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Background: IL-1β plays a critical role in the pathophysiology of neuroinflammation. The presence of cleaved IL-1β (cIL-1β) in the neurons of the dorsal root ganglion (DRG) implicates its function in biological signaling arising from the sensory neuron. This study was conducted to analyze the role of IL-1β in nociceptive transduction after tissue injury. Methods: A plantar incision was made in C57BL/6 mice, following which immunohistochemistry and RNA scope in situ hybridization were performed at various time points to analyze cIL-1β, caspase-1, and IL-1 receptor 1 (IL-1R1) expression in the DRG. The effect of intrathecal administration of a caspase-1 inhibitor or regional anesthesia using local anesthetics on cIL-1β expression and pain hypersensitivity was analyzed by immunohistochemistry and behavioral analysis. ERK phosphorylation was also analyzed to investigate the effect of IL-1β on the activity of spinal dorsal horn neurons. Results: cIL-1β expression was significantly increased in caspase-1-positive DRG neurons 5 min after the plantar incision. Intrathecal caspase-1 inhibitor treatment inhibited IL-1β cleavage and pain hypersensitivity after the plantar incision. IL-1R1 was also detected in the DRG neurons, although the majority of IL-1R1-expressing neurons lacked cIL-1β expression. Regional anesthesia using local anesthetics prevented cIL-1β processing. Plantar incision-induced phosphorylation of ERK was inhibited by the caspase-1 inhibitor. Conclusion: IL-1β in the DRG neuron undergoes rapid cleavage in response to tissue injury in an activity-dependent manner. Cleaved IL-1β causes injury-induced functional activation of sensory neurons and pain hypersensitivity. IL-1β in the primary afferent neurons is involved in physiological nociceptive signal transduction. [ABSTRACT FROM AUTHOR]

Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aβ), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aβ), the goal of this work was to examine Aβ-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aβ-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin. [ABSTRACT FROM AUTHOR]

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a chronic, non-infectious condition affecting the nasal mucosa, primarily mediated mainly by IgE. Recent studies reveal that AR is intricately associated not only with type 2 immunity but also with neuroimmunity. Nociceptive neurons, a subset of primary sensory neurons, are pivotal in detecting external nociceptive stimuli and modulating immune responses. This review examines nociceptive neuron receptors and elucidates how neuropeptides released by these neurons impact the immune system. Additionally, we summarize the role of immune cells and inflammatory mediators on nociceptive neurons. A comprehensive understanding of the dynamic interplay between nociceptive neurons and the immune system augments our understanding of the neuroimmune mechanisms underlying AR, thereby opening novel avenues for AR treatment modalities. [ABSTRACT FROM AUTHOR]

Background: Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants. Methods: We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(−/−) and TRPV1(−/−) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo. Results: Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(−/−) mouse DRG neurons but was not significant in the TRPV1(−/−) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(−/−) mice. Conclusions: These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole. [ABSTRACT FROM AUTHOR]

Background: Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants. Methods: We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(−/−) and TRPV1(−/−) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo. Results: Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(−/−) mouse DRG neurons but was not significant in the TRPV1(−/−) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(−/−) mice. Conclusions: These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose–response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

The evolutionary expansion of sensory neuron populations detecting important environmental cues is widespread, but functionally enigmatic. We investigated this phenomenon through comparison of homologous olfactory pathways of Drosophila melanogaster and its close relative Drosophila sechellia, an extreme specialist for Morinda citrifolia noni fruit. D. sechellia has evolved species-specific expansions in select, noni-detecting olfactory sensory neuron (OSN) populations, through multigenic changes. Activation and inhibition of defined proportions of neurons demonstrate that OSN number increases contribute to stronger, more persistent, noni-odour tracking behaviour. These expansions result in increased synaptic connections of sensory neurons with their projection neuron (PN) partners, which are conserved in number between species. Surprisingly, having more OSNs does not lead to greater odour-evoked PN sensitivity or reliability. Rather, pathways with increased sensory pooling exhibit reduced PN adaptation, likely through weakened lateral inhibition. Our work reveals an unexpected functional impact of sensory neuron population expansions to explain ecologically-relevant, species-specific behaviour. Sensory neuron population expansions are common in evolution but of unclear function. Here, the authors show that, in drosophilid olfactory systems, increased sensory neuron number impacts interneuron dynamics, but not sensitivity, to promote olfactory-guided behaviour. [ABSTRACT FROM AUTHOR]

Insects rely on olfaction for mating, finding oviposition sites, and locating hosts. Hyphantria cunea is a serious pest that severely damages forests. Differential expression analysis of olfactory-related genes between males and females is the basis for elucidating the functions of olfactory-related proteins in H. cunea. In this study, Illumina HiSeqTM 4000 high-throughput sequencing technology was used to perform transcriptome sequencing of the antennal tissues of adult male and female H. cunea. Functional annotation was conducted using the NR, Swiss-Prot, KOG, KEGG, and GO databases, and the results showed that the antennal transcriptome of adult H. cunea contained 50,158 unigenes. Differential expression analysis identified 3923 genes that were significantly differentially expressed between male and female antennae. A total of 221 olfactory-related genes were annotated, and 96 sex-biased genes were identified, including 13 odorant receptors (ORs), 48 odorant binding proteins (OBPs), 7 chemosensory proteins (CSPs), 10 ionotropic receptors (IRs), 10 sensory neuron membrane proteins (SNMPs), 2 gustatory receptors (GRs), and 6 odorant-degrading enzymes (ODEs), indicating that there were differences in olfaction between male and female H. cunea. Quantitative real-time PCR was used to verify the expression levels of 21 putative general odorant receptor genes in male and female antennae. HcunOR4 and HcunOR5 showed female-biased expression; HcunOR48, HcunOR49 and HcunOR50 showed male-biased expression. The results were consistent with the transcriptome differential analysis. The screening of male-biased odorant receptor genes might provide a theoretical basis for the functional characterization of odorant receptors for recognizing sex pheromones in H. cunea. [ABSTRACT FROM AUTHOR]

