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Sensory disturbances and central nervous system symptoms are important in patients with Minamata disease. In the peripheral nervous system of these patients, motor nerves are not strongly injured, whereas sensory nerves are predominantly affected. In this study, we investigated the mechanisms underlying the sensory-predominant impairment of the peripheral nervous system caused by methylmercury. We found that the types of cell death in rat dorsal root ganglion (DRG) neurons caused by methylmercury included apoptosis, necrosis, and necroptosis. Methylmercury induced apoptosis in cultured rat DRG neurons but not in anterior horn neurons or Schwann cells. Additionally, methylmercury activated both caspase 8 and caspase 3 in DRG neurons. It increased the expression of tumor necrosis factor (TNF) receptor-1 and the phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL). The expression of TNF-α was increased in macrophage-like RAW264.7 cells by methylmercury. The increase was suggested to be mediated by the NF-κB pathway. Moreover, methylmercury induced neurological symptoms, evaluated by a hindlimb extension response, were significantly less severe in TNF-α knockout mice. Based on these results and our previous studies, we propose the following hypothesis regarding the pathogenesis of sensory nerve-predominant damage by methylmercury: First, methylmercury accumulates within sensory nerve neurons and initiates cell death mechanisms, such as apoptosis, on a small scale. Second, cell death triggers the infiltration of macrophages into the sensory fibers. Third, the macrophages are stimulated by methylmercury and secrete TNF-α through the NF-κB pathway. Fourth, TNF-α induces cell death mechanisms, including necrosis, apoptosis through the caspase 8/3 pathway, and necroptosis through the TNFR1-RIP1-RIP3-MLKL pathway, activated by methylmercury in sensory neurons. Consequently, methylmercury exhibits potent cytotoxicity specific to the DRG/sensory nerve cells in the peripheral nervous system. This chain of events caused by methylmercury may contribute to sensory disturbances in patients with Minamata disease. [ABSTRACT FROM AUTHOR]

Objective: Heterotopic ossification (HO) refers to the abnormal development of bone in soft tissue rather than within bone itself. Previous research has shown that sensory nerve prostaglandin E2 receptor 4 (EP4) signaling not only governs pain perception but also influences bone formation. However, the relationship between sensory nerve EP4 and the pathogenesis of HO in the Achilles tendon remains unclear. This study aims to investigate this relationship and the underlying mechanisms. Methods: We generated sensory nerve EP4-specific knockout mice, with the genotype of Avil-CreEP4fl/fl, was propagated. Transcriptome sequencing and bioinformatics analysis techniques were used to identify the potential molecular pathways involving with sensory nerve EP4. Additionally, a neurectomy mouse model was created by transecting the sciatic nerve transection, to examine the effects and mechanisms of peripheral innervation on HO in vivo. Micro-CT, immunofluorescence (IF), Hematoxylin and Eosin (H&E) Staining, Safranin O-Fast Green staining and western blotting were used to analyze changes in cellular and tissue components. Results: We here observed an increase in sensory nerve EP4 and H-type vessels during the pathogenesis of HO in both human subjects and mice. Proximal neurectomy through sciatic nerve transection or the targeted knockout of EP4 in sensory nerves hindered angiogenesis-dependent bone formation and the development of HO at the traumatic site of the Achilles tendon. Furthermore, we identified the Efnb2 (Ephrin-B2)/Dll4 (Delta-like ligand 4) axis as a potential downstream element influenced by sensory nerve EP4 in the regulation of HO. Notably, administration of an EP4 inhibitor demonstrated the ability to alleviate HO. Based on these findings, sensory nerve EP4 emerges as an innovative and promising approach for managing HO. Conclusion: Our findings demonstrate that the sensory nerve EP4 promotes ectopic bone formation by modulating angiogenesis-associated osteogenesis during HO. The translational potential of this article: Our results provide a mechanistic rationale for targeting sensory nerve EP4 as a promising candidate for HO therapy.

Dental pulp stem cells (DPSCs) are responsible for maintaining pulp structure and function after pulp injury. DPSCs migrate directionally to the injury site before differentiating into odontoblast-like cells, which is a prerequisite and a determinant in pulp repair. Increasing evidence suggests that sensory neuron-stem cell crosstalk is critical for maintaining normal physiological functions, and sensory nerves influence stem cells mainly by neuropeptides. However, the role of sensory nerves on DPSC behaviors after pulp injury is largely unexplored. Here, we find that sensory nerves released significant amounts of calcitonin gene-related peptide (CGRP) near the injury site, acting directly on DPSCs via receptor activity modifying protein 1 (RAMP1) to promote collective migration of DPSCs to the injury site, and ultimately promoting pulp repair. Specifically, sensory denervation leads to poor pulp repair and ectopic mineralization, in parallel with that DPSCs failed to be recruited to the injury site. Furthermore, in vitro evidence shows that sensory nerve-deficient microenvironment suppressed DPSC migration prominently among all related behaviors. Mechanistically, the CGRP-Ramp1 axis between sensory neurons and DPSCs was screened by single-cell RNA-seq analysis and immunohistochemical studies confirmed that the expression of CGRP rather than Ramp1 increases substantially near the damaged site. We further demonstrated that CGRP released by sensory nerves binds the receptor Ramp1 on DPSCs to facilitate cell collective migration by an indirect co-culture system using conditioned medium from trigeminal neurons, CGRP recombinant protein and antagonists BIBN4096. The treatment with exogenous CGRP promoted the recruitment of DPSCs, and ultimately enhanced the quality of pulp repair. Targeting the sensory nerve could therefore provide a new strategy for stem cell-based pulp repair and regeneration. [ABSTRACT FROM AUTHOR]

Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D‐P‐Ak (polydopamine‐PLGA‐akermanite), designed to fit within the defect site while minimizing injury. The D‐P‐Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene‐related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo‐inductive biomaterials with potential for further clinical applications. [ABSTRACT FROM AUTHOR]

The skeletal system is highly innervated. As research in bone biology progresses, the coupling mechanism between sensory neurons and bone remodeling is receiving increasing attention. Bone pain mediated by sensory neurons plays a crucial role in the development, diagnosis, treatment, and efficacy evaluation of bone diseases. Although the specific mechanism underlying bone pain remains incompletely understood at present, studies have indicated that osteoclasts, the primary mediators of bone resorption, play a significant role in nociceptive bone pain and neuropathic bone pain. Therefore, this review summarizes recent relevant research and explores the mechanism by which osteoclasts mediate bone pain, including the acidic microenvironment, inflammatory environment, and pain factors secreted by osteoclasts that stimulate nociceptors and the neuropathic changes induced by osteoclasts on sensory neurons. Additionally, the role of osteoclasts in mediating bone pain in different bone diseases is also discussed. The aim of this article is to provide a summary of the progress in research on osteoclast-mediated bone pain and to offer new insights and targets for the treatment of bone pain. [ABSTRACT FROM AUTHOR]

