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Previous work identified nociceptive Schwann cells that can initiate pain. Consistent with the existence of inherently mechanosensitive sensory Schwann cells, we found that in mice, the mechanosensory function of almost all nociceptors, including those signaling fast pain, were dependent on sensory Schwann cells. In polymodal nociceptors, sensory Schwann cells signal mechanical, but not cold or heat pain. Terminal Schwann cells also surround mechanoreceptor nerve-endings within the Meissner's corpuscle and in hair follicle lanceolate endings that both signal vibrotactile touch. Within Meissner´s corpuscles, two molecularly and functionally distinct sensory Schwann cells positive for Sox10 and Sox2 differentially modulate rapidly adapting mechanoreceptor function. Using optogenetics we show that Meissner's corpuscle Schwann cells are necessary for the perception of low threshold vibrotactile stimuli. These results show that sensory Schwann cells within diverse glio-neural mechanosensory end-organs are sensors for mechanical pain as well as necessary for touch perception. Schwann cells associated with most sensory receptors in the skin actively participate in the transduction of mechanical stimuli. Here the authors show that silencing these sensory Schwann cells is sufficient to reduce touch perception and can inhibit mechanical pain in mice. [ABSTRACT FROM AUTHOR]

Force feedback could be valuable in adapting walking to diverse terrains, but the effects of changes in substrate inclination on discharges of sensory receptors that encode forces have rarely been examined. In insects, force feedback is provided by campaniform sensilla, mechanoreceptors that monitor forces as cuticular strains. We neurographically recorded responses of stick insect tibial campaniform sensilla to "naturalistic" forces (joint torques) that occur at the hind leg femur-tibia (FT) joint in uphill, downhill, and level walking. The FT joint torques, obtained in a previous study that used inverse dynamics to analyze data from freely moving stick insects, are quite variable during level walking (including changes in sign) but are larger in magnitude and more consistent when traversing sloped surfaces. Similar to vertebrates, insects used predominantly extension torque in propulsion on uphill slopes and flexion torques to brake forward motion when going downhill. Sensory discharges to joint torques reflected the torque direction but, unexpectedly, often occurred as multiple bursts that encoded the rate of change of positive forces (dF/dt) even when force levels were high. All discharges also showed hysteresis (history dependence), as firing substantially decreased or ceased during transient force decrements. These findings have been tested in simulation in a mathematical model of the sensilla (Szczecinski NS, Dallmann CJ, Quinn RD, Zill SN. Bioinspir Biomim 16: 065001, 2021) that accurately reproduced the biological data. Our results suggest the hypothesis that sensory feedback from the femoro-tibial joint indicating force dynamics (dF/dt) can be used to counter the instability in traversing sloped surfaces in animals and, potentially, in walking machines. [ABSTRACT FROM AUTHOR]