The TRESK (K2P18.1, KCNK18) background potassium channel is expressed in primary sensory neurons and has been reported to contribute to the regulation of pain sensations. In the present study, we examined the interaction of TRESK with NDFIP1 (Nedd4 family-interacting protein 1) in the Xenopus oocyte expression system by two-electrode voltage clamp and biochemical methods. We showed that the coexpression of NDFIP1 abolished the TRESK current under the condition where the other K+ channels were not affected. Mutations in the three PPxY motifs of NDFIP1, which are responsible for the interaction with the Nedd4 ubiquitin ligase, prevented a reduction in the TRESK current. Furthermore, the overexpression of a dominant-negative Nedd4 construct in the oocytes coexpressing TRESK with NDFIP1 partially reversed the down-modulating effect of the adaptor protein on the K+ current. The biochemical data were also consistent with the functional results. An interaction between epitope-tagged versions of TRESK and NDFIP1 was verified by co-immunoprecipitation experiments. The coexpression of NDFIP1 with TRESK induced the ubiquitination of the channel protein. Altogether, the results suggest that TRESK is directly controlled by and highly sensitive to the activation of the NDFIP1-Nedd4 system. The NDFIP1-mediated reduction in the TRESK component may induce depolarization, increase excitability, and attenuate the calcium dependence of the membrane potential by reducing the calcineurin-activated fraction in the ensemble background K+ current. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting KATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that KATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction. [ABSTRACT FROM AUTHOR]

Graphosoma rubrolineatum (Hemiptera: Pentatomidae) is an important pest of vegetables and herbs (e.g., Umbelliferae and Cruciferae) in China, Siberia, Korea, and Japan. Insects are highly dependent on their olfactory system to detect odorants. However, no molecular-mediated olfactory genes in G. rubrolineatum have yet been identified. In this study, we first established the antennal transcriptome of G. rubrolineatum and identified 189 candidate olfactory genes, including 31 odorant-binding proteins (OBPs), 15 chemosensory proteins (CSPs), four sensory neuron membrane proteins (SNMPs),94 odorant receptors (ORs), 23 ionotropic receptors (IRs), and 22 gustatory receptors (GRs). Additionally, phylogenetic trees were constructed for olfactory genes between G. rubrolineatum and other hemipteran insects. We also detected the expression profiles of ten OBPs, five CSPs, two SNMPs, five ORs, four IRs, and four GRs by real-time quantitative PCR. The results revealed that most genes (GrubOBP1/11/31, GrubCSP3/8, GrubSNMP1a/1b, GrubOrco/OR9/11/13, GrubGR1/4/22, GrubIR25/75h/76b/GluR1) were highly expressed in the antennae, GrubOBP13/31 and GrubCSP4/11/12 were highly expressed in the legs, while GrubOBP20 and GrubGR19 were highly expressed in the wings. Our results will enrich the gene inventory of G. rubrolineatum and provide further insight into the molecular chemosensory mechanisms of G. rubrolineatum. [ABSTRACT FROM AUTHOR]

Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration–response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain. [ABSTRACT FROM AUTHOR]

Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1 −/− but not Trpa1 −/− mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1 −/− mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons. [ABSTRACT FROM AUTHOR]

This article discusses the role of sensory neurons in tissue repair and regeneration, particularly in the context of diabetic and neuropathic conditions. The authors found that nociceptive sensory neurons release calcitonin gene-related peptide (CGRP) in response to acute injury, which modulates immune cells and creates an anti-inflammatory and pro-healing environment. However, in diabetic patients, there is a decrease in CGRP levels, which may contribute to impaired tissue healing. The authors propose that delivering engineered CGRP or CGRP analogues could be a potential therapeutic strategy to promote tissue healing in diabetic patients and other conditions where immune responses are dysfunctional. However, caution is needed when using CGRP inhibitors, as they may impair wound healing. Overall, this discovery has the potential to improve healing outcomes and enhance quality of life for patients with various conditions. [Extracted from the article]

Herpes zoster (HZ), resulting from the reactivation of the varicella‐zoster virus, is a significant disease. This study aimed to explore the factors influencing sensory neuron involvement in HZ at different locations and its association with postherpetic neuralgia (PHN). A total of 3143 cases were retrieved from an electronic medical record system, including 2676 cases of HZ and 467 cases of PHN. Gender, age, site of onset, past surgical history, and comorbidities were analyzed using a multifactorial logistic regression model. The results revealed correlations between age, gender, comorbidities (diabetes, coronary heart disease, percutaneous coronary intervention [PCI]), and sensory neuron involvement in HZ. Specifically, older age, female gender, and comorbid conditions such as diabetes/coronary heart disease were associated with sacral dorsal root ganglion (DRG) involvement, while PCI history was associated with lumbar DRG involvement. Additionally, sensory neuron involvement at different locations by HZ was linked to PHN. Furthermore, independent risk factors for PHN included thoracic DRG involvement, older age, and comorbidities (diabetes, surgical history, malignancy). It is crucial to prevent damage to the DRG, especially in individuals with comorbidities, through activities avoidance and active treatment, to minimize the occurrence of PHN. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to explore manipulation of the Myc protein interactome, members of an oncogene group, in enhancing the intrinsic growth of injured peripheral adult postmitotic neurons and the nerves they supply. New approaches to enhance adult neuron growth properties are a key strategy in improving nerve regeneration. Methods: Expression and impact of Myc interactome members c‐Myc, N‐Myc, Mad1, and Max were evaluated within naive and "preconditioned" adult sensory neurons and Schwann cells (SCs), using siRNA and transfection of CRISPR/Cas9 or luciferase reporter in vitro. Morphological, behavioral, and electrophysiological indices of nerve regeneration were analyzed in vivo. Results: c‐Myc, N‐Myc, Max, and Mad were expressed in adult sensory neurons and in partnering SCs. In vitro knockdown (KD) of either Mad1 or Max, competitive inhibitors of Myc, unleashed heightened neurite outgrowth in both naive uninjured or preconditioned adult neurons. In contrast, KD or inhibition of both isoforms of Myc was required to suppress growth. In SCs, Mad1 KD not only enhanced migratory behavior but also conditioned increased outgrowth in separately cultured adult sensory neurons. In vivo, local Mad1 KD improved electrophysiological, behavioral, and structural indices of nerve regeneration out to 60 days of follow‐up. Interpretation: Members of the Myc interactome, specifically Mad1, are novel targets for improving nerve regeneration. Unleashing of Myc growth signaling through Mad1 KD enhances the regrowth of both peripheral neurons and SCs to facilitate better regrowth of nerves. ANN NEUROL 2024;96:216–230 [ABSTRACT FROM AUTHOR]