Cancer-induced bone pain (CIBP) is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis. CIBP constitutes a specific pain state with distinct characteristics; however, it shares similarities with inflammatory and neuropathic pain. At present, although various therapies have been developed for this condition, complete relief from CIBP in patients with cancer is yet to be achieved. Hence, it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs. Herein, we focused on the peripheral mechanism associated with the initiation of CIBP, which involves tissue injury in the bone and changes in the tumor microenvironment (TME) and dorsal root ganglion. The nerve–cancer and cancer–immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis, ultimately leading to CIBP. The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review. [ABSTRACT FROM AUTHOR]

Introduction: Adenosine plays an important role in increasing glucose uptake into muscles. Adenosine deaminase (ADA) enzymes convert adenosine into inosine and 2′-deoxyinosine. Increased ADA activity leads to the reduction of adenosine, subsequently lowering glucose absorption in skeletal muscles. Uncontrolled diabetes tends to result in complications such as diabetic neuropathy. To investigate the association between serum ADA levels and lower limb nerve conduction velocity in individuals with type II diabetes mellitus. Methods: This study included 60 participants, with 30 patients in the diabetes group and the remaining 30 in the control group. Serum ADA levels were measured, and nerve conduction recordings were performed on the lower limb’s motor peroneal, tibial, and sensory sural nerves. Results: In diabetes patients, lower limb sensory sural nerves, motor tibial, and peroneal nerves showed increased latency, reduced amplitude, and decreased nerve conduction velocity compared to the control group. ADA levels were found to be higher in diabetic patients than in the control group. A negative correlation was observed between sensory sural nerve conduction velocity and ADA levels, with females exhibiting more negative correlations than males. No association was found between motor peroneal and motor tibial nerve conduction parameters and ADA levels. Conclusion: Sensory nerves are affected much earlier than motor nerves under hyperglycemic conditions. Elevated ADA levels indicate reduced insulin sensitivity, and the depletion of adenosine contributes to nerve damage. ADA levels could be useful in diagnosing early peripheral nerve damage. [ABSTRACT FROM AUTHOR]

Abstract Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D‐P‐Ak (polydopamine‐PLGA‐akermanite), designed to fit within the defect site while minimizing injury. The D‐P‐Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene‐related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo‐inductive biomaterials with potential for further clinical applications.

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.

Objective To analyze the diagnostic value of combined detection of nerve F-wave conduction velocity(CV) and fasting C-Peptide (FC-P) level in evaluating diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 30 T2DM patients with DPN who were treated at Ma’anshan People's Hospital from September 2020 to June 2022 were selected as the observation group, 30 T2DM patients without DPN were selected as the control group, and 30 healthy volunteers from the same period were recruited as the blank group. The levels of FC-P, 2 h postprandial C peptide (PC-P), fasting blood glucose (FBG), 2 h postprandial blood glucose (PBG) and glycosylated hemoglobin (HbA1c) were compared among the three groups. Nerve conduction velocity (including sensory CV, motor CV) and F-wave CV were compared among the three groups. Binary logistic regression was used to analyze the risk factors of DPN in T2DM patients. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of various indicators for the occurence of DPN. Results Compared with control group and blank group, the serum levels of FC-P and PC-P were lower, and the levels of FBG, PBG and HbA1c were higher in the observation group (P＜0.05). The serum levels of FC-P and PC-P in the control group were lower than those in the blank group, and the levels of FBG, PBG and HbA1c in the control group were higher than those in the blank group (P＜0.05). Sensory CV, motor CV and F-wave CV were the slowest in the observation group, followed by the control group, and the fastest in the blank group (P＜0.05). Binary logistic regression analysis showed that slow F-wave CV of median nerve and low FC-P level were the risk factors for DPN in diabetic patients. When median nerve F-wave CV (cut-off point was 48.05 m/s) combined with FC-P (cut-off point was 1.61 pmol/L), the area under ROC of DPN in patients with early diagnosis of diabetes was 0.819, the sensitivity was 82.60% and the specificity was 88.40%. Conclusion The combined detection of nerve F-wave CV and FC-P level can improve the predictive value of DPN in T2DM patients, and can be used for the diagnosis of early DPN patients.

The trigeminal nerve is the sensory afferent of the orofacial regions and divided into three major branches. Cell bodies of the trigeminal nerve lie in the trigeminal ganglion and are surrounded by satellite cells. There is a close interaction between ganglion cells via satellite cells, but the function is not fully understood. In the present study, we clarified the ganglion cells' three‐dimensional (3D) localization, which is essential to understand the functions of cell–cell interactions in the trigeminal ganglion. Fast blue was injected into 12 sites of the rat orofacial regions, and ganglion cells were retrogradely labeled. The labeled trigeminal ganglia were cleared by modified 3DISCO, imaged with confocal laser‐scanning microscopy, and reconstructed in 3D. Histograms of the major axes of the fast blue‐positive somata revealed that the peak major axes of the cells innervating the skin/mucosa were smaller than those of cells innervating the deep structures. Ganglion cells innervating the ophthalmic, maxillary, and mandibular divisions were distributed in the anterodorsal, central, and posterolateral portions of the trigeminal ganglion, respectively, with considerable overlap in the border region. The intermingling in the distribution of ganglion cells within each division was also high, in particular, within the mandibular division. Specifically, intermingling was observed in combinations of tongue and masseter/temporal muscles, maxillary/mandibular molars and masseter/temporal muscles, and tongue and mandibular molars. Double retrograde labeling confirmed that some ganglion cells innervating these combinations were closely apposed. Our data provide essential information for understanding the function of ganglion cell–cell interactions via satellite cells. [ABSTRACT FROM AUTHOR]