The transduction from mechanical to electrical signal or energy, and vice versa, has wide applications spanning wearable electronics, medical devices, human‐machine interfaces, prosthetics, synthetic biology, soft robotics, augmented reality (AR), internet‐of‐things (IoT), smart cities, environmental monitoring, energy conversation, and energy harvesting. Although many biological processes such as those in sensory receptors and cell communication uses ions, much of existing artificial intelligent sensory and processing systems operate based solely on electrons as signal or energy carriers. Therefore, the realization of natively ionic devices can significantly advance the frontiers of both capabilities and applications. This invited paper introduces the piezoionic effect, surveying the historical evolution, scientific description, methodology, application, future outlook, and current debates. This work complements existing ones in that it is an in‐depth analysis of key attributes of the piezoionics field but, unlike a conventional review, does not emphasize the categorization of individual works, though is also provided. This work is also aimed at facilitating the understanding and evaluation of the piezoionics field in terms of its key capabilities, promises, fundamental limitations, technical challenges, and practical applications. Piezoionics as a biomimetic mechanical‐electrical transduction mechanism is expected to grow rapidly. Through in‐depth analysis and working out implications for the future, it is hoped that this paper provides a foundation for further exploration, discussion, and collaboration across different fields. The community looks forward to the piezoionic effect evolving into a mainstream paradigm for the ubiquitous realization of sensors, actuators, interfaces, as well as energy harvesters and beyond. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide (CGRP), a neuropeptide composed of 37 amino acids secreted from the sensory nerve endings, reportedly possesses various physiological effects, such as vasodilation and neurotransmission. Recently, there have been increasing reports of the involvement of CGRP in bone metabolism; however, its specific role in the pathogenesis of periodontitis, particularly in the repair and healing processes, remains to be elucidated. Therefore, this study aimed to investigate dynamic expression patterns of CGRP during the destruction and regeneration processes of periodontal tissues in a mouse model of experimental periodontitis. We also explored the effects of CGRP on periodontal ligament cells, which can differentiate to hard tissue-forming cells (cementoblasts or osteoblasts). Our findings demonstrated that CGRP stimulation promotes the differentiation of periodontal ligament cells into hard tissue-forming cells. Experimental results using a ligature-induced periodontitis mouse model also suggested fluctuations in CGRP expression during periodontal tissue healing, underscoring the vital role of CGRP signaling in alveolar bone recovery. The study results highlight the important role of nerves in the periodontal ligament not only in sensory reception in the periphery, as previously known, but also in periodontal tissue homeostasis and tissue repair processes. [ABSTRACT FROM AUTHOR]

Summary Sensory receptor gene families have undergone extensive expansion and loss across vertebrate evolution, leading to significant variation in receptor counts between species. However, due to their species-specific nature, conventional reference-based annotation tools often underestimate the true number of sensory receptors in a given species. While there has been an exponential increase in the taxonomic diversity of publicly available genome assemblies in recent years, only ∼30% of vertebrate species on the NCBI database are currently annotated. To overcome these limitations, we developed 'Sensommatic', an automated and accessible sensory receptor annotation pipeline. Sensommatic implements BLAST and AUGUSTUS to mine and predict sensory receptor genes from whole genome assemblies, adopting a one-to-many gene mapping approach. While designed for vertebrates, Sensommatic can be extended to run on non-vertebrate species by generating customized reference files, making it a scalable and generalizable tool. Availability and implementation Source code and associated files are available at: https://github.com/GMHughes/Sensommatic [ABSTRACT FROM AUTHOR]

The combustion of fossil fuels contributes to air pollution (AP), which was linked to about 8.79 million global deaths in 2018, mainly due to respiratory and cardiovascular-related effects. Among these, particulate air pollution (PM2.5) stands out as a major risk factor for heart health, especially during vulnerable phases. Our prior study showed that premature exposure to 1,2-naphthoquinone (1,2-NQ), a chemical found in diesel exhaust particles (DEP), exacerbated asthma in adulthood. Moreover, increased concentration of 1,2-NQ contributed to airway inflammation triggered by PM2.5, employing neurogenic pathways related to the up-regulation of transient receptor potential vanilloid 1 (TRPV1). However, the potential impact of early-life exposure to 1,2-naphthoquinone (1,2-NQ) on atrial fibrillation (AF) has not yet been investigated. This study aims to investigate how inhaling 1,2-NQ in early life affects the autonomic adrenergic system and the role played by TRPV1 in these heart disturbances. C57Bl/6 neonate male mice were exposed to 1,2-NQ (100 nM) or its vehicle at 6, 8, and 10 days of life. Early exposure to 1,2-NQ impairs adrenergic responses in the right atria without markedly affecting cholinergic responses. ECG analysis revealed altered rhythmicity in young mice, suggesting increased sympathetic nervous system activity. Furthermore, 1,2-NQ affected β1-adrenergic receptor agonist-mediated positive chronotropism, which was prevented by metoprolol, a β1 receptor blocker. Capsazepine, a TRPV1 blocker but not a TRPC5 blocker, reversed 1,2-NQ-induced cardiac changes. In conclusion, neonate mice exposure to AP 1,2-NQ results in an elevated risk of developing cardiac adrenergic dysfunction, potentially leading to atrial arrhythmia at a young age. [ABSTRACT FROM AUTHOR]