Sensory neurons densely innervate the myocardium. The role of their sensing and response to acute and prolonged ischemia is largely unclear. In a cellular model of ischemia-reperfusion injury, the presence of sensory neurons increases cardiomyocyte survival. Here, after the exclusion of classical neurotransmitter release, and measurement of cytokine release, we modified the experiment from a direct co-culture of primary murine cardiomyocytes and sensory neurons to a transfer of the supernatant. Sensory neurons were exposed to ischemia and the resulting conditioned supernatant was transferred onto cardiomyocytes. This approach largely increased the tolerance of cardiomyocytes to ischemia and reperfusion. Towards the identification of the mechanism, it was demonstrated that after ten-fold dilution, the conditioned solution lost its protective effect. The effect remained after removal of extracellular vesicles by ultracentrifugation, and was not affected by exposure to protease activity, and fractionation pointed towards a hydrophilic agent. Solutions conditioned by HEK293t cells or 3T3 fibroblasts also increase cardiomyocyte survival, but to a lower degree. A metabolomic search identified 64 at least two-fold changed metabolites and lipids. Many of these could be identified and are involved in essential cellular functions. In the presented model for ischemia-reperfusion, sensory neurons secrete one or more cardioprotective substances that can improve cardiomyocyte survival. [ABSTRACT FROM AUTHOR]

Although methods for generating human induced pluripotent stem cell (hiPSC)-derived motor nerve organoids are well established, those for sensory nerve organoids are not. Therefore, this study investigated the feasibility of generating sensory nerve organoids composed of hiPSC-derived sensory neurons using a microfluidic approach. Notably, sensory neuronal axons from neurospheres containing 100,000 cells were unidirectionally elongated to form sensory nerve organoids over 6 mm long axon bundles within 14 days using I-shaped microchannels in microfluidic devices composed of polydimethylsiloxane (PDMS) chips and glass substrates. Additionally, the organoids were successfully cultured for more than 60 days by exchanging the culture medium. The percentage of nuclei located in the distal part of the axon bundles (the region 3−6 mm from the entrance of the microchannel) compared to the total number of cells in the neurosphere was 0.005% for live cells and 0.008% for dead cells. Molecular characterization confirmed the presence of the sensory neuron marker ISL LIM homeobox 1 (ISL1) and the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Moreover, capsaicin stimulation activated TRPV1 in organoids, as evidenced by significant calcium ion influx. Conclusively, this study demonstrated the feasibility of long-term organoid culture and the potential applications of sensory nerve organoids in bioengineered nociceptive sensors. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a major long-lasting side effect of some chemotherapy drugs, which threatens cancer survival rate. CIPN mostly affects sensory neurons and occasionally motor neurons, causing numbness, tingling, discomfort, and burning pain in the upper and lower extremities. The pathophysiology of CIPN is not completely understood; however, it is believed that chemotherapies induce peripheral neuropathy via directly damaging mitochondria, impairing the function of ion channels, triggering immunological mechanisms, and disrupting microtubules. The treatment of CIPN is a medical challenge, and there are no approved pharmacological options. Currently, duloxetine and other antidepressants, antioxidant, anti-inflammatory, and ion-channel targeted therapies are commonly used in clinics to relieve the symptoms of CIPN. Several other types of drugs, such as cannabinoids, sigma−1 receptor antagonists, and nicotinamides ribose, are being evaluated in preclinical and clinical studies. This paper summarizes the information related to the physiology of CIPN and medicines that could be used for treating this condition. [ABSTRACT FROM AUTHOR]

Introduction: Damage to the corneal nerves can result in discomfort and chronic pain, profoundly impacting the quality of life of patients. Development of novel in vitro method is crucial to better understand corneal nerve regeneration and to find new treatments for the patients. Existing in vitro models often overlook the physiology of primary sensory neurons, for which the soma is separated from the nerve endings. Methods: To overcome this limitation, our novel model combines a compartmentalized microfluidic culture of trigeminal ganglion neurons from adult mice with live-imaging and automated 3D image analysis offering robust way to assess axonal regrowth after axotomy. Results: Physical axotomy performed by a two-second aspiration led to a reproducible 70% axonal loss and altered the phenotype of the neurons, increasing the number of substance P-positive neurons 72h post-axotomy. To validate our new model, we investigated axonal regeneration after exposure to pharmacological compounds. We selected various targets known to enhance or inhibit axonal regrowth and analyzed their basal expression in trigeminal ganglion cells by scRNAseq. NGF/GDNF, insulin, and Dooku-1 (Piezo1 antagonist) enhanced regrowth by 81, 74 and 157%, respectively, while Yoda-1 (Piezo1 agonist) had no effect. Furthermore, SARM1-IN-2 (Sarm1 inhibitor) inhibited axonal regrowth, leading to only 6% regrowth after 72h of exposure (versus 34% regrowth without any compound). Discussion: Combining compartmentalized trigeminal neuronal culture with advanced imaging and analysis allowed a thorough evaluation of the extent of the axotomy and subsequent axonal regrowth. This innovative approach holds great promise for advancing our understanding of corneal nerve injuries and regeneration and ultimately improving the quality of life for patients suffering from sensory abnormalities, and related conditions. [ABSTRACT FROM AUTHOR]