Respiratory viral infection can lead to activation of sensory afferent nerves as indicated by the consequential sore throat, sneezing, coughing, and reflex secretions. In addition to causing troubling symptoms, sensory nerve activation likely accelerates viral spreading. The mechanism how viruses activate sensory nerve terminals during infection is unknown. In this study, we investigate whether coronavirus spike protein activates sensory nerves terminating in the airways. We used isolated vagally‐innervated mouse trachea‐lung preparation for two‐photon microscopy and extracellular electrophysiological recordings. Using two‐photon Ca2+ imaging, we evaluated a total number of 786 vagal bronchopulmonary nerves in six experiments. Approximately 49% of the sensory fibers were activated by S1 protein (4 μg/mL intratracheally). Extracellular nerve recording showed the S1 protein evoked action potential discharge in sensory C‐fibers; of 39 airway C‐fibers (one fiber per mouse), 17 were activated. Additionally, Fura‐2 Ca2+ imaging was performed on neurons dissociated from vagal sensory ganglia (n = 254 from 22 mice). The result showed that 63% of neurons responded to S1 protein. SARS‐CoV‐2 S1 protein can lead to direct activation of sensory C‐fiber nerve terminals in the bronchopulmonary tract. Direct activation of C‐fibers may contribute to coronavirus symptoms, and amplify viral spreading in a population. [ABSTRACT FROM AUTHOR]

Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (our hypothesis). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7–9 days) or chronic (8 weeks) mild (SCImi: 10 g × 12.5 mm) or moderate (SCImo: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCImi groups and animals with subacute SCImo. However, delayed NT did not produce neurological scale upgrading conversion for SCImo rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies. [ABSTRACT FROM AUTHOR]

Airway nerves regulate vital airway functions including bronchoconstriction, cough, and control of respiration. Dysregulation of airway nerves underlies the development and manifestations of airway diseases such as chronic cough, where sensitization of neural pathways leads to excessive cough triggering. Nerves are heterogeneous in both expression and function. Recent advances in confocal imaging and in targeted genetic manipulation of airway nerves have expanded our ability to visualize neural organization, study neuro-immune interactions, and selectively modulate nerve activation. As a result, we have an unprecedented ability to quantitatively assess neural remodeling and its role in the development of airway disease. This review highlights our existing understanding of neural heterogeneity and how advances in methodology have illuminated airway nerve morphology and function in health and disease. [ABSTRACT FROM AUTHOR]

Sensory nerves belong to the afferent nerve part of the peripheral nervous system. Their role is to accept the stimuli inside and outside the body and transmit them to the center nerve system to form sensations or reflexes. Sensory nerve damage can be caused by trauma, tumor invasion, surgical injury, etc. Sensory nerve injury may cause decline or loss of some sensory organs function in patients. Damage of important sensory nerves such as optic nerves and auditory nerves can bring profound troubles to patients' lives. So far, the main clinical method to repair sensory nerves is autologous nerve transplantation. However, its application is limited by various factors, and the recovery effect of nerve function is often limited. Stem cells have the potential of multi-directional differentiation, which can differentiate into Schwann cells, and then secrete neurotrophic factors to promote axonal growth and myelin regeneration. Schwann cells directionally proliferate and form Büngner zones which guide nerve regeneration. Stem cells can also differentiate into neurons and construct nerve defect repair materials, which is an ideal choice for nerve repair. At present, the tissue engineering technology based on stem cells, combined with several key biotechnology, such as the use of biopolymerized or artificial surface micro-patterning nerve conduit to bridge nerve defects, and the use of microspheres to achieve the controlled release of extracellular matrix proteins and neurotrophic factors, is being widely studied and has achieved certain research results. This article reviews the research progress of stem cells in the repair of several major sensory nerves, such as optic nerves, olfactory nerves, cochlear nerves and sensory nerve fibers of sciatic nerve, expecting to provide a new perspective for neural repair of stem cells, broaden the preclinical research in nerve repair, and provide reference for follow-up clinical application.

Abstract Respiratory viral infection can lead to activation of sensory afferent nerves as indicated by the consequential sore throat, sneezing, coughing, and reflex secretions. In addition to causing troubling symptoms, sensory nerve activation likely accelerates viral spreading. The mechanism how viruses activate sensory nerve terminals during infection is unknown. In this study, we investigate whether coronavirus spike protein activates sensory nerves terminating in the airways. We used isolated vagally‐innervated mouse trachea‐lung preparation for two‐photon microscopy and extracellular electrophysiological recordings. Using two‐photon Ca2+ imaging, we evaluated a total number of 786 vagal bronchopulmonary nerves in six experiments. Approximately 49% of the sensory fibers were activated by S1 protein (4 μg/mL intratracheally). Extracellular nerve recording showed the S1 protein evoked action potential discharge in sensory C‐fibers; of 39 airway C‐fibers (one fiber per mouse), 17 were activated. Additionally, Fura‐2 Ca2+ imaging was performed on neurons dissociated from vagal sensory ganglia (n = 254 from 22 mice). The result showed that 63% of neurons responded to S1 protein. SARS‐CoV‐2 S1 protein can lead to direct activation of sensory C‐fiber nerve terminals in the bronchopulmonary tract. Direct activation of C‐fibers may contribute to coronavirus symptoms, and amplify viral spreading in a population.

Sensory nerves belong to the afferent nerve part of the peripheral nervous system. Their role is to accept the stimuli inside and outside the body and transmit them to the center nerve system to form sensations or reflexes. Sensory nerve damage can be caused by trauma, tumor invasion, surgical injury, etc. Sensory nerve injury may cause decline or loss of some sensory organs function in patients. Damage of important sensory nerves such as optic nerves and auditory nerves can bring profound troubles to patients' lives. So far, the main clinical method to repair sensory nerves is autologous nerve transplantation. However, its application is limited by various factors, and the recovery effect of nerve function is often limited. Stem cells have the potential of multidirectional differentiation, which can differentiate into Schwann cells, and then secrete neurotrophic factors to promote axonal growth and myelin regeneration. Schwann cells directionally proliferate and form Büngner zones which guide nerve regeneration. Stem cells can also differentiate into neurons and construct nerve defect repair materials, which is an ideal choice for nerve repair. At present, the tissue engineering technology based on stem cells, combined with several key biotechnology, such as the use of biopolymerized or artificial surface micro-patterning nerve conduit to bridge nerve defects, and the use of microspheres to achieve the controlled release of extracellular matrix proteins and neurotrophic factors, is being widely studied and has achieved certain research results. This article reviews the research progress of stem cells in the repair of several major sensory nerves, such as optic nerves, olfactory nerves, cochlear nerves and sensory nerve fibers of sciatic nerve, expecting to provide a new perspective for neural repair of stem cells, broaden the preclinical research in nerve repair, and provide reference for follow-up clinical application [ABSTRACT FROM AUTHOR]

Background: Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. Methods: Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS. Results: Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P