Considerable evidence suggests that oxytocin, as a regulatory nonapeptide, participates in modulatory mechanisms of nociception. Nonetheless, the role of this hypothalamic hormone and its receptor in the sensory pathway has yet to be fully explored. The present study performed immunohistochemistry, enzyme-linked immunosorbent assay, and RT-qPCR analysis to assess changes in the expression of the neuronal oxytocin receptor in female rats following tight ligation of the sciatic nerve after 1, 3, and 7 days of survival. Oxytocin receptor immunoreactivity was present in both dorsal root ganglia and lumbar spinal cord segments, but not accumulated at the site of the ligation of the peripheral nerve branch. We found a time-dependent change in the expression of oxytocin receptor mRNA in L5 dorsal root ganglion neurons, as well as an increase in the level of the receptor protein in the lumbar segment of the spinal cord. A peak in the expression was observed on day 3, which downturned slightly by day 7 after the nerve ligation. These results show that OTR expression is up-regulated in response to peripheral nerve lesions. We assume that the importance of OTR is to modify spinal presynaptic inputs of the sensory neurons upon injury-induced activation, thus to be targets of the descending oxytocinergic neurons from supraspinal levels. The findings of this study support the concept that oxytocin plays a role in somatosensory transmission. [ABSTRACT FROM AUTHOR]

In the carotid body of laboratory rodents, adenosine 5′-triphosphate (ATP)-mediated transmission is regarded as critical for transmission from chemoreceptor type I cells to P2X3 purinoceptor-expressing sensory nerve endings. The present study investigated the distribution of P2X3-immunoreactive sensory nerve endings in the carotid body of the adult male Japanese monkey (Macaca fuscata) using multilabeling immunofluorescence. Immunoreactivity for P2X3 was detected in nerve endings associated with chemoreceptor type I cells immunoreactive for synaptophysin. Spherical or flattened terminal parts of P2X3-immunoreactive nerve endings were in close apposition to the perinuclear cytoplasm of synaptophysin-immunoreactive type I cells. Immunoreactivity for ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), which hydrolyzes extracellular ATP, was localized in the cell body and cytoplasmic processes of S100B-immunoreactive cells. NTPDase2-immunoreactive cells surrounded P2X3-immunoreactive terminal parts and synaptophysin-immunoreactive type I cells, but did not intrude into attachment surfaces between terminal parts and type I cells. These results suggest ATP-mediated transmission between type I cells and sensory nerve endings in the carotid body of the Japanese monkey, as well as those of rodents. [ABSTRACT FROM AUTHOR]

Computational models can be critical to linking complex properties of muscle spindle organs to the sensory information that they encode during behaviours such as postural sway and locomotion where few muscle spindle recordings exist. Here, we augment a biophysical muscle spindle model to predict the muscle spindle sensory signal. Muscle spindles comprise several intrafusal muscle fibres with varied myosin expression and are innervated by sensory neurons that fire during muscle stretch. We demonstrate how cross‐bridge dynamics from thick and thin filament interactions affect the sensory receptor potential at the spike initiating region. Equivalent to the Ia afferent's instantaneous firing rate, the receptor potential is modelled as a linear sum of the force and rate change of force (yank) of a dynamic bag1 fibre and the force of a static bag2/chain fibre. We show the importance of inter‐filament interactions in (i) generating large changes in force at stretch onset that drive initial bursts and (ii) faster recovery of bag fibre force and receptor potential following a shortening. We show how myosin attachment and detachment rates qualitatively alter the receptor potential. Finally, we show the effect of faster recovery of receptor potential on cyclic stretch–shorten cycles. Specifically, the model predicts history‐dependence in muscle spindle receptor potentials as a function of inter‐stretch interval (ISI), pre‐stretch amplitude and the amplitude of sinusoidal stretches. This model provides a computational platform for predicting muscle spindle response in behaviourally relevant stretches and can link myosin expression seen in healthy and diseased intrafusal muscle fibres to muscle spindle function. What is the central question of the study?A computational biophysical muscle model was used to ask how muscle cross‐bridge dynamics shape the information that can be encoded by intrafusal muscle fibres within the muscle spindle.What is the main finding and its importance?Both actin and myosin dynamics and their interactions can shape muscle spindle sensory signals and are necessary to simulate history‐dependent muscle spindle firing properties to be more in line with experimental observations. The tuned muscle spindle model shows that non‐linear and history‐dependent muscle spindle firing properties to sinusoids reported previously emerge from intrafusal cross‐bridge dynamics. [ABSTRACT FROM AUTHOR]