Background: The identification of novel toxins from overlooked and taxonomically exceptional species bears potential for various pharmacological applications. The remipede Xibalbanus tulumensis, an underwater cave-dwelling crustacean, is the only crustacean for which a venom system has been described. Its venom contains several xibalbin peptides that have an inhibitor cysteine knot (ICK) scaffold. Results: Our screenings revealed that all tested xibalbin variants particularly inhibit potassium channels. Xib1 and xib13 with their eight-cysteine domain similar to spider knottins also inhibit voltage-gated sodium channels. No activity was noted on calcium channels. Expanding the functional testing, we demonstrate that xib1 and xib13 increase PKA-II and Erk1/2 sensitization signaling in nociceptive neurons, which may initiate pain sensitization. Our phylogenetic analysis suggests that xib13 either originates from the common ancestor of pancrustaceans or earlier while xib1 is more restricted to remipedes. The ten-cysteine scaffolded xib2 emerged from xib1, a result that is supported by our phylogenetic and machine learning-based analyses. Conclusions: Our functional characterization of synthesized variants of xib1, xib2, and xib13 elucidates their potential as inhibitors of potassium channels in mammalian systems. The specific interaction of xib2 with Kv1.6 channels, which are relevant to treating variants of epilepsy, shows potential for further studies. At higher concentrations, xib1 and xib13 activate the kinases PKA-II and ERK1/2 in mammalian sensory neurons, suggesting pain sensitization and potential applications related to pain research and therapy. While tested insect channels suggest that all probably act as neurotoxins, the biological function of xib1, xib2, and xib13 requires further elucidation. A novel finding on their evolutionary origin is the apparent emergence of X. tulumensis-specific xib2 from xib1. Our study is an important cornerstone for future studies to untangle the origin and function of these enigmatic proteins as important components of remipede but also other pancrustacean and arthropod venoms. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic. [ABSTRACT FROM AUTHOR]

Peripheral nerve damage often leads to the onset of neuropathic pain (NeuP). This condition afflicts millions of people, significantly burdening healthcare systems and putting strain on families' financial well-being. Here, we will focus on the role of peripheral sensory neurons, specifically the Dorsal Root Ganglia neurons (DRG neurons) in the development of NeuP. After axotomy, DRG neurons activate regenerative signals of axons-soma communication to promote a gene program that activates an axonal branching and elongation processes. The results of a neuronal morphological cytoskeleton change are not always associated with functional recovery. Moreover, any axonal misstargeting may contribute to NeuP development. In this review, we will explore the epidemiology of NeuP and its molecular causes at the level of the peripheral nervous system and the target organs, with major focus on the neuronal crosstalk between intrinsic and extrinsic factors. Specifically, we will describe how failures in the neuronal regenerative program can exacerbate NeuP. [ABSTRACT FROM AUTHOR]

Background: Lucilia cuprina (Wiedemann, 1830) (Diptera: Calliphoridae) is the main causative agent of flystrike of sheep in Australia and New Zealand. Female flies lay eggs in an open wound or natural orifice, and the developing larvae eat the host's tissues, a condition called myiasis. To improve our understanding of host-seeking behavior, we quantified gene expression in male and female antennae based on their behavior. Methods: A spatial olfactometer was used to evaluate the olfactory response of L. cuprina mated males and gravid females to fresh or rotting beef. Antennal RNA-Seq analysis was used to identify sensory receptors differentially expressed between groups. Results: Lucilia cuprina females were more attracted to rotten compared to fresh beef (> fivefold increase). However, males and some females did not respond to either type of beef. RNA-Seq analysis was performed on antennae dissected from attracted females, non-attracted females and males. Transcripts encoding sensory receptors from 11 gene families were identified above a threshold (≥ 5 transcript per million) including 49 ATP-binding cassette transporters (ABCs), two ammonium transporters (AMTs), 37 odorant receptors (ORs), 16 ionotropic receptors (IRs), 5 gustatory receptors (GRs), 22 odorant-binding proteins (OBPs), 9 CD36-sensory neuron membrane proteins (CD36/SNMPs), 4 chemosensory proteins (CSPs), 4 myeloid lipid-recognition (ML) and Niemann-Pick C2 disease proteins (ML/NPC2), 2 pickpocket receptors (PPKs) and 3 transient receptor potential channels (TRPs). Differential expression analyses identified sex-biased sensory receptors. Conclusions: We identified sensory receptors that were differentially expressed between the antennae of both sexes and hence may be associated with host detection by female flies. The most promising for future investigations were as follows: an odorant receptor (LcupOR46) which is female-biased in L. cuprina and Cochliomyia hominivorax Coquerel, 1858; an ABC transporter (ABC G23.1) that was the sole sensory receptor upregulated in the antennae of females attracted to rotting beef compared to non-attracted females; a female-biased ammonia transporter (AMT_Rh50), which was previously associated with ammonium detection in Drosophila melanogaster Meigen, 1830. This is the first report suggesting a possible role for ABC transporters in L. cuprina olfaction and potentially in other insects. [ABSTRACT FROM AUTHOR]

The red palm weevil (RPW), Rhynchophorus ferrugineus (Olivier), also known as the Asian palm weevil, is an invasive pest that causes widespread damage to palm trees around the globe. As pheromone communication is crucial for their mass attack and survival on palm trees, the olfactory concept of pest control strategies has been widely explored recently. We aim to understand the molecular basis of olfaction in RPW by studying one of the key olfactory proteins in insect pheromone communication, sensory neuron membrane proteins (SNMPs). SNMPs belong to the CD36 (cluster of differentiation 36) family that perform two distinct olfactory roles in insects, either in pheromone (odorant) transfer to the odorant receptors (SNMP1) or in the pheromone clearing process (SNMP2). In this study, we performed antennal transcriptomic screening and identified six SNMPs, mapping them on the R. ferrugineus genome, and confirmed four distinct SNMPs. Both SNMP1 proteins in RPW, viz., RferSNMPu1 and RferSNMPu2, were mapped onto the same scaffold in different loci in the RPW genome. To further understand the function of these proteins, we first classified them using phylogenetic analysis and checked their tissue-specific expression patterns. Further, we measured the relative transcript abundance of SNMPs in laboratory-reared, field-collected adults and pheromone-exposure experiments, ultimately identifying RferSNMPu1 as a potential candidate for functional analysis. We mapped RferSNMPu1 expression in the antennae and found that expression patterns were similar in both sexes. We used RNAi-based gene silencing to knockdown RferSNMPu1 and tested the changes in the RPW responses to aggregation pheromone compounds, 4-methyl-5-nonanol (ferrugineol) and 4-methyl-5-nonanone (ferrugineone), and a kairomone, ethyl acetate using electroantennogram (EAG) recordings. We found a significant reduction in the EAG recordings in the RferSNMPu1 knockdown strain of adult RPWs, confirming its potential role in pheromone detection. The structural modelling revealed the key domains in the RferSNMPu1 structure, which could likely be involved in pheromone detection based on the identified ectodomain tunnels. Our studies on RferSNMPu1 with a putative role in pheromone detection provide valuable insight into understanding the olfaction in R. ferrugineus as well as in other Curculionids, as SNMPs are under-explored in terms of its functional role in insect olfaction. Most importantly, RferSNMPu1 can be used as a potential target for the olfactory communication disruption in the R. ferrugineus control strategies. [ABSTRACT FROM AUTHOR]