Introduction: Electroacupuncture (EA) has a favorable impact on blood glucose stability. Blood glucose homeostasis is linked to sexual dimorphism. The majority of research has, however, focused on male participants, and sex differences have not been adequately taken into account. Methods: Here, we investigated how EA intervention affected pancreatic metabolic stress and explored if there were any sex-related changes in the maintenance of pancreatic function following intraperitoneal injection of a 10 g/kg glucose solution. Results: The transient receptor potential vanilloid 1 (TRPV1) calcitonin gene-related peptide (CGRP)-β cell pathway of the male pancreas is vital to maintain glucose metabolism in mice. In contrast, there is a sex bias in TRPV1, which implies that female mice have additional routes for preserving glucose homeostasis. EA is ineffective on Trpv1-/- male mice. It also revealed that TRPV1 in male mice served as a crucial mediator for the EA control of blood glucose. Meanwhile, the sympathetic marker tyrosine hydroxylase showed higher expression in the male pancreas, while the cholinergic marker choline acetyltransferase is expressed predominantly in female mice. Injecting γ-aminobutyric acid into the paraventricular nucleus of male mice caused a disruption in blood glucose and a lack of response to EA. It verified that male mice had a more pronounced sympathetic innervation of the pancreas than female mice. Conclusion: Our research has demonstrated that the TRPV1 sensory afferent nerve and sympathetic efferent nerve are capable of maintaining glucose homeostasis, exhibiting a distinct sexual dimorphism. Furthermore, this regulation is contingent on the EA effect. [ABSTRACT FROM AUTHOR]

The upstream role of sensory innervation during bone homeostasis is widely underestimated in bone repairing strategies. Herein, a neuromodulation approach is proposed to orchestrate bone defect healing by constructing engineered sensory nerves (eSN) in situ to leverage the adaptation feature of SN during tissue formation. NGF liberated from ECM‐constructed eSN effectively promotes sensory neuron differentiation and enhances CGRP secretion, which lead to improved RAOECs mobility and osteogenic differentiation of BMSC. In turn, such eSN effectively drives ossification in vivo via NGF‐TrkA signaling pathway, which substantially accelerates critical size bone defect healing. More importantly, eSN also adaptively suppresses excessive bone formation and promotes bone remodeling by activating osteoclasts via CGRP‐dependent mechanism when combined with BMP‐2 delivery, which ingeniously alleviates side effects of BMP‐2. In sum, this eSN approach offers a valuable avenue to harness the adaptive role of neural system to optimize bone homeostasis under various clinical scenario. [ABSTRACT FROM AUTHOR]

Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS. Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma. [ABSTRACT FROM AUTHOR]

Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (our hypothesis). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7–9 days) or chronic (8 weeks) mild (SCImi: 10 g × 12.5 mm) or moderate (SCImo: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCImi groups and animals with subacute SCImo. However, delayed NT did not produce neurological scale upgrading conversion for SCImo rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies.

Abstract The upstream role of sensory innervation during bone homeostasis is widely underestimated in bone repairing strategies. Herein, a neuromodulation approach is proposed to orchestrate bone defect healing by constructing engineered sensory nerves (eSN) in situ to leverage the adaptation feature of SN during tissue formation. NGF liberated from ECM‐constructed eSN effectively promotes sensory neuron differentiation and enhances CGRP secretion, which lead to improved RAOECs mobility and osteogenic differentiation of BMSC. In turn, such eSN effectively drives ossification in vivo via NGF‐TrkA signaling pathway, which substantially accelerates critical size bone defect healing. More importantly, eSN also adaptively suppresses excessive bone formation and promotes bone remodeling by activating osteoclasts via CGRP‐dependent mechanism when combined with BMP‐2 delivery, which ingeniously alleviates side effects of BMP‐2. In sum, this eSN approach offers a valuable avenue to harness the adaptive role of neural system to optimize bone homeostasis under various clinical scenario.

Background We aimed to evaluate the presence of sural sparing pattern (SSP) and sensory ratio in pediatric Guillain–Barré syndrome (GBS), their distribution to subtypes, and their relationship with demographic and clinical features with a focus on the disability and muscle strength. Methods This single-center retrospective study was conducted on pediatric GBS patients of both sexes with 2 years follow-up and two nerve conduction studies in which SSP and sensory ratio were calculated. Three subgroups of SSP were formed by separate calculation of median (SSP-m) and ulnar (SSP-u) and both median and ulnar sensory nerve action potentials (SNAPs; SSP-total). Muscle strength and disability were evaluated with the Medical Research Council (MRC) sum score and Hughes functional grading scale (HFGS), respectively. Results SSP total was identified in 70.6% (n: 24) of the patients, while sensory ratio >1 was observed in 20 (66.7%) patients. Patients with SSP-m, SSP-u, SSP-total, or sensory ratio >1 had higher HFGS scores, while patients with SSP-m, SSP-u, or SSP-total had lower MRC sum scores. SSP parameters were significantly associated with muscle strength and disability scores in acute motor axonal neuropathy patients. Conclusion Both SSP and sensory ratio can be used for diagnostic and prognostic purposes. Disability and muscle strength are associated with SSP and sensory ratio in pediatric GBS. [ABSTRACT FROM AUTHOR]

Sensory nerves promote osteogenesis through the release of neuropeptides. However, the potential application and mechanism in which sensory nerves promote healing of bone defects in the presence of biomaterials remain elusive. The present study identified that new bone formation was more abundantly produced after implantation of silicified collagen scaffolds into defects created in the distal femur of rats. The wound sites were accompanied by extensive nerve innervation and angiogenesis. Sensory nerve dysfunction by capsaicin injection resulted in significant inhibition of silicon-induced osteogenesis in the aforementioned rodent model. Application of extracellular silicon in vitro induced axon outgrowth and increased expression of semaphorin 3 A (Sema3A) and semaphorin 4D (Sema4D) in the dorsal root ganglion (DRG), as detected by the upregulation of signaling molecules. Culture medium derived from silicon-stimulated DRG cells promoted proliferation and differentiation of bone marrow mesenchymal stem cells and endothelial progenitor cells. These effects were inhibited by the use of Sema3A neutralizing antibodies but not by Sema4D neutralizing antibodies. Knockdown of Sema3A in DRG blocked silicon-induced osteogenesis and angiogenesis almost completely in a femoral defect rat model, whereas overexpression of Sema3A promoted the silicon-induced phenomena. Activation of “mechanistic target of rapamycin” (mTOR) pathway and increase of Sema3A production were identified in the DRG of rats that were implanted with silicified collagen scaffolds. These findings support the role of silicon in inducing Sema3A production by sensory nerves, which, in turn, stimulates osteogenesis and angiogenesis. Taken together, silicon has therapeutic potential in orthopedic rehabilitation.

