Pathophysiology Of Neuropathic Pain Research Articles

Exploring characteristic features for effective HCN1 channel inhibition using integrated analytical approaches: 3D QSAR, molecular docking, homology modelling, ADME and molecular dynamics.

Neuropathic pain (NP) is characterized by hyperalgesia, allodynia, and spontaneous pain. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel involved in neuronal hyperexcitability, has emerged as an important target for the drug development of NP. HCN channels exist in four different isoforms, where HCN1 is majorly expressed in dorsal root ganglion having an imperative role in NP pathophysiology. A specific HCN1 channel inhibitor will hold the better potential to treat NP without disturbing the physiological roles of other HCN isoforms. The main objective is to identify and analyze the chemical properties of scaffolds with higher HCN1 channel specificity. The 3D-QSAR studies highlight the hydrophobic & hydrogen bond donor groups enhance specificity towards the HCN1 channel. Further, the molecular interaction of the scaffolds with the HCN1 pore was studied by generating an open-pore model of the HCN1 channel using homology modelling and then docking the molecules with it. In addition, the important residues involved in the interaction between HCN1 pore and scaffolds were also identified. Moreover, ADME predictions revealed that compounds had good oral bioavailability and solubility characteristics. Subsequently, molecular dynamics simulation studies revealed the better stability of the lead molecules A7 and A9 during interactions and ascertained them as potential drug candidates. Cumulative studies provided the important structural features for enhancing HCN1 channel-specific inhibition, paving the way to design and develop novel specific HCN1 channel inhibitors.

Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum

Spinal cord injury (SCI) often leads to central neuropathic pain, a condition associated with significant morbidity and is challenging in terms of the clinical management. Despite extensive efforts, identifying effective biomarkers for neuropathic pain remains elusive. Here we propose a novel approach combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with artificial neural networks (ANNs) to discriminate between mass spectral profiles associated with chronic neuropathic pain induced by SCI in female mice. Functional evaluations revealed persistent chronic neuropathic pain following mild SCI as well as minor locomotor disruptions, confirming the value of collecting serum samples. Mass spectra analysis revealed distinct profiles between chronic SCI and sham controls. On applying ANNs, 100% success was achieved in distinguishing between the two groups through the intensities of m/z peaks. Additionally, the ANNs also successfully discriminated between chronic and acute SCI phases. When reflexive pain response data was integrated with mass spectra, there was no improvement in the classification. These findings offer insights into neuropathic pain pathophysiology and underscore the potential of MALDI-TOF MS coupled with ANNs as a diagnostic tool for chronic neuropathic pain, potentially guiding attempts to discover biomarkers and develop treatments.

A novel animal model of symptomatic neuroma for assessing neuropathic pain

IntroductionFollowing amputation, peripheral nerves lack distal targets for regeneration, often resulting in symptomatic neuromas and debilitating neuropathic pain. Animal models can establish a practical method for symptomatic neuroma formation for better understanding of neuropathic pain pathophysiology through behavioral and histological assessments. We created a clinically translatable animal model of symptomatic neuroma to mimic neuropathic pain in patients and assess sexual differences in pain behaviors. MethodsTwenty-two male and female rats were randomly assigned to one of two experimental groups: (1) neuroma surgery, or (2) sham surgery. For the neuroma experimental group, the tibial nerve was transected in the thigh, and the proximal segment was placed under the skin for mechanical testing at the site of neuroma. For the sham surgery, rats underwent tibial nerve isolation without transection. Behavioral testing consisted of neuroma-site pain, mechanical allodynia, cold allodynia, and thermal hyperalgesia at baseline, and then weekly over 8 weeks. ResultsMale and female neuroma rats demonstrated significantly higher neuroma-site pain response compared to sham groups starting at weeks 3 and 4, indicating symptomatic neuroma formation. Weekly assessment of mechanical and cold allodynia among neuroma groups showed a significant difference in pain behavior compared to sham groups (p < 0.001). Overall, males and females did not display significant differences in their pain responses. Histology revealed a characteristic neuroma bulb at week 8, including disorganized axons, fibrotic tissue, Schwann cell displacement, and immune cell infiltration. ConclusionThis novel animal model is a useful tool to investigate underlying mechanisms of neuroma formation and neuropathic pain.