Sensory neurons specialize in detecting and signaling the presence of diverse environmental stimuli. Neuronal injury or disease may undermine such signaling, diminishing the availability of crucial information. Can animals distinguish between a stimulus not being present and the inability to sense that stimulus in the first place? To address this question, we studied Caenorhabditis elegans nematode worms that lack gentle body touch sensation due to genetic mechanoreceptor dysfunction. We previously showed that worms can compensate for the loss of touch by enhancing their sense of smell, via an FLP-20 neuropeptide pathway. Here, we find that touch-deficient worms exhibit, in addition to sensory compensation, also cautious-like behavior, as if preemptively avoiding potential undetectable hazards. Intriguingly, these behavioral adjustments are abolished when the touch neurons are removed, suggesting that touch neurons are required for signaling the unavailability of touch information, in addition to their conventional role of signaling touch stimulation. Furthermore, we found that the ASE taste neurons, which similarly to the touch neurons, express the FLP-20 neuropeptide, exhibit altered FLP-20 expression levels in a touch-dependent manner, thus cooperating with the touch circuit. These results imply a novel form of neuronal signaling that enables C. elegans to distinguish between lack of touch stimulation and loss of touch sensation, producing adaptive behavioral adjustments that could overcome the inability to detect potential threats. Sensory loss deprives animals of important information. This study shows that Caenorhabditis elegans worms lacking touch sensation show cautious-like behaviors, indicating that the touch neurons provide not only information about the presence or absence of touch stimuli, but also about the unavailability of touch information. [ABSTRACT FROM AUTHOR]

The efficient coding approach proposes that neural systems represent as much sensory information as biological constraints allow. It aims at formalizing encoding as a constrained optimal process. A different approach, that aims at formalizing decoding, proposes that neural systems instantiate a generative model of the sensory world. Here, we put forth a normative framework that characterizes neural systems as jointly optimizing encoding and decoding. It takes the form of a variational autoencoder: sensory stimuli are encoded in the noisy activity of neurons to be interpreted by a flexible decoder; encoding must allow for an accurate stimulus reconstruction from neural activity. Jointly, neural activity is required to represent the statistics of latent features which are mapped by the decoder into distributions over sensory stimuli; decoding correspondingly optimizes the accuracy of the generative model. This framework yields in a family of encoding-decoding models, which result in equally accurate generative models, indexed by a measure of the stimulus-induced deviation of neural activity from the marginal distribution over neural activity. Each member of this family predicts a specific relation between properties of the sensory neurons—such as the arrangement of the tuning curve means (preferred stimuli) and widths (degrees of selectivity) in the population—as a function of the statistics of the sensory world. Our approach thus generalizes the efficient coding approach. Notably, here, the form of the constraint on the optimization derives from the requirement of an accurate generative model, while it is arbitrary in efficient coding models. Moreover, solutions do not require the knowledge of the stimulus distribution, but are learned on the basis of data samples; the constraint further acts as regularizer, allowing the model to generalize beyond the training data. Finally, we characterize the family of models we obtain through alternate measures of performance, such as the error in stimulus reconstruction. We find that a range of models admits comparable performance; in particular, a population of sensory neurons with broad tuning curves as observed experimentally yields both low reconstruction stimulus error and an accurate generative model that generalizes robustly to unseen data. Author summary: Our brain represents the sensory world in the activity of populations of neurons. Two theories have addressed the nature of these representations. The first theory—efficient coding—posits that neurons encode as much information as possible about sensory stimuli, subject to resource constraints such as limits on energy consumption. The second one—generative modeling—focuses on decoding, and is organized around the idea that neural activity plays the role of a latent variable from which sensory stimuli can be simulated. Our work subsumes the two approaches in a unifying framework based on the mathematics of variational autoencoders. Unlike in efficient coding, which assumes full knowledge of stimulus statistics, here representations are learned from examples, in a joint optimization of encoding and decoding. This new framework yields a range of optimal representations, corresponding to different models of neural selectivity and reconstruction performances, depending on the resource constraint. The form of the constraint is not arbitrary but derives from the optimization framework, and its strength tunes the ability of the model to generalize beyond the training example. Central to the approach, and to the nature of the representations it implies, is the interplay of encoding and decoding, itself central to brain processing. [ABSTRACT FROM AUTHOR]

Eugenol (EUG) is a bioactive monoterpenoid used as an analgesic, preservative, and flavoring agent. Our new data show EUG as a voltage-gated Na+ channel (VGSC) inhibitor, comparable but not identical to lidocaine (LID). EUG inhibits both total and only TTX-R voltage-activated Na+ currents (INa) recorded from VGSCs naturally expressed on dorsal root ganglion sensory neurons in rats. Inhibition is quick, fully reversible, and dose-dependent. Our biophysical and pharmacological analyses showed that EUG and LID inhibit VGSCs with different mechanisms. EUG inhibits VGSCs with a dose–response relationship characterized by a Hill coefficient of 2, while this parameter for the inhibition by LID is 1. Furthermore, in a different way from LID, EUG modified the voltage dependence of both the VGSC activation and inactivation processes and the recovery from fast inactivated states and the entry to slow inactivated states. In addition, we suggest that EUG, but not LID, interacts with VGSC pre-open–closed states, according to our data. [ABSTRACT FROM AUTHOR]

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses. neuron navigator-3 (NAV3) is involved in neuronal morphogenesis, vision, and neuromuscular responses, and the biallelic/mono-allelic variants of NAV3 are causative of a spectrum of neurodevelopmental disorders [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of dietary sesame oil and ginger oil supplements on the dorsal root ganglia following a sciatic nerve crush model in male Wistar albino rats. Crush injury models have been done by means of graded forceps (50 Newton). The animals were given a daily sesame oil (4 ml/kg/day) and ginger oil (400 mg/kg/day) via oral gavage for a period of 28 days. Dorsal root ganglia from the L5 levels were harvested. Processing of tissues was done for electron microscopy and light microscopy. Immunohistochemical staining with active caspase-3 antibody and qualitative ultrastructural analyses of tissues were made by a light and a transmission electron microscope, respectively. The results showed that crush injury leads to remarkable ultrastructural changes in sensory neurons, such as swollen mitochondria, disruption of cristae structure, glial cell proliferation and, consequently, phagocytosis of the damaged neuron. These ultrastructural changes were less evident in the treated groups, and both natural compounds reduced the expression of activated caspase-3, which may also affect ultrastructural changes. The application of the natural products sesame oil and ginger oil may represent a supportive approach to the protection of sensory neurons against the destructive effects of peripheral nerve crush injury. [ABSTRACT FROM AUTHOR]

Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse‐like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll‐like receptors and protease‐activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro‐inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins. Synopsis: Hyperactivation of kinesins has been linked to neurodegenerative conditions. This study shows that a hyperactive version of OSM-3, a member of kinesin-2 superfamily that drives anterograde intraflagellar transport in C. elegans, is expelled from neurons for degradation in glial cells. Hyperactive OSM-3CA kinesin is absent from cilia and forms dynamic puncta within the neurites of sensory neurons. OSM-3CA puncta are ejected from sensory neurons and engulfed by neighboring cephalic sheath glia cells in a manner dependent of the phagocytic receptor CED-1. Mutations that reduce OSM-3CA activity or increase its microtubule binding protect OSM-3CA and restore normal cilia. ALS-linked hyperactive kinesin-1 is also expelled from neurons when ectopically expressed in C. elegans. Phagocytic receptor CED-1 enables glial uptake and subsequent degradation of hyperactive kinesins in C. elegans. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K+ channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K+ channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K+ channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures. [ABSTRACT FROM AUTHOR]

Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this 'superficial' simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time. In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction. [ABSTRACT FROM AUTHOR]

Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high‐energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two‐pore‐domain K+ channel (K2P) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin‐mediated TREK1/2 pathway may provide a therapeutic approach for ameliorating PDNP. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management. Psoriasis is a skin disease associated with neurogenic inflammation. Here, the authors activation of ASIC3 on sensory neurons that leads to the release of CGRP, which triggers inflammation through dendritic cells and drives psoriatic inflammation. [ABSTRACT FROM AUTHOR]

Zygaenoidea is a superfamily of lepidopterans containing many venomous species, including the Limacodidae (nettle caterpillars) and Megalopygidae (asp caterpillars). Venom proteomes have been recently documented for several species from each of these families, but further data are required to understand the evolution of venom in Zygaenoidea. In this study, we examined the 'electric' caterpillar from North-Eastern Australia, a limacodid caterpillar densely covered in venomous spines. We used DNA barcoding to identify this caterpillar as the larva of the moth Comana monomorpha (Turner, 1904). We report the clinical symptoms of C. monomorpha envenomation, which include acute pain, and erythema and oedema lasting for more than a week. Combining transcriptomics of venom spines with proteomics of venom harvested from the spine tips revealed a venom markedly different in composition from previously examined limacodid venoms that are rich in peptides. In contrast, the venom of C. monomorpha is rich in aerolysin-like proteins similar to those found in venoms of asp caterpillars (Megalopygidae). Consistent with this composition, the venom potently permeabilises sensory neurons and human neuroblastoma cells. This study highlights the diversity of venom composition in Limacodidae. [ABSTRACT FROM AUTHOR]

Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of Caenorhabditis elegans neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study reveals that neuronal cilia defects trigger the unfolded protein response of the endoplasmic reticulum (UPRER) within intestinal cells, a process dependent on the insulin/insulin-like growth factor 1 (IGF-1) signaling transcription factor and the release of neuronal signaling molecules. While inhibiting UPRER doesn't alter the lifespan of wild-type worms, it normalizes the extended lifespan of ciliary mutants. Notably, deactivating the cyclic nucleotide-gated (CNG) channel TAX-4 on the ciliary membrane promotes lifespan extension through a UPRER-dependent mechanism. Conversely, constitutive activation of TAX-4 attenuates intestinal UPRER in ciliary mutants. Administering a CNG channel blocker to worm larvae activates intestinal ER UPRER and increases adult longevity. These findings suggest that ciliary dysfunction in sensory neurons triggers intestinal UPRER, contributing to lifespan extension and implying that transiently inhibiting ciliary channel activity may effectively prolong lifespan. [ABSTRACT FROM AUTHOR]

The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multi-dendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1) in vitro. Through targeted genetic manipulations, we confirm that an LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases the dendritic complexity in CIV neurons. Furthermore, both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus, we examine CIV dendritic development in disease conditions as well. The expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through the regulation of TORC1 in both health and disease. [ABSTRACT FROM AUTHOR]

Background: Interleukin 24 (IL-24) has been implicated in the nociceptive signaling. However, direct evidence and the precise molecular mechanism underlying IL-24's role in peripheral nociception remain unclear. Methods: Using patch clamp recording, molecular biological analysis, immunofluorescence labeling, siRNA-mediated knockdown approach and behavior tests, we elucidated the effects of IL-24 on sensory neuronal excitability and peripheral pain sensitivity mediated by T-type Ca2+ channels (T-type channels). Results: IL-24 enhances T-type channel currents (T-currents) in trigeminal ganglion (TG) neurons in a reversible and dose-dependent manner, primarily by activating the interleukin-22 receptor 1 (IL-22R1). Furthermore, we found that the IL-24-induced T-type channel response is mediated through tyrosine-protein kinase Lyn, but not its common downstream target JAK1. IL-24 application significantly activated protein kinase A; this effect was independent of cAMP and prevented by Lyn antagonism. Inhibition of PKA prevented the IL-24-induced T-current response, whereas inhibition of protein kinase C or MAPK kinases had no effect. Functionally, IL-24 increased TG neuronal excitability and enhanced pain sensitivity to mechanical stimuli in mice, both of which were suppressed by blocking T-type channels. In a trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve, inhibiting IL-22R1 signaling alleviated mechanical allodynia, which was reversed by blocking T-type channels or knocking down Cav3.2. Conclusion: Our findings reveal that IL-24 enhances T-currents by stimulating IL-22R1 coupled to Lyn-dependent PKA signaling, leading to TG neuronal hyperexcitability and pain hypersensitivity. Understanding the mechanism of IL-24/IL-22R1 signaling in sensory neurons may pave the way for innovative therapeutic strategies in pain management. [ABSTRACT FROM AUTHOR]