Objective: Obesity and nutrient oversupply increase mammalian target of rapamycin (mTOR) signaling in multiple cell types and organs, contributing to the onset of insulin resistance and complications of metabolic disease. However, it remains unclear when and where mTOR activation mediates these effects, limiting options for therapeutic intervention. The objective of this study was to isolate the role of constitutive mTOR activation in Nav1.8-expressing peripheral neurons in the onset of diet-induced obesity, bone loss, and metabolic disease. Methods: In humans, loss of function mutations in tuberous sclerosis complex 2 (TSC2) lead to maximal constitutive activation of mTOR. To mirror this in mice, we bred Nav1.8-Cre with TSC2fl/fl animals to conditionally delete TSC2 in Nav1.8-expressing neurons. Male and female mice were studied from 4- to 34-weeks of age and a subset of animals were fed a high-fat diet (HFD) for 24-weeks. Assays of metabolism, body composition, bone morphology, and behavior were performed. Results: By lineage tracing, Nav1.8-Cre targeted peripheral sensory neurons, a subpopulation of postganglionic sympathetics, and several regions of the brain. Conditional knockout of TSC2 in Nav1.8-expressing neurons (Nav1.8-TSC2KO) selectively upregulated neuronal mTORC1 signaling. Male, but not female, Nav1.8-TSC2KO mice had a 4–10% decrease in body size at baseline. When challenged with HFD, both male and female Nav1.8-TSC2KO mice resisted diet-induced gains in body mass. However, this did not protect against HFD-induced metabolic dysfunction and bone loss. In addition, despite not gaining weight, Nav1.8-TSC2KO mice fed HFD still developed high body fat, a unique phenotype previously referred to as ‘normal weight obesity’. Nav1.8-TSC2KO mice also had signs of chronic itch, mild increases in anxiety-like behavior, and sex-specific alterations in HFD-induced fat distribution that led to enhanced visceral obesity in males and preferential deposition of subcutaneous fat in females. Conclusions: Knockout of TSC2 in Nav1.8+ neurons increases itch- and anxiety-like behaviors and substantially modifies fat storage and metabolic responses to HFD. Though this prevents HFD-induced weight gain, it masks depot-specific fat expansion and persistent detrimental effects on metabolic health and peripheral organs such as bone, mimicking the ‘normal weight obesity’ phenotype that is of growing concern. This supports a mechanism by which increased neuronal mTOR signaling can predispose to altered adipose tissue distribution, adipose tissue expansion, impaired peripheral metabolism, and detrimental changes to skeletal health with HFD – despite resistance to weight gain.

As animals mature from embryonic to adult stages, the skin grows and acquires specialized appendages, like hairs, feathers, and scales. How cutaneous blood vessels and sensory axons adapt to these dramatic changes is poorly understood. By characterizing skin maturation in zebrafish, we discovered that sensory axons are delivered to the adult epidermis in organized nerves patterned by features in bony scales. These nerves associate with blood vessels and osteoblasts above scales. Osteoblasts create paths in scales that independently guide nerves and blood vessels during both development and regeneration. By preventing scale regeneration and examining mutants lacking scales, we found that scales recruit, organize, and polarize axons and blood vessels to evenly distribute them in the skin. These studies uncover mechanisms for achieving comprehensive innervation and vascularization of the adult skin and suggest that scales coordinate a metamorphosis-like transformation of the skin with sensory axon and vascular remodeling.

Sensory afferent fibers are an important component of motor nerves and compose the majority of axons in many nerves traditionally thought of as "pure" motor nerves. These sensory afferent fibers innervate special sensory end organs in muscle, including muscle spindles that respond to changes in muscle length and Golgi tendons that detect muscle tension. Both play a major role in proprioception, sensorimotor extremity control feedback, and force regulation. After peripheral nerve injury, there is histological and electrophysiological evidence that sensory afferents can reinnervate muscle, including muscle that was not the nerve's original target. Reinnervation can occur after different nerve injury and muscle models, including muscle graft, crush, and transection injuries, and occurs in a nonspecific manner, allowing for cross‐innervation to occur. Evidence of cross‐innervation includes the following: muscle spindle and Golgi tendon afferent‐receptor mismatch, vagal sensory fiber reinnervation of muscle, and cutaneous afferent reinnervation of muscle spindle or Golgi tendons. There are several notable clinical applications of sensory reinnervation and cross‐reinnervation of muscle, including restoration of optimal motor control after peripheral nerve repair, flap sensation, sensory protection of denervated muscle, neuroma treatment and prevention, and facilitation of prosthetic sensorimotor control. This review focuses on sensory nerve regeneration and reinnervation in muscle, and the clinical applications of this phenomena. Understanding the physiology and limitations of sensory nerve regeneration and reinnervation in muscle may ultimately facilitate improvement of its clinical applications. [ABSTRACT FROM AUTHOR]

Objectives: Nerve growth factor (NGF) and sensory nerves are key factors in established osteoarthritis (OA) knee pain. We investigated the time course of NGF expression and sensory nerve growth across early and late stages of OA progression in rat knees.Design: Knee OA was induced by medial meniscectomy in rats. OA histopathology, NGF expression, and calcitonin gene-related peptide immunoreactive (CGRP-IR) nerves were quantified pre-surgery and post-surgery at weeks 1, 2, 4 and 6. Pain-related behavior was evaluated using dynamic weight distribution and mechanical sensitivity of the hind paw.Results: NGF expression in chondrocytes increased from week 1 and remained elevated until the advanced stage. In synovium, NGF expression increased only in early stages, whereas in osteochondral channels and bone marrow, NGF expression increased in the later stages of OA progression. CGRP-IR nerve density in suprapatellar pouch peaked at week 4 and decreased at week 6, whereas in osteochondral channels and bone marrow, CGRP-IR innervation increased through week 6. Percent ipsilateral weight-bearing decreased throughout the OA time course, whereas reduced paw withdrawal thresholds were observed only in later stages.Conclusion: During progression of knee OA, time-dependent alterations of NGF expression and CGRP-IR sensory innervation are knee tissue specific. NGF expression increased in early stages and decreased in advanced stage in the synovium but continued to increase in osteochondral channels and bone marrow. Increases in CGRP- IR sensory innervation followed increases in NGF expression, implicating that NGF is a key driver of articular nerve growth associated with OA pain. [ABSTRACT FROM AUTHOR]

Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone's abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment. [ABSTRACT FROM AUTHOR]

The joints have abundant sensory nerves and sympathetic nerve fibers,which convert physical and chemical stimuli in the joints into nerve impulses that are transmitted to the central nervous system and participate in the hypersensitivity reactions of inflammatory joint diseases such as osteoarthritis (OA).This paper summarizes the distribution and functional characteristics of intra-articular nerves and focuses on the mechanism of the vagus-sympathetic autonomic circuit in regulating the immune microenvironment in joints in the case of OA.In addition,intra-articular inflammatory cytokines represented by tumor necrosis factor-α and interleukin-6 directly or indirectly induce sensory nerve action potential and activate the pain transduction pathway from the local joint to the central nervous system.The sensory nerves in the joints in the case of OA are also involved in the recruitment of immune cells and inflammatory cytokines.This neuro-immune interaction model not only provides a variety of new targets for the treatment of OA but also suggests that the treatment of OA should adopt a holistic view with comprehensive consideration of the nerve and immune microenvironment in the bone and joint and their mutual influences.