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain.

Neuropathic pain (NPP) remains a clinically challenging condition, driven by the activation of spinal astrocytes and the complex release of inflammatory mediators. This study aimed to examine the roles of Rab8a and SNARE complex proteins in activated astrocytes to uncover the underlying mechanisms of NPP. The research was conducted using a rat model with chronic constriction injury (CCI) of the sciatic nerve and primary astrocytes treated with lipopolysaccharide. Enhanced expression of Rab8a was noted specifically in spinal dorsal horn astrocytes through immunofluorescence. Electron microscopy observations showed increased vesicular transport and exocytic activity in activated astrocytes, which was corroborated by elevated levels of inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α detected through quantitative PCR. Western blot analyses confirmed significant upregulation of Rab8a, VAMP2, and Syntaxin16 in these cells. Furthermore, the application of botulinum neurotoxin type A (BONT/A) reduced the levels of vesicle transport-associated proteins, inhibiting vesicular transport in activated astrocytes. These findings suggest that the Rab8a/SNARE pathway in astrocytes enhances vesicle transport and anchoring, increasing the secretion of bioactive molecules that may play a crucial role in the pathophysiology of NPP. Inhibiting this pathway with BONT/A offers a novel therapeutic target for managing NPP, highlighting its potential utility in clinical interventions.

Newly discovered functions of miRNAs in neuropathic pain: Transitioning from recent discoveries to innovative underlying mechanisms.

Neuropathic pain is a widespread clinical issue caused by somatosensory nervous system damage, affecting numerous individuals. It poses considerable economic and public health challenges, and managing it can be challenging due to unclear underlying mechanisms. Nevertheless, emerging evidence suggests that neurogenic inflammation and neuroinflammation play a role in developing pain patterns. Emerging evidence suggests that neurogenic inflammation and neuroinflammation play significant roles in developing neuropathic pain within the nervous system. Increased/decreased miRNA expression patterns could affect the progression of neuropathic and inflammatory pain by controlling nerve regeneration, neuroinflammation, and the expression of abnormal ion channels. However, our limited knowledge of miRNA targets hinders a complete grasp of miRNA's functions. Meanwhile, exploring exosomal miRNA, a recently uncovered role, has significantly advanced our comprehension of neuropathic pain's pathophysiology in recent times. In this review, we present a comprehensive overview of the latest miRNA studies and explore the possible ways miRNAs might play a role in the development of neuropathic pain.

Potential Role of Oxidative Stress on the Pathophysiology of Neuropathic Pain in the Inflammatory Diseases

Potential Role of Oxidative Stress on the Pathophysiology of Neuropathic Pain in the Inflammatory Diseases

Cerebrospinal fluid immune cells appear similar across neuropathic and non-neuropathic pain conditions.

Microglia have been implicated in the pathophysiology of neuropathic pain. Here, we sought to investigate whether cerebrospinal fluid (CSF) might be used as a proxy-measure of microglial activation in human participants. We preformed fluorescence-activated cell sorting (FACS) of CSF immune cell populations derived from individuals who experienced pain with neuropathic features. We sorted CD4+, CD8+ T cells and monocytes and analyzed their transcriptome using RNA sequencing. We also performed Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing to characterize the expression of all CSF immune cells in a patient with postherpetic neuralgia and in a patient with neuropathic pain after failed back surgery. Immune cell numbers and phenotypes were not obviously different between individuals regardless of the etiology of their pain. This was true when examining our own dataset, as well as when comparing it to previously published single-cell RNA sequencing data of human CSF. In all instances, CSF monocytes showed expression of myeloid cell markers commonly associated with microglia ( P2RY12, TMEM119 and OLFML3), which will make it difficult to ascertain the origin of CSF proteins: do they derive directly from circulating CSF monocytes or could some originate in spinal cord microglia in the parenchyma? We conclude that it will not be straightforward to use CSF as a biomarker for microglial function in humans.