Human-induced pluripotent stem cells (iPS cells) are efficiently differentiated into sensory neurons. These cells express the voltage-gated sodium channel NaV1.7, which is a validated pain target. NaV1.7 deficiency leads to pain insensitivity, whereas NaV1.7 gain-of-function mutants are associated with chronic pain. During differentiation, the sensory neurons start spontaneous action potential firing around day 22, with increasing firing rate until day 40. Here, we used CRISPR/Cas9 genome editing to generate a HA-tag NaV1.7 to follow its expression during differentiation. We used two protocols to generate sensory neurons: the classical small molecule approach and a directed differentiation methodology and assessed surface NaV1.7 expression by Airyscan high-resolution microscopy. Our results show that maturation of at least 49 days is necessary to observe robust NaV1.7 surface expression in both protocols. Electric activity of the sensory neurons precedes NaV1.7 surface expression. A clinically effective NaV1.7 blocker is still missing, and we expect this iPS cell model system to be useful for drug discovery and disease modeling. [ABSTRACT FROM AUTHOR]

It is remarkable how teeth maintain their healthy condition under exceptionally high levels of mechanical loading. This suggests the presence of inherent mechanical adaptation mechanisms within their structure to counter constant stress. Dentin, situated between enamel and pulp, plays a crucial role in mechanically supporting tooth function. Its intermediate stiffness and viscoelastic properties, attributed to its mineralized, nanofibrous extracellular matrix, provide flexibility, strength, and rigidity, enabling it to withstand mechanical loading without fracturing. Moreover, dentin's unique architectural features, such as odontoblast processes within dentinal tubules and spatial compartmentalization between odontoblasts in dentin and sensory neurons in pulp, contribute to a distinctive sensory perception of external stimuli while acting as a defensive barrier for the dentin-pulp complex. Since dentin's architecture governs its functions in nociception and repair in response to mechanical stimuli, understanding dentin mechanobiology is crucial for developing treatments for pain management in dentin-associated diseases and dentin-pulp regeneration. This review discusses how dentin's physical features regulate mechano-sensing, focusing on mechano-sensitive ion channels. Additionally, we explore advanced in vitro platforms that mimic dentin's physical features, providing deeper insights into fundamental mechanobiological phenomena and laying the groundwork for effective mechano-therapeutic strategies for dentinal diseases. [ABSTRACT FROM AUTHOR]

Methyl-CpG-binding protein 2 (Mecp2) is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of Mecp2 in the PNS on specific central regions, we generated Mecp2fl/flAdvillincre mice with the sensory-neuron-specific deletion of the Mecp2 gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to Mecp2fl/fl mice, Mecp2fl/flAdvillincre mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in Mecp2fl/flAdvillincre mice than in Mecp2fl/fl mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of Mecp2fl/flAdvillincre mice compared to Mecp2fl/fl mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of Mecp2fl/flAdvillincre mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Stick insects and their mechanoreceptors are important models for neurobiology and physiology. Mechanoreceptors are sensory systems that detect mechanical stimuli like wind, airborne sound, substrate vibration, or gravity. They are present in insects in highly diverse forms. Here, the morphology of a mechanosensory complex (the subgenual organ complex) with two distinct organs in the legs of a stick insect (Sipyloidea chlorotica) is described for animals that were newly hatched. The overall organisation of this sensory complex is unique in stick insects, and the present study extends the current knowledge from adult insects to the early juvenile instars. The morphological results show a connection between the two sensory organs (subgenual organ and distal organ) by a thin membrane, which had already been documented in adult stick insects. By the time of hatching, both the sensory neurons activated by mechanical stimuli as well as further tissues in the sensory complex are present, and they likely develop during embryogenesis. The sensory organs could also be functional at hatching. This report discusses the implications of a connection between the subgenual organ and the distal organ, suggesting that the membrane would influence the displacements of the two organs. The subgenual organ complex of stick insects has a unique neuroanatomical organisation with two elaborate chordotonal organs, the subgenual organ and the distal organ. These organs are present in all leg pairs and are already developed in newly hatched stick insects. The present study analyses for the first time the morphology of sensory organs in the subgenual organ complex for a membrane connecting the two sensory organs in newly hatched insects (Sipyloidea chlorotica (Audinet-Serville 1838)). The stick insect legs were analysed following hatching by axonal tracing and light microscopy. The subgenual organ complex in first juvenile instars shows the sensory organs and a thin membrane connecting the sensory organs resembling the morphology of adult animals. Rarely was this membrane not detected, where it is assumed as not developed during embryogenesis. The connection appears to influence the shape of the subgenual organ, with one end extending towards the distal organ as under tension. These findings are discussed for the following functional implications: (1) the physiological responses of the subgenual organ complex to mechanical stimuli after hatching, (2) the influence of the membrane on the displacement of the sensory organs, and (3) the connection between the subgenual organ and distal organ as a possible functional coupling. [ABSTRACT FROM AUTHOR]

Chronic pain, a complex and debilitating condition, involves intricate interactions between central and peripheral inflammatory processes. Cytokines, specifically tumor necrosis factor (TNF) and interleukins (IL), are key mediators in the initiation and maintenance of chronic pain states. Sensory neurons expressing receptors for cytokines like TNF, IL-1, and IL-6 are implicated in peripheral sensitization, contributing to increased signaling of painful sensations. The potential of targeting TNF and IL for therapeutic intervention in chronic pain states is the focus of this review, with preclinical and clinical evidence supporting the use of TNF and IL modulators for pain management. The physiological and pathological roles of TNF in neuropathic pain is complex. Experimental evidence highlights the effectiveness of TNF modulation in mitigating pain symptoms in animal models and displays promising outcomes of clinical trials with TNF inhibitors, such as infliximab and etanercept. ILs, a diverse group of cytokines, including IL-1, IL-6, and IL-17, are discussed for their contributions to chronic pain through inflammation and peripheral sensitization. Specific IL modulators, such as secukinumab and tocilizumab, have shown potential in managing chronic neuropathic pain, as demonstrated in various studies and clinical trials. The pharmacokinetics, safety profiles, and challenges associated with TNF and IL modulators highlight the need for cautious medication monitoring in clinical practice. Comparative evaluations have revealed distinct efficacy and safety profiles among different cytokine modulators, emphasizing the need for personalized approaches based on the specific underlying causes of pain. Further research is necessary to elucidate the intricate mechanisms by which cytokines contribute to chronic pain, as well as to understand why they may affect pain differently in various contexts. Additionally, long-term safety profiles of cytokine modulators require more thorough investigation. This continued exploration holds the promise of enhancing our comprehension of cytokine modulation in chronic pain and shaping more potent therapeutic strategies for the future. [ABSTRACT FROM AUTHOR]