Abstract Background Toll-like receptor 7 (TLR7) is an innate immune receptor that detects viral single-stranded RNA and triggers the production of proinflammatory cytokines and type 1 interferons in immune cells. TLR7 agonists also modulate sensory nerve function by increasing neuronal excitability, although studies are conflicting whether sensory neurons specifically express TLR7. This uncertainty has confounded the development of a mechanistic understanding of TLR7 function in nervous tissues. Methods TLR7 expression was tested using in situ hybridization with species-specific RNA probes in vagal and dorsal root sensory ganglia in wild-type and TLR7 knockout (KO) mice and in guinea pigs. Since TLR7 KO mice were generated by inserting an Escherichia coli lacZ gene in exon 3 of the mouse TLR7 gene, wild-type and TLR7 (KO) mouse vagal ganglia were also labeled for lacZ. In situ labeling was compared to immunohistochemistry using TLR7 antibody probes. The effects of influenza A infection on TLR7 expression in sensory ganglia and in the spleen were also assessed. Results In situ probes detected TLR7 in the spleen and in small support cells adjacent to sensory neurons in the dorsal root and vagal ganglia in wild-type mice and guinea pigs, but not in TLR7 KO mice. TLR7 was co-expressed with the macrophage marker Iba1 and the satellite glial cell marker GFAP, but not with the neuronal marker PGP9.5, indicating that TLR7 is not expressed by sensory nerves in either vagal or dorsal root ganglia in mice or guinea pigs. In contrast, TLR7 antibodies labeled small- and medium-sized neurons in wild-type and TLR7 KO mice in a TLR7-independent manner. Influenza A infection caused significant weight loss and upregulation of TLR7 in the spleens, but not in vagal ganglia, in mice. Conclusion TLR7 is expressed by macrophages and satellite glial cells, but not neurons in sensory ganglia suggesting TLR7’s neuromodulatory effects are mediated indirectly via activation of neuronally-associated support cells, not through activation of neurons directly. Our data also suggest TLR7’s primary role in neuronal tissues is not related to antiviral immunity.

Recent studies have demonstrated that immunological disease progression is closely related to abnormal function of the central nervous system (CNS). Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic immune disease of unknown etiology. In addition to joint pathological damage, RA has been linked to neuropsychiatric comorbidities, including depression, schizophrenia, and anxiety, increasing the risk of neurodegenerative diseases in life. Immune cells and their secreted immune factors will stimulate the peripheral and central neuronal systems that regulate innate and adaptive immunity. The understanding of autoimmune diseases has largely advanced insights into the molecular mechanisms of neuroimmune interaction. Here, we review our current understanding of CNS comorbidities and potential physiological mechanisms in patients with RA, with a focus on the complex and diverse regulation of mood and distinct patterns of peripheral immune activation in patients with rheumatoid arthritis. And in our review, we also discussed the role that has been played by peripheral neurons and CNS in terms of neuron mechanisms in RA immune challenges, and the related neuron-immune crosstalk. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous inflammatory airway disease that develops in response to a combination of genetic predisposition and environmental exposures. Patients with asthma are grouped into phenotypes with shared clinical features and biomarker profiles to help tailor specific therapies. However, factors driving development of specific phenotypes are poorly understood. Prenatal exposure to maternal asthma is a unique risk factor for childhood asthma. Here we tested whether maternal asthma skews asthma phenotypes in offspring. We compared airway hyperreactivity and inflammatory and neurotrophin lung signatures before and after allergen challenge in offspring born to mice exposed to house dust mite (HDM) or vehicle during pregnancy. Maternal HDM exposure potentiated offspring responses to HDM allergen, significantly increasing both airway hyperreactivity and airway eosinophilia compared with control mice. Maternal HDM exposure broadly skewed the offspring cytokine response from a classic allergen-induced T-helper cell type 2 (Th2)-predominant signature in HDM-treated offspring of vehicle-exposed mothers, toward a mixed Th17/Th1 phenotype in HDM-treated offspring of HDM-exposed mothers. Morphologic analysis determined that maternal HDM exposure also increased airway epithelial sensory nerve density and induced distinct neurotrophin signatures to support airway hyperinnervation. Our results demonstrate that maternal allergen exposure alters fetal lung development and promotes a unique inflammatory phenotype at baseline and in response to allergen that persists into adulthood. [ABSTRACT FROM AUTHOR]

"Nasal hyperreactivity" is a key feature in various phenotypes of upper airway diseases, whereby reactions of the nasal epithelium to diverse chemical and physical stimuli are exacerbated. In this review, we illustrate how nasal hyperreactivity can result from at least three types of mechanisms: (1) impaired barrier function, (2) hypersensitivity to external and endogenous stimuli, and (3) potentiation of efferent systems. We describe the known molecular basis of hyperreactivity related to the functional impairment of epithelial cells and somatosensory innervation, and indicate that the thermal, chemical, and mechanical sensors determining hyperreactivity in humans remain to be identified. We delineate research directions that may provide new insights into nasal hyperreactivity associated with rhinitis/rhinosinusitis pathophysiology and therapeutics. The elucidation of the molecular mechanisms underlying nasal hyperreactivity is essential for the treatment of rhinitis according to the precepts of precision medicine. [ABSTRACT FROM AUTHOR]

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis. [ABSTRACT FROM AUTHOR]