REPRINTED WITH PERMISSION OF IASP – PAIN 164 (2023) 3–13: Ambroxol for neuropathic pain: hiding in plain sight?

Ambroxol is a multifaceted drug with primarily mucoactive and secretolytic actions, along with anti-inflammatory, antioxidant, and local anaesthetic properties. It has a long history of use in the treatment of respiratory tract diseases and has shown to be efficacious in relieving sore throat. In more recent years, ambroxol has gained interest for its potential usefulness in treating neuropathic pain. Research into this area has been slow, despite clear preclinical evidence to support its primary analgesic mechanism of action—blockade of voltage-gated sodium (Nav) channels in sensory neurons. Ambroxol is a commercially available inhibitor of Nav1.8, a crucial player in the pathophysiology of neuropathic pain, and Nav1.7, a particularly exciting target for the treatment of chronic pain. In this review, we discuss the analgesic mechanisms of action of ambroxol, as well as proposed synergistic properties, followed by the preclinical and clinical results of its use in the treatment of persistent pain and neuropathic pain symptoms, including trigeminal neuralgia, fibromyalgia, and complex regional pain syndrome. With its well-established safety profile, extensive preclinical and clinical drug data, and early evidence of clinical effectiveness, ambroxol is an old drug worthy of further investigation for repurposing. As a patent-expired drug, a push is needed to progress the drug to clinical trials for neuropathic pain. We encourage the pharmaceutical industry to look at patented drug formulations and take an active role in bringing an optimized version for neuropathic pain to market.

Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study

Aims/hypothesisWhile the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN.MethodsThe EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up.ResultsAt baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03).Conclusions/interpretationIn this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.Graphical

Employing the sustained-release properties of poly(lactic-co-glycolic acid) nanoparticles to reveal a novel mechanism of sodium-hydrogen exchanger 1 in neuropathic pain

Neuropathic pain is caused by injury or disease of the somatosensory system, and its course is usually chronic. Several studies have been dedicated to investigating neuropathic pain-related targets; however, little attention has been paid to the persistent alterations that these targets, some of which may be crucial to the pathophysiology of neuropathic pain. The present study aimed to identify potential targets that may play a crucial role in neuropathic pain and validate their long-term impact. Through bioinformatics analysis of RNA sequencing results, we identified Slc9a1 and validated the reduced expression of sodium-hydrogen exchanger 1 (NHE1), the protein that Slc9a1 encodes, in the spinal nerve ligation (SNL) model. Colocalization analysis revealed that NHE1 is primarily co-localized with vesicular glutamate transporter 2-positive neurons. In vitro experiments confirmed that poly(lactic-co-glycolic acid) nanoparticles loaded with siRNA successfully inhibited NHE1 in SH-SY5Y cells, lowered intracellular pH, and increased intracellular calcium concentrations. In vivo experiments showed that sustained suppression of spinal NHE1 expression by siRNA-loaded nanoparticles resulted in delayed hyperalgesia in naïve and SNL model rats, whereas amiloride-induced transient suppression of NHE1 expression yielded no significant changes in pain sensitivity. We identified Slc9a1, which encodes NHE1, as a key gene in neuropathic pain. Utilizing the sustained release properties of nanoparticles enabled us to elucidate the chronic role of decreased NHE1 expression, establishing its significance in the mechanisms of neuropathic pain.

The emerging role of pyroptosis in neuropathic pain.

Neuropathic pain caused by somatosensory system injuries is notoriously difficult to treat. Previous research has shown that neuroinflammation and cell death have been implicated in the pathophysiology of neuropathic pain. Pyroptosis is a form of programmed cell death associated with inflammatory processes, as it can enhance or sustain the inflammatory response by releasing pro-inflammatory cytokines. This review presents the current knowledge on pyroptosis and its underlying mechanisms, including the canonical and noncanonical pathways. Moreover, we discuss recent findings on the role of pyroptosis in neuropathic pain and its potential as a therapeutic target. In conclusion, this review highlights the potential significance of pyroptosis as a promising target for developing innovative therapies to treat neuropathic pain.