The choice of treatment for lumbar spinal stenosis (LSS) depends on symptom severity. When severe motor issues with urinary dysfunction are not present, conservative treatment is often considered to be the priority. One such conservative treatment is epidural injection, which is effective in alleviating inflammation and the pain caused by LSS-affected nerves. In this study, Shinbaro2 (Sh2), pharmacopuncture using natural herbal medicines for patients with disc diseases, is introduced as an epidural to treat LSS in a rat model. The treatment of primary sensory neurons from the rats' dorsal root ganglion (DRG) neurons with Sh2 at various concentrations (0.5, 1, and 2 mg/mL) was found to be safe and non-toxic. Furthermore, it remarkably stimulated axonal outgrowth even under H2O2-treated conditions, indicating its potential for stimulating nerve regeneration. When LSS rats received epidural injections of two different concentrations of Sh2 (1 and 2 mg/kg) once daily for 4 weeks, a significant reduction was seen in ED1+ macrophages surrounding the silicone block used for LSS induction. Moreover, epidural injection of Sh2 in the DRG led to a significant suppression of pain-related factors. Notably, Sh2 treatment resulted in improved locomotor recovery, as evaluated by the Basso, Beattie, and Bresnahan scale and the horizontal ladder test. Additionally, hind paw hypersensitivity, assessed using the Von Frey test, was reduced, and normal gait was restored. Our findings demonstrate that epidural Sh2 injection not only reduced inflammation but also improved locomotor function and pain in LSS model rats. Thus, Sh2 delivery via epidural injection has potential as an effective treatment option for LSS. [ABSTRACT FROM AUTHOR]

Background: Key to the advancement of the field of bioelectronic medicine is the identification of novel pathways of neural regulation of immune function. Sensory neurons (termed nociceptors) recognize harmful stimuli and initiate a protective response by eliciting pain and defensive behavior. Nociceptors also interact with immune cells to regulate host defense and inflammatory responses. However, it is still unclear whether nociceptors participate in regulating primary IgG antibody responses to novel antigens. Methods: To understand the role of transient receptor potential vanilloid 1 (TRPV1)-expressing neurons in IgG responses, we generated TRPV1-Cre/Rosa-ChannelRhodopsin2 mice for precise optogenetic activation of TRPV1 + neurons and TRPV1-Cre/Lox-diphtheria toxin A mice for targeted ablation of TRPV1-expressing neurons. Antigen-specific antibody responses were longitudinally monitored for 28 days. Results: Here we show that TRPV1 expressing neurons are required to develop an antigen-specific immune response. We demonstrate that selective optogenetic stimulation of TRPV1+ nociceptors during immunization significantly enhances primary IgG antibody responses to novel antigens. Further, mice rendered deficient in TRPV1- expressing nociceptors fail to develop primary IgG antibody responses to keyhole limpet hemocyanin or haptenated antigen. Conclusion: This functional and genetic evidence indicates a critical role for nociceptor TRPV1 in antigen-specific primary antibody responses to novel antigens. These results also support consideration of potential therapeutic manipulation of nociceptor pathways using bioelectronic devices to enhance immune responses to foreign antigens. Summary: Genetic and selective functional evidence reveals that TRPV1+ nociceptors are required for primary IgG antibody responses to novel antigens and stimulating TRPV1+ nociceptors enhances primary IgG antibody responses to novel antigens. [ABSTRACT FROM AUTHOR]

Owing to the highly parallel network structure of the biological neural network and its triggered processing mode, tactile sensory neurons can realize the perception of external signals and the functions of perception, memory, and data processing by adjusting the synaptic weight. In this paper, a piezoresistive pressure sensor is combined with a memristor to design an artificial tactile sensory neuron. The polyurethane sponge sensor has excellent sensitivity and can convert physical stimuli into electrical signals, and the chitosan‐based memristor has stable bipolar resistive switching characteristics, allowing further information to be memorized and processed. The neuron can respond to tactile stimuli of different degrees, durations, and frequencies; realize potentiation/depression modulation, paired‐pulse facilitation, and spike‐timing‐dependent plasticity; exhibit spike‐rate‐dependent plasticity; and store and erase tactile information through memistor state switching, which has great application potential in biological sensing systems. [ABSTRACT FROM AUTHOR]

Objective: Nav1.8 expression is restricted to sensory neurons; it was hypothesized that aberrant expression and function of this channel at the site of injury contributed to pathological pain. However, the specific contributions of Nav1.8 to neuropathic pain are not as clear as its role in inflammatory pain. The aim of this study is to understand how Nav1.8 present in peripheral sensory neurons regulate neuronal excitability and induce various electrophysiological features on neuropathic pain. Methods: To study the effect of changes in sodium channel Nav1.8 kinetics, Hodgkin-Huxley type conductance-based models of spiking neurons were constructed using the NEURON v8.2 simulation software. We constructed a single-compartment model of neuronal soma that contained Nav1.8 channels with the ionic mechanisms adapted from some existing small DRG neuron models. We then validated and compared the model with our experimental data from in vivo recordings on soma of small dorsal root ganglion (DRG) sensory neurons in animal models of neuropathic pain (NEP). Results: We show that Nav1.8 is an important parameter for the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability. The typical increased excitability seen is dominated by a left shift in the steady state of activation of this channel and is further modulated by this channel's maximum conductance and steady state of inactivation. Therefore, modified action potential shape, decreased threshold, and increased repetitive firing of sensory neurons in our neuropathic animal models may be orchestrated by these modulations on Nav1.8. Conclusion: Computational modeling is a novel strategy to understand the generation of chronic pain. In this study, we highlight that changes to the channel functions of Nav1.8 within the small DRG neuron may contribute to neuropathic pain. [ABSTRACT FROM AUTHOR]