Objective: Restless legs syndrome (RLS) presents with sensory symptoms such as burning in the legs, patients want to move their legs. Symptoms become apparent at rest and at night. The aim of this study was to investigate the relationship between sensory nerve conduction and hematologic parameters in RLS. Materials and Methods: Forty-five patients with RLS and 45 healthy controls were included in the study. Age, sex, and chronic diseases of the patients were questioned. Hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and ferritin values were recorded. Ulnar, median, and sural sensory nerve amplitude, latency and conduction velocity were evaluated in a electroneuromyography laboratory. Data were analyzed using descriptive, parametric and nonparametric tests with the SPSS 21 software. Results: There were 22 (49%) female and 23 (51%) male patients with RLS in the study. The mean age was 57.31±14.47 years. Mean blood values were as follows: Hemoglobin (g/dl) 14.06±1.88; MCV (fl) 85.70 (55.7-96.5); MCH (pg) 28.45 (17.6-32.5), and ferritin (ng/ml) 31.30 (4-848). There was no difference in terms of blood values between RLS and control group (p>0.05). Sural nerve conduction velocity was slower in patients with RLS (p=0.01). Sural nerve latency was longer (p=0.01). Other nerve conduction parameters were equal in the study and control groups (p>0.05) Conclusion: Central nervous system dopaminergic mechanisms, genetic transmission, and low ferritin levels are the main factors in the pathogenesis of RLS. There is less focus on the peripheral nervous system. In this study, sural nerve conduction velocity and latency were associated with RLS. However, there was no correlation between ferritin levels and nerve conduction.

New Findings: What is the central question of this study?Are sensory nerve‐mediated vasodilatation and the NO‐dependent contribution to that response attenuated in the cutaneous microvasculature of women who have had preeclampsia?What is the main finding and its importance?Women who have had preeclampsia demonstrate attenuated microvascular endothelium‐dependent dilatation compared to women with a history of uncomplicated pregnancy. However, there are no differences in sensory nerve‐mediated vasodilatation between groups. This suggests that the neurogenic response is not altered following preeclampsia, and that the NO‐dependent vasodilatation of the neurogenic response is not related to endothelium‐dependent NO‐mediated dilatation in these women. Women who have had preeclampsia (PE) demonstrate microvascular endothelial dysfunction, mediated in part by reduced nitric oxide (NO)‐dependent mechanisms. Localized heating of the skin induces a biphasic vasodilatation response: a sensory nerve‐mediated initial peak, followed by a sustained endothelium‐dependent plateau. We have previously shown that the endothelium‐dependent plateau is attenuated in PE. However, it is unknown if the sensory nerve‐mediated initial peak is similarly attenuated. Therefore, the purpose of this study was to examine the effect of PE history on sensory nerve‐mediated vasodilatation and the NO‐dependent contribution to that response. We hypothesized that PE would have an attenuated initial peak and a reduced NO‐dependent contribution to that response compared to women with a history of normotensive pregnancy (healthy controls, HC). Nine HC (31 ± 4 years) and nine PE (28 ± 6 years) underwent a standard local heating protocol (42°C; 0.1°C s–1). Two intradermal microdialysis fibres were placed in the skin of the ventral forearm for the continuous local delivery of lactated Ringer solution alone (control) or 15‐mM NG‐nitro‐l‐arginine methyl ester for nitric oxide synthase (NOS) inhibition. Red blood cell flux was measured at each site by laser Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28‐mM SNP + local heat 43°C). There were no differences in the initial peak between groups (HC: 79 ± 8 vs. PE: 80 ± 10%CVCmax; P = 0.936). NOS inhibition attenuated the initial peak in both HC (57 ± 18% CVCmax; P = 0.003) and PE (54 ± 10%CVCmax; P = 0.002). However, there were no differences in the NO‐dependent portion of the initial peak (HC: 23 ± 16 vs. PE: 24 ± 9%; P = 0.777). The local heating plateau (HC: 99 ± 4 vs. PE: 88 ± 7%CVCmax; P = 0.001) and NO contribution to the plateau (HC: 31 ± 9 vs. PE: 17 ± 14%; P = 0.02) were attenuated in PE. There was no relation between NO‐dependent dilatation in the initial peak and NO‐dependent dilatation in the plateau across groups (R2 = 0.005; P = 0.943). Women who have had PE demonstrate attenuated microvascular endothelium‐dependent dilatation. However, there are no differences in sensory nerve‐mediated vasodilatation following PE, suggesting that the NO‐dependent vasodilatation of the neurogenic response is not related to endothelium‐dependent NO‐mediated dilatation in these women. [ABSTRACT FROM AUTHOR]

Objectives: To assess the influence of age and gender on sensory nerve axonal excitability parameters. Methods: Thirty‐three healthy subjects (21 women) were included, with a mean age of 34.6 (range 21–76). Median sensory nerve excitability measurements (index finger) were performed using the TRONDNF nerve excitability protocol of the QTRAC program. Results: Peak sensory nerve action potential (SNAP) amplitude was significantly higher among women (27.1 vs. 9.2 μV; p =.022), and strength–duration time constant (SDTC) was significantly higher in men (0.7 vs. 0.5; p =.011), not dependent on age. Greater age was negatively correlated with resting I/V slope, not dependent on gender (r = –0.4; p =.024). No other changes in excitability properties with increasing age were found. Conclusions: Physiological features like as age and gender do not have a relevant impact on sensory nerve excitability measurements, which can have implications regarding pharmacological treatments. [ABSTRACT FROM AUTHOR]

Sensory and motor nerve fibers of peripheral nerves have different anatomies and regeneration functions after injury. To gain a clear understanding of the biological processes behind these differences, we used a labeling technique termed isobaric tags for relative and absolute quantitation to investigate the protein profiles of spinal nerve tissues from Sprague-Dawley rats. In response to Wallerian degeneration, a total of 626 proteins were screened in sensory nerves, of which 368 were upregulated and 258 were downregulated. In addition, 637 proteins were screened in motor nerves, of which 372 were upregulated and 265 were downregulated. All identified proteins were analyzed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of bioinformatics, and the presence of several key proteins closely related to Wallerian degeneration were tested and verified using quantitative real-time polymerase chain reaction analyses. The differentially expressed proteins only identified in the sensory nerves were mainly relevant to various biological processes that included cell-cell adhesion, carbohydrate metabolic processes and cell adhesion, whereas differentially expressed proteins only identified in the motor nerves were mainly relevant to biological processes associated with the glycolytic process, cell redox homeostasis, and protein folding. In the aspect of the cellular component, the differentially expressed proteins in the sensory and motor nerves were commonly related to extracellular exosomes, the myelin sheath, and focal adhesion. According to the Kyoto Encyclopedia of Genes and Genomes, the differentially expressed proteins identified are primarily related to various types of metabolic pathways. In conclusion, the present study screened differentially expressed proteins to reveal more about the di?erences and similarities between sensory and motor nerves during Wallerian degeneration. The present findings could provide a reference point for a future investigation into the differences between sensory and motor nerves in Wallerian degeneration and the characteristics of peripheral nerve regeneration. The study was approved by the Ethics Committee of the Chinese PLA General Hospital, China (approval No. 2016-x9-07) in September 2016.