The effects of air pollution on health are gaining increasing research interest with limited data on skin alterations available. It was suggested that air pollution is a trigger factor for sensitive skin (SS). However, this data was based on surveys with a lack of experimental data. SS is related to altered skin nerve endings and cutaneous neurogenic inflammation. TTe present study was to assess the in vitro effect of particulate matter (PM) on epidermis and nerve ending homeostasis. PM samples were collected according to a validated protocol. Reconstructed human epidermis (RHE, Episkin®) was exposed to PM and subsequently the supernatants were transferred to a culture of PC12 cells differentiated into sensory neurons (SN). Cell viability, axonal growth and neuropeptide‐release were measured. The modulation of the expression of different inflammatory, keratinocytes differentiation and neurites growth markers was assessed. PM samples contained a high proportion of particles with a size below 1 μm and a complex chemical composition. Transcriptomic and immunohistochemical analyses revealed that PM altered keratinocytes terminal differentiation and induced an inflammatory response. While viability and functionality of the SN were not modified, their outgrowth was significantly decreased after incubation with PM‐exposed Episkin® supernatants. This was closely related to the modification of nerve growth factor/semaphorin 3A balance. This study showed that air pollutants have negative effects on keratinocytes and sensory nerve endings including inflammatory responses. These effects are probably involved in the SS pathophysiology and might be involved in inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Hair cells are the principal sensory receptors of the vertebrate auditory system, where they transduce sounds through mechanically gated ion channels that permit cations to flow from the surrounding endolymph into the cells. The lateral line of zebrafish has served as a key model system for understanding hair cell physiology and development, often with the belief that these hair cells employ a similar transduction mechanism. In this study, we demonstrate that these hair cells are exposed to an unregulated external environment with cation concentrations that are too low to support transduction. Our results indicate that hair cell excitation is instead mediated by a substantially different mechanism involving the outward flow of anions. Further investigation of hair cell transduction in a diversity of sensory systems and species will likely yield deep insights into the physiology of these unique cells. [ABSTRACT FROM AUTHOR]

Changes in sensory afferent activity contribute to the transition from acute to chronic pain. However, it is unlikely that a single sensory receptor is entirely responsible for persistent pain. It is more probable that extended changes to multiple receptor proteins expressed by afferent neurons support persistent pain. A-Kinase Anchoring Protein 79/150 (AKAP) is an intracellular scaffolding protein expressed in sensory neurons that spatially and temporally coordinates signaling events. Since AKAP scaffolds biochemical modifications of multiple TRP receptors linked to pain phenotypes, we probed for other ionotropic receptors that may be mediated by AKAP and contribute to persistent pain. Here, we identify a role for AKAP modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor (AMPA-R) functionality in sensory neurons. Pharmacological manipulation of distinct AMPA-R subunits significantly reduces persistent mechanical hypersensitivity observed during hyperalgesic priming. Stimulation of both protein kinases C and A (PKC, PKA, respectively) modulate AMPA-R subunit GluR1 and GluR2 phosphorylation and surface expression in an AKAP-dependent manner in primary cultures of DRG neurons. Furthermore, AKAP knock out reduces sensitized AMPA-R responsivity in DRG neurons. Collectively, these data indicate that AKAP scaffolds AMPA-R subunit organization in DRG neurons that may contribute to the transition from acute-to-chronic pain. [ABSTRACT FROM AUTHOR]

