pain condition characterized by its dynamic nature and diversity of clinical presentation. Since the late 1980s, several animal models of peripheral nerve injury have been introduced, and the preclinical research field has witnessed an explosion of knowledge regarding the neural and molecular mechanisms of neuropathic pain. Despite the intense effort from both basic science and clinical pain research, the mechanisms of neuropathic pain remain largely unclear, and few new treatment options have been proven to be beneficial for the clinical management of neuropathic pain.The overall challenge facing preclinical research and clinical management of neuropathic pain is the theme of this extremely informative book published by the IASP Press. The book is a fine product of a scientific meeting organized by the book editors. Each of these topics listed in the book, ranging from the neural/molecular and disease-specific targets of neuropathic pain interventions to pain measurement and new technologies, was debated and deliberated during the meeting. As a researcher and pain clinician who has been interested in neuropathic pain, I find this book to be highly refreshing, loaded with the most updated information from a list of who is who in the field of neuropathic pain research and clinical management.A unique feature of this book is the inclusion of several rapporteur reports serving as the lead chapter for each section. Each rapporteur report contains the consensus from the meeting attendants on a particular research area as well as the discussion process that led to the consensus. These rapporteur reports, four of which are in this book, provide the readers with a rare opportunity to understand the thinking process of these experts who have devoted their effort to studying the mechanisms of neuropathic pain. The contents of these rapporteur reports are well balanced, carefully organized, and clearly presented. Particularly, research questions are raised within these rapporteur reports, which are aimed at guiding future research efforts in this field.Over several years, there have been many talks regarding the lack of adequate progress in both preclinical and clinical research on neuropathic pain and its clinical management. This book provides a realistic look at the current status of neuropathic pain research and treatment as well as the challenges ahead of us. For this reason, I highly recommend this book to those who are interested in the research and/or clinical management of neuropathic pain.Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. jmao@partners.org

Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury.

The extracellular protease cascade of plasminogen activators and plasminogen are known to regulate neuronal plasticity and extracellular matrix modification, and to be important factors involved in producing long-term potentiation in the CNS. The purpose of this study is to examine the expression of plasminogen activators in primary afferents and its role in nociceptive pathways after peripheral nerve injury. We found the induction of mRNAs for tissue type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) in the rat dorsal root ganglia following sciatic nerve transection. Immunoreactivity for tPA was increased in laminae I and II of the dorsal horn and, importantly, the increase in proteolytic activity mediated by tPA was observed in the same area. As neither immunoreactivity for uPA nor uPA-mediated proteolysis was observed, we further examined the effects of tPA on dorsal horn excitability and neuropathic pain behaviour. Intrathecal injection of a specific inhibitor of tPA decreased electrical stimulation-induced Fos expression in dorsal horn neurons following axotomy, and also prevented the development of thermal hyperalgesia following partial sciatic nerve ligation. These findings suggest that the increased tPA in the dorsal horn due to mRNA expression in the dorsal root ganglia increases the dorsal horn excitability and has an important role in pain behaviour after peripheral nerve injury. The tPA-mediated hypersensitivity in dorsal horn neurons may be a novel molecular mechanism of neuropathic pain.

Molecular mechanism of neuropathic pain.

Pain is the most common clinical symptom for which people seek medical care. Although effective therapy for inflammatory pain is possible, current therapy for neuropathic pain is still inadequate. Even the strongest painkiller, morphine, is reported to be ineffective against neuropathic pain in the clinic. The lack of effective therapeutic agents for neuropathic pain is due to the fact that its underlying mechanisms are still not fully understood. Recently, pain researchers have been trying to identify the cellular and molecular processes that lead to neuropathic pain. Understanding the molecular mechanisms of neuropathic pain would certainly provide a hope for the future development of effective therapies for this intractable painful disease.