Abstract Objectives To assess the influence of age and gender on sensory nerve axonal excitability parameters. Methods Thirty‐three healthy subjects (21 women) were included, with a mean age of 34.6 (range 21–76). Median sensory nerve excitability measurements (index finger) were performed using the TRONDNF nerve excitability protocol of the QTRAC program. Results Peak sensory nerve action potential (SNAP) amplitude was significantly higher among women (27.1 vs. 9.2 μV; p = .022), and strength–duration time constant (SDTC) was significantly higher in men (0.7 vs. 0.5; p = .011), not dependent on age. Greater age was negatively correlated with resting I/V slope, not dependent on gender (r = –0.4; p = .024). No other changes in excitability properties with increasing age were found. Conclusions Physiological features like as age and gender do not have a relevant impact on sensory nerve excitability measurements, which can have implications regarding pharmacological treatments.

We developed a rat dorsal root ganglion (DRG)-derived sensory nerve organotypic model by culturing DRG explants on an organoid culture device. With this method, a large number of organotypic cultures can be produced simultaneously with high reproducibility simply by seeding DRG explants derived from rat embryos. Unlike previous DRG explant models, this organotypic model consists of a ganglion and an axon bundle with myelinated A fibers, unmyelinated C fibers, and stereo-myelin-forming nodes of Ranvier. The model also exhibits Ca 2+ signaling in cell bodies in response to application of chemical stimuli to nerve terminals. Further, axonal transection increases the activating transcription factor 3 mRNA level in ganglia. Axons and myelin are shown to regenerate 14 days following transection. Our sensory organotypic model enables analysis of neuronal excitability in response to pain stimuli and tracking of morphological changes in the axon bundle over weeks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain., Competing Interests: DP, KB, XH, JZ, VK, JZ, XC No competing interests declared, MW Reviewing editor, eLife, (© 2023, Pan et al.)

Background: Toll-like receptor 7 (TLR7) is an innate immune receptor that detects viral single-stranded RNA and triggers the production of proinflammatory cytokines and type 1 interferons in immune cells. TLR7 agonists also modulate sensory nerve function by increasing neuronal excitability, although studies are conflicting whether sensory neurons specifically express TLR7. This uncertainty has confounded the development of a mechanistic understanding of TLR7 function in nervous tissues.Methods: TLR7 expression was tested using in situ hybridization with species-specific RNA probes in vagal and dorsal root sensory ganglia in wild-type and TLR7 knockout (KO) mice and in guinea pigs. Since TLR7 KO mice were generated by inserting an Escherichia coli lacZ gene in exon 3 of the mouse TLR7 gene, wild-type and TLR7 (KO) mouse vagal ganglia were also labeled for lacZ. In situ labeling was compared to immunohistochemistry using TLR7 antibody probes. The effects of influenza A infection on TLR7 expression in sensory ganglia and in the spleen were also assessed.Results: In situ probes detected TLR7 in the spleen and in small support cells adjacent to sensory neurons in the dorsal root and vagal ganglia in wild-type mice and guinea pigs, but not in TLR7 KO mice. TLR7 was co-expressed with the macrophage marker Iba1 and the satellite glial cell marker GFAP, but not with the neuronal marker PGP9.5, indicating that TLR7 is not expressed by sensory nerves in either vagal or dorsal root ganglia in mice or guinea pigs. In contrast, TLR7 antibodies labeled small- and medium-sized neurons in wild-type and TLR7 KO mice in a TLR7-independent manner. Influenza A infection caused significant weight loss and upregulation of TLR7 in the spleens, but not in vagal ganglia, in mice.Conclusion: TLR7 is expressed by macrophages and satellite glial cells, but not neurons in sensory ganglia suggesting TLR7's neuromodulatory effects are mediated indirectly via activation of neuronally-associated support cells, not through activation of neurons directly. Our data also suggest TLR7's primary role in neuronal tissues is not related to antiviral immunity. [ABSTRACT FROM AUTHOR]

Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone’s abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment.

Genicular nerve radiofrequency ablation (RFA) is increasingly being performed to treat chronic pain due to knee osteoarthritis (KOA). This narrative review provides a concise summary of the relevant neuroanatomy, randomized controlled trials, appropriate patient selection, and safety relating to genicular RFA. Cadaveric studies demonstrate significant variability in the location of the genicular nerves, which has stimulated debate about the ideal target locations for genicular RFA. Despite this, favorable outcomes have been observed in studies targeting only the superior medial genicular nerve, inferior medial genicular nerve, and superior lateral genicular nerve. Several randomized controlled trials demonstrate superiority of genicular RFA compared with intra-articular steroid, viscosupplementation, and oral analgesics. Genicular RFA of the superior medial genicular nerve, inferior medial genicular nerve, and superior lateral genicular nerve appears to be an effective treatment for painful KOA, but targeting additional sensory nerves may further improve treatment success. Although genicular RFA appears relatively safe on the basis of the available data, additional large-scale studies are needed to provide greater confidence. [ABSTRACT FROM AUTHOR]

[Display omitted] The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping–induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping–induced disruption. Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury. [ABSTRACT FROM AUTHOR]

BackgroundAlthough the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear.ObjectiveWe sought to determine whether immune cell-derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31-induced itch.MethodsWe used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects.ResultsAmong all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31-induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)-deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca(2+) release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31-induced scratching in vivo.ConclusionIL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA(+)/TRPV1(+)/TRPA1(+) neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma.

Recent studies have demonstrated that immunological disease progression is closely related to abnormal function of the central nervous system (CNS). Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic immune disease of unknown etiology. In addition to joint pathological damage, RA has been linked to neuropsychiatric comorbidities, including depression, schizophrenia, and anxiety, increasing the risk of neurodegenerative diseases in life. Immune cells and their secreted immune factors will stimulate the peripheral and central neuronal systems that regulate innate and adaptive immunity. The understanding of autoimmune diseases has largely advanced insights into the molecular mechanisms of neuroimmune interaction. Here, we review our current understanding of CNS comorbidities and potential physiological mechanisms in patients with RA, with a focus on the complex and diverse regulation of mood and distinct patterns of peripheral immune activation in patients with rheumatoid arthritis. And in our review, we also discussed the role that has been played by peripheral neurons and CNS in terms of neuron mechanisms in RA immune challenges, and the related neuron-immune crosstalk.