Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Small fiber neuropathy (SFN) is a common and debilitating disease in which the terminals of small diameter sensory axons degenerate, producing sensory loss, and in many patients neuropathic pain. While a substantial number of cases are attributable to diabetes, almost 50% are idiopathic. An underappreciated aspect of the disease is its late onset in most patients. Animal models of human genetic mutations that produce SFN also display age-dependent phenotypes suggesting that aging is an important contributor to the risk of development of the disease. In this review we define how particular sensory neurons are affected in SFN and discuss how aging may drive the disease. We also evaluate how animal models of SFN can define disease mechanisms that will provide insight into early risk detection and suggest novel therapeutic interventions.

UNASSIGNED: There is a great need to find alternative treatments for chronic pain which have become a healthcare problem. We discuss current therapeutic targeting Nav1.7.
UNASSIGNED: Nav1.7 is a sodium ion channel protein that is associated with several human pain genetic syndromes. It has been found that mutations associated with Nav1.7 lead to the loss of the ability to perceive pain in individuals that are otherwise normal. Several therapeutic interventions are presently undergoing preclinical and research using the methodology of damping Nav1.7 expressions as a methodology to decrease the sensation of pain leading to analgesia.
UNASSIGNED: It is our strong belief that there is a viable future in the targeting of protein of Nav1.7 for the relief of chronic pain in humans. The review will look at the genomics associated with SCN1A and proteomic of Nav1.7 as a foundation to explain the mechanism of the therapeutic interventions targeting Nav1.7, the human disease that are associated with Nav1.7, and the current development of treatment for chronic pain whether in preclinical or clinical trials targeting Nav1.7 expressions. The development of therapeutic antagonists targeting Nav1.7 could be a viable alternative to the current treatments which have led to the opioid crisis. Therefore, Nav1.7 targeted treatment has a major clinical significance that will have positive consequences as it relates to chronic pain interventions.

Gain-of-function mutations in Scn9a, which encodes the peripheral sensory neuron-enriched voltage-gated sodium channel Nav1.7, cause paroxysmal extreme pain disorder (PEPD), inherited erythromelalgia (IEM), and small fiber neuropathy (SFN). Conversely, loss-of-function mutations in the gene are linked to congenital insensitivity to pain (CIP). These mutations are evidence for a link between altered sodium conductance and neuronal excitability leading to somatosensory aberrations, pain, or its loss. Our previous work in young adult mice with the Nav1.7 gain-of-function mutation, I228M, showed the expected DRG neuron hyperexcitability, but unexpectedly the mice had normal mechanical and thermal behavioral sensitivity. We now show that with aging both male and female mice with this mutation unexpectedly develop a profound insensitivity to noxious heat and cold, as well skin lesions that span the body. Electrophysiology demonstrates that, in contrast to young mice, aged I228M mouse DRGs have a profound loss of sodium conductance and changes in activation and slow inactivation dynamics, representing a loss-of-function. Through RNA sequencing we explored how these age-related changes may produce the phenotypic changes and found a striking and specific decrease in C-low threshold mechanoreceptor- (cLTMR) associated gene expression, suggesting a potential contribution of this DRG neuron subtype to Nav1.7 dysfunction phenotypes. A GOF mutation in a voltage-gated channel can therefore produce over a prolonged time, highly complex and unexpected alterations in the nervous system beyond excitability changes.

One of the genes associated with pain perception is SCN9A, which encodes an α-subunit of the voltage gated sodium channel, NaV1.7, a crucial player in peripheral pain sensation. It has been suggested that a common missense polymorphism within SCN9A (rs6746030; G>A; R1150W) may affect nociception in the general population, but its effects of pain perception in athletes remain unknown. Therefore, the aim of the study was to investigate the association between a polymorphism within SCN9A (rs6746030) and pain perception (pain threshold and pain tolerance) in the group of combat athletes (n = 214) and students (n = 92) who did not participate in sports at a professional level. Genotyping was carried out using TaqMan Real-Time PCR method. No significant differences were found between the SCN9A genotype distributions with respect to the pain threshold. However, the probability of having a high pain threshold was higher in the combat sports group than in the control group. The probability of having a decreased pain tolerance was higher in the carriers of the GA and AA genotype than in the homozygotes of the GG genotype. Moreover, the possibility of having a high pain threshold was higher in the combat athlete group than in the control group. The results of our study suggest that the SCN9A rs6746030 polymorphism may affect pain perception. However, the additional effect of the experimental group may suggest that pain tolerance is significantly modulated by other factors, such as the systematic exposure of the athletes\' bodies to short-term high-intensity stimuli during training sessions.