Urolithin A alleviates neuropathic pain and activates mitophagy.

Neuropathic pain (NP) occurs frequently in the general population and has a negative impact on the quality of life. There is no effective therapy available yet owing to the complex pathophysiology of NP. In our previous study, we found that urolithin A (UA), a naturally occurring microflora-derived metabolite, could relieve NP in mice by inhibiting the activation of microglia and release of inflammation factors. Here in this study, we sought to investigate whether mitophagy would be activated when UA alleviated NP in mice. We showed that the autophagy flow was blocked in the spinal dorsal horn of the chronic constriction injury (CCI) mice when the most obvious pain behavior occurs. Intraperitoneal injection of UA markedly activated the mitophagy mediated by PTEN-induced kinase 1/Parkin, promoted mitobiogenesis in both neurons and microglia, and alleviated NP in the CCI mice. In summary, our data suggest that UA alleviates NP in mice and meanwhile induces mitophagy activation, which highlights a therapeutic potential of UA in the treatment of NP.

SIX1 induced HULC modulates neuropathic pain and Schwann cell oxidative stress after sciatic nerve injury

Neuropathic pain is a severe and debilitating condition caused by damage to the peripheral nerve or central nervous system. Although several mechanisms have been identified, the underlying pathophysiology of neuropathic pain is still not fully understood. Unfortunately, few effective therapies are available for this condition. Therefore, there is an urgent need to investigate the underlying mechanisms of neuropathic pain to develop more effective treatments. Long non-coding RNAs (lncRNAs) have recently gained attention due to their potential to modulate protein expression through various mechanisms. LncRNAs have been implicated in many diseases, including neuropathic pain. This study aimed to identify a novel lncRNA involved in neuropathic pain progression. The lncRNA microarray analysis showed that lncRNA Upregulated in Liver Cancer (HULC) was significantly upregulated in spinal cord tissue of sciatic nerve injury (SNI) rats. Further experiments confirmed that HULC promoted neuropathic pain progression and aggravated H2O2-induced Schwann cell injury. Mechanistically, Sine Oculis Homeobox 1 (SIX1) regulated the transcriptional expression of HULC, and both SIX1 and HULC were involved in neuropathic pain and Schwann cell injury. The results of our research indicate the existence of a previously unknown SIX1/HULC axis that plays a significant role in the development and progression of neuropathic pain, shedding light on the complex mechanisms that underlie this debilitating condition. These findings offer novel insights into the molecular pathways involved in neuropathic pain. This study underscores the potential of targeting lncRNAs as a viable approach to alleviate the suffering of patients with neuropathic pain.

Combination Gene Delivery Reduces Spinal Cord Pathology in Rats With Peripheral Neuropathic Pain

Although peripheral neuropathic pain is caused by peripheral nerve injury, it is not simply a peripheral nervous system disease. It causes abnormalities in both the central and peripheral nervous systems. Pathological phenomena, such as hyperactivation of sensory neurons and inflammation, are observed in both the dorsal root ganglion and spinal cord. Pain signals originating from the periphery are transmitted to the brain via the SC, and the signals are modulated by pathologically changing SC conditions. Therefore, the modulation of SC pathology is important for peripheral NP treatment. We investigated the effects of KLS-2031 (recombinant adeno-associated viruses expressing glutamate decarboxylase 65, glial cell-derived neurotrophic factor, and interleukin-10) delivered to the dorsal root ganglion on aberrant neuronal excitability and neuroinflammation in the SC of rats with peripheral NP. Results showed that KLS-2031 administration restored excessive excitatory transmission and inhibitory signals in substantia gelatinosa neurons. Moreover, KLS-2031 restored the in vivo hypersensitivity of wide dynamic range neurons and mitigated neuroinflammation in the SC by regulating microglia and astrocytes. Collectively, these findings demonstrated that KLS-2031 efficiently suppressed pathological pain signals and inflammation in the SC of peripheral NP model, and is a potential novel therapeutic approach for NP in clinical settings. PerspectiveOur study demonstrated that KLS-2031, a combination gene therapy delivered by transforaminal epidural injection, not only mitigates neuroinflammation but also improves SC neurophysiological function, including excitatory-inhibitory balance. These findings support the potential of KLS-2031 as a novel modality that targets multiple aspects of the complex pathophysiology of neuropathic pain.

Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain

Neuropathic pain is a common, debilitating chronic pain condition caused by damage or a disease affecting the somatosensory nervous system. Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively. Tiam1 is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendritic and synaptic growth during hippocampal development by inducing actin cytoskeletal remodeling. Here, using multiple neuropathic pain animal models, we show that Tiam1 coordinates synaptic structural and functional plasticity in the spinal dorsal horn via actin cytoskeleton reorganization and synaptic NMDAR stabilization and that these actions are essential for the initiation, transition, and maintenance of neuropathic pain. Furthermore, an antisense oligonucleotides (ASO) targeting spinal Tiam1 persistently alleviate neuropathic pain sensitivity. Our findings suggest that Tiam1-coordinated synaptic functional and structural plasticity underlies the pathophysiology of neuropathic pain and that intervention of Tiam1-mediated maladaptive synaptic plasticity has long-lasting consequences in neuropathic pain management.

Pharmacological Modulation of the MIP-1 Family and Their Receptors Reduces Neuropathic Pain Symptoms and Influences Morphine Analgesia: Evidence from a Mouse Model

Neuropathic pain pathophysiology is not fully understood, but it was recently shown that MIP-1 family members (CCL3, CCL4, and CCL9) have strong pronociceptive properties. Our goal was to examine how pharmacological modulation of these chemokines and their receptors (CCR1 and CCR5) influence hypersensitivity after nerve injury in Albino Swiss male mice. The spinal changes in the mRNA/protein levels of the abovementioned chemokines and their receptors were measured using RT-qPCR and ELISA/Western blot techniques in a mouse model of chronic constriction injury of the sciatic nerve. Behavioral studies were performed using the von Frey and cold plate tests after pharmacological treatment with neutralizing antibodies (nAbs) against chemokines or antagonists (CCR1-J113863, CCR5-TAK-220/AZD-5672) alone and in coadministration with morphine on Day 7, when the hypersensitivity was fully developed. Our results showed enhanced protein levels of CCL3 and CCL9 1 and 7 days after nerve injury. The single intrathecal administration of CCL3 or CCL9 nAb, J113863, TAK-220, or AZD-5672 diminished neuropathic pain symptoms and enhanced morphine analgesia. These findings highlight the important roles of CCL3 and CCL9 in neuropathic pain and additionally indicate that these chemokines play essential roles in opioid analgesia. The obtained results suggest CCR1 and CCR5 as new, interesting targets in neuropathy treatment.

Sex Differences in the Expression of Neuroimmune Molecules in the Spinal Cord of a Mouse Model of Antiretroviral-Induced Neuropathic Pain.

Nucleoside reverse transcriptase inhibitors (NRTIs), drugs used to treat HIV infection, can cause neuropathic pain (NP) and neuroinflammation. An NRTI, 2'-3'-dideoxycytidine (ddC), was reported to induce mechanical allodynia and increase proinflammatory cytokines in the brains of female mice. In some models of NP, microglia activation is important for NP pathophysiology in male mice, while T cells are important in female mice. Age-matched female and male mice (BALB/c strain) treated intraperitoneally once daily with ddC for 5 days developed mechanical allodynia. Treatment with ddC increased Cd11b, H2-Aa, Cd3e, Mapk1, Il1b, Tnf, and Il10 mRNA levels in the spinal cords of female, but not male, mice, whereas there was no alteration found in Gfap and Mapk14 transcripts in both sexes on day 7 after ddC administration. The protein expression of CD11b and phospho-p38 MAPK was significantly increased in the spinal cords of ddC-treated female, but not male, mice, whereas Iba1 protein was elevated in ddC-treated male mice. There was no change in GFAP, CD3e, and phospho-p44/42 MAPK protein levels in both sexes. Thus, changes in neuroimmune cells and molecules in the spinal cords during ddC-induced neuroinflammation were sex-dependent, with female mice being more prone to neuroimmune changes than male mice.