It has increasingly been recognized that electrical currents play a pivotal role in cell migration and tissue repair, in a process named "galvanotaxis". In this review, we summarize the current evidence supporting the potential benefits of electric stimulation (ES) in the physiology of peripheral nerve repair (PNR). Moreover, we discuss the potential of piezoelectric materials in this context. The use of these materials has deserved great attention, as the movement of the body or of the external environment can be used to power internally the electrical properties of devices used for providing ES or acting as sensory receptors in artificial skin (e-skin). The fact that organic materials sustain spontaneous degradation inside the body means their piezoelectric effect is limited in duration. In the case of PNR, this is not necessarily problematic, as ES is only required during the regeneration period. Arguably, piezoelectric materials have the potential to revolutionize PNR with new biomedical devices that range from scaffolds and nerve-guiding conduits to sensory or efferent components of e-skin. However, much remains to be learned regarding piezoelectric materials, their use in manufacturing of biomedical devices, and their sterilization process, to fine-tune their safe, effective, and predictable in vivo application. [ABSTRACT FROM AUTHOR]

Abstract Background Cleaning symbioses are captivating interspecific interactions in which a cleaner fish removes ectoparasites from its client, contributing to the health and diversity of natural fish communities and aquaculture systems. However, the genetic signatures underlying this specialized behaviour remain poorly explored. To shed light on this, we generated a high-quality chromosome-scale genome of the bluestreak cleaner wrasse Labroides dimidiatus, a dedicated cleaner with cleaning as primary feeding mechanism throughout its life. Results Compared with facultative and non-cleaner wrasses, L. dimidiatus was found with notable contractions in olfactory receptors implying their limited importance in dedicated cleaning. Instead, given its distinct tactile pre-conflict strategies, L. dimidiatus may rely more heavily on touch sensory perception, with heightened gene expression in the brain in anticipation of cleaning. Additionally, a reduction in NLR family CARD domain-containing protein 3 might enhance innate immunity of L. dimidiatus, probably assisting to reduce the impacts from parasite infections. In addition, convergent substitutions for a taste receptor and bone development genes across cleaners (L. dimidiatus and facultative cleaners) may provide them with evolved food discrimination abilities and jaw morphology that differentiate them from non-cleaners. Moreover, L. dimidiatus may exhibit specialized neural signal transductions for cleaning, as evidenced by positive selection in genes related to the glutamatergic synapse pathway. Interestingly, numerous glutamate receptors also demonstrated significantly higher expression in L. dimidiatus not engaged in cleaning, as compared to those involved in cleaning. Besides, apparent contractions in L. dimidiatus for protocadherins, which are responsible for neuronal development, may further promote specialized neural signal transductions in this species. Conclusions This study reveals that L. dimidiatus harbours substantial losses in specific gene families, convergent evolutions across cleaners and a large-scale high gene expression in preparation for cleaning, allowing for adaptation to the dedicated cleaning behaviour.