Personalized management of neuropathic pain is an unmet clinical need due to heterogeneity of the underlying aetiologies, incompletely understood pathophysiological mechanisms and limited efficacy of existing treatments. Recent studies on microRNA in pain preclinical models have begun to yield insights into pain-related mechanisms, identifying nociception-related species differences and pinpointing potential drug candidates. With the aim of bridging the translational gap towards the clinic, we generated a human pain-related integrative miRNA and mRNA molecular profile of the epidermis, the tissue hosting small nerve fibres, in a deeply phenotyped cohort of patients with sodium channel-related painful neuropathy not responding to currently available therapies. We identified four miRNAs strongly discriminating patients from healthy individuals, confirming their effect on differentially expressed gene targets driving peripheral sensory transduction, transmission, modulation and post-transcriptional modifications, with strong effects on gene targets including NEDD4. We identified a complex epidermal miRNA-mRNA network based on tissue-specific experimental data suggesting a cross-talk between epidermal cells and axons in neuropathy pain. Using immunofluorescence assay and confocal microscopy, we observed that Nav1.7 signal intensity in keratinocytes strongly inversely correlated with NEDD4 expression that was downregulated by miR-30 family, suggesting post-transcriptional fine tuning of pain-related protein expression. Our targeted molecular profiling advances the understanding of specific neuropathic pain fine signatures and may accelerate process towards personalized medicine in patients with neuropathic pain.

The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9a R185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9a R185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9a R185H mice show a pain phenotype, suggesting that the SCN9A R185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.

Erythromelalgia is a rare clinical syndrome involving erythema, warmth, and burning pain in one or more of the extremities. Primary erythromelalgia is idiopathic and can begin during childhood or adulthood. In the pediatric population, auricular erythromelalgia is rare, and its etiology is not well understood. We present a case of a four-year-old boy who presented with recurrent episodes of red, painful pinnae. We also discuss previous literature on red ear syndrome and erythromelalgia.

BACKGROUND: Intravenous lidocaine has been shown to reduce opioid consumption and is associated with favourable outcomes after surgery. In this study, we explored whether intraoperative lidocaine reduces intraoperative opioid use and length of stay (LOS) and improves long-term survival after primary debulking surgery for ovarian cancer and explored the correlation between SCN9A expression and ovarian cancer prognosis.
METHODS: This retrospective study included patients who underwent primary debulking surgery(PDS) for ovarian cancer from January 2015 to December 2018. The patients were divided into non-lidocaine and lidocaine [bolus injection of 1.5 mg/kg lidocaine at the induction of anaesthesia followed by a continuous infusion of 2 mg/(kg∙h) intraoperatively] groups. Intraoperative opioid consumption, the verbal numeric rating scale (VNRS) at rest and LOS were recorded. Propensity score matching was used to minimize bias, and disease-free survival (DFS) and overall survival (OS) were compared between the two groups.
RESULTS: After propensity score matching(PSM), the demographics were not significantly different between the groups. The intraoperative sufentanil consumption in the lidocaine group was significantly lower than that in the non-lidocaine group (Mean: 35.6 μg vs. 43.2 μg, P=0.035). LOS was similar between the groups (12.0 days vs. 12.4 days, P=0.386). There was a significant difference in DFS between the groups (32.3% vs. 21.6%, P=0.015), and OS rates were significantly higher in the lidocaine group than in the non-lidocaine group (35.2% vs. 25.6%, P=0.042). Multivariate analysis indicated that intraoperative lidocaine infusion was associated with prolonged OS and DFS.
CONCLUSIONS: Intraoperative intravenous lidocaine infusion appears to be associated with improved OS and DFS in patients undergoing primary debulking surgery for ovarian cancer. Our study has the limitations of a retrospective review. Hence, our results should be confirmed by a prospective randomized controlled trial.

Charcot neuroarthropathy is a systemic disease with pathological changes in the musculoskeletal system, which leads to fractures, dislocations, and deformities involving multiple bones and joints, particularly those of the feet. While the common underlying cause of Charcot neuroarthropathy is diabetes mellitus, it is also associated with congenital insensitivity to pain (CIP). CIP is a rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. In this study, we report a patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel SCN9A mutation. This report involves the case of a middle-aged man who suffered from CIP, had repeated painless fractures, and developed bone and joint destruction. The physical and radiological examinations revealed that multiple joints were swollen and deformed, and soft-tissue trauma was evident. We identified a novel homozygous SCN9A mutation (p.Cys1339Arg) by whole-exome sequencing (WES), which was verified using Sanger sequencing. In addition, the wild-type (WT) and mutated p. Cys1339Arg were assessed in HEK293 cells expressing Nav1.7, and the results showed that p. Cys1339Arg almost abolished the Nav1.7 sodium current. In conclusion, Charcot neuroarthropathy associated with CIP demonstrated a wider spectrum of Charcot neuroarthropathy than was previously recognized or documented. In addition, this finding is conducive to understanding the critical amino acids for maintaining the function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.