Emerging roles of miRNAs in neuropathic pain: From new findings to novel mechanisms.

Neuropathic pain, which results from damage to the somatosensory nervous system, is a global clinical condition that affects many people. Neuropathic pain imposes significant economic and public health burdens and is often difficult to manage because the underlying mechanisms remain unclear. However, mounting evidence indicates a role for neurogenic inflammation and neuroinflammation in pain pattern development. There is increasing evidence that the activation of neurogenic inflammation and neuroinflammation in the nervous system contribute to neuropathic pain. Altered miRNA expression profiles might be involved in the pathogenesis of both inflammatory and neuropathic pain by regulating neuroinflammation, nerve regeneration, and abnormal ion channel expression. However, the lack of knowledge about miRNA target genes prevents a full understanding of the biological functions of miRNAs. At the same time, an extensive study on exosomal miRNA, a newly discovered role, has advanced our understanding of the pathophysiology of neuropathic pain in recent years. This section provides a comprehensive overview of the current understanding of miRNA research and discusses the potential mechanisms of miRNAs in neuropathic pain.

Effects of NADPH Oxidase Isoform-2 (NOX2) Inhibition on Behavioral Responses and Neuroinflammation in a Mouse Model of Neuropathic Pain

NADPH oxidase isoform-2 (NOX2) has been implicated in the pathophysiology of neuropathic pain (NP), mostly through the modulation of neuroinflammation. Since it is also accepted that some neuroimmune mechanisms underlying NP are sex-dependent, we aimed to evaluate the effects of early systemic treatment with the NOX2-selective inhibitor (NOX2i) GSK2795039 on behavioral responses and spinal neuroinflammation in spared nerve injury (SNI)-induced NP in male and female mice. Mechanical sensitivity was evaluated with the von Frey test, while general well-being and anxiety-like behavior were assessed with burrowing and light/dark box tests. Spinal microglial activation and cytokines IL-1β, IL-6, and IL-10, as well as macrophage colony-stimulating factor (M-CSF) were evaluated by immunofluorescence and multiplex immunoassay, respectively. NOX2i treatment reduced SNI-induced mechanical hypersensitivity and early SNI-induced microglial activation in both sexes. SNI-females, but not males, showed a transient reduction in burrowing activity. NOX2i treatment did not improve their burrowing activity, but tendentially reduced their anxiety-like behavior. NOX2i marginally decreased IL-6 in females, and increased M-CSF in males. Our findings suggest that NOX2-selective inhibition may be a potential therapeutic strategy for NP in both male and female individuals, with particular interest in females due to its apparent favorable impact in anxiety-like behavior.

Increased extracellular release of microRNAs from dorsal root ganglion cells in a rat model of neuropathic pain caused by peripheral nerve injury.

microRNAs (miRNAs) are extracellularly released by cells for intercellular communication, while intracellularly, they inhibit the expression of specific genes. An increasing number of studies suggest that extracellular miRNAs have great potential as both therapeutic targets and disease-specific biomarkers in a variety of diseases, including pain disorders. However, little is known about miRNA release from dorsal root ganglion (DRG) neurons in neuropathic pain caused by peripheral nerve injury. In this study, we investigated the changes in the extracellular release of miRNAs from DRG neurons in a rat model of neuropathic pain induced by chronic constriction injury of the sciatic nerve. We found increased release of six miRNAs (let-7d, miR-21, miR-142-3p, miR-146b, miR-203-3p and miR-221) from primary cultured DRG neurons prepared from rats 7 days after nerve injury. Among these, miR-221 was also increased in serum from days 7 to 28 after nerve injury. In contrast, serum miR-221 levels and its release from DRG neurons were unchanged in an inflammatory pain model produced by intraplantar injection of complete Freund's adjuvant. These results suggest that the increased release of specific miRNAs by DRG neurons may be involved in the pathophysiology of neuropathic pain through extracellular as well as intracellular mechanisms. Furthermore, serum miR-221 may be useful as a biomarker of neuropathic pain caused by peripheral nerve injury.