Ciliated sensory cells such as photo- and olfactory receptors employ multiple types of opsins or hundreds of unique olfactory G-protein coupled receptors to respond to various wavelengths of light or odorants. With respect to hearing and balance, the mechanotransduction machinery involves fewer variants; however, emerging evidence suggests that specialization occurs at the molecular level. To address how the mechanotransduction complex varies in the inner ear, we characterized the expression of paralogous genes that encode components required for mechanotransduction in zebrafish hair cells using RNA-FISH and bioinformatic analysis. Our data indicate striking zonal differences in the expression of two components of the mechanotransduction complex which are known to physically interact, the transmembrane channel-like 1 and 2 (tmc1/2) family members and the calcium and integrin binding 2 and 3 (cib2/3) paralogues. tmc1, tmc2b, and cib3 are largely expressed in peripheral or extrastriolar hair cells, whereas tmc2a and cib2 are enriched in central or striolar hair cells. In addition, a gene implicated in deaf-blindness, ush1c, is highly enriched in a subset of extrastriolar hair cells. These results indicate that specific combinations of these components may optimize responses to mechanical stimuli in subtypes of sensory receptors within the inner ear. [ABSTRACT FROM AUTHOR]

Inflammation in the intestines causes abdominal pain that is challenging to manage. The terminals of sensory neurons innervating the gut are surrounded by glia. Here, using a mouse model of acute colitis, we found that enteric glia contribute to visceral pain by secreting factors that sensitized sensory nerves innervating the gut in response to inflammation. Acute colitis induced a transient increase in the production of proinflammatory cytokines in the intestines of male and female mice. Of these, IL-1β was produced in part by glia and augmented the opening of the intercellular communication hemichannel connexin-43 in glia, which made normally innocuous stimuli painful in female mice. Chemogenetic glial activation paired with calcium imaging in nerve terminals demonstrated that glia sensitized gut-innervating nociceptors only under inflammatory conditions. This inflammatory, glial-driven visceral hypersensitivity involved an increased abundance of the enzyme COX-2 in glia, resulting in greater production and release of prostaglandin E2 that activated EP4 receptors on sensory nerve terminals. Blocking EP4 receptors reduced nociceptor sensitivity in response to glial stimulation in tissue samples from colitis-model mice, and impairing glial connexin-43 reduced visceral hypersensitivity induced by IL-1β in female mice. The findings suggest that therapies targeting enteric glial–neuron signaling might alleviate visceral pain caused by inflammatory disorders. Editor's summary: The pain associated with gut inflammation can be debilitating, chronic, and difficult to manage. Morales-Soto et al. found that local glial cells may be major contributors to this inflammatory pain. Inducing inflammation in the gut in mice provoked enteric glia to secrete prostaglandin E2, which activated receptors on gut-innervating sensory neurons that sensitized the neurons to stimuli that were otherwise not noxious. Activating the glia in the absence of inflammation did not stimulate neurons or produce visceral pain. The findings reveal a cellular and molecular source of pain in the intestines that is specifically inflammation associated and that may be therapeutically targetable. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]

Background: Women are disproportionately affected by migraine, representing up to 75% of all migraine cases. This discrepancy has been proposed to be influenced by differences in hormone levels between the sexes. One such hormone is progesterone. Calcitonin gene-related peptide (CGRP) system is an important factor in migraine pathophysiology and could be influenced by circulating hormones. The purpose of this study was to investigate the distribution of progesterone and its receptor (PR) in the trigeminovascular system, and to examine the role of progesterone to modulate sensory neurotransmission. Methods: Trigeminal ganglion (TG), hypothalamus, dura mater, and the basilar artery from male and female rats were carefully dissected. Expression of progesterone and PR proteins, and mRNA levels from TG and hypothalamus were analyzed by immunohistochemistry and real-time quantitative PCR. CGRP release from TG and dura mater were measured using an enzyme-linked immunosorbent assay. In addition, the vasomotor effect of progesterone on male and female basilar artery segments was investigated with myography. Results: Progesterone and progesterone receptor -A (PR-A) immunoreactivity were found in TG. Progesterone was located predominantly in cell membranes and in Aδ-fibers, and PR-A was found in neuronal cytoplasm and nucleus, and in satellite glial cells. The number of positive progesterone immunoreactive cells in the TG was higher in female compared to male rats. The PR mRNA was expressed in both hypothalamus and TG; however, the PR expression level was significantly higher in the hypothalamus. Progesterone did not induce a significant change neither in basal level nor upon stimulated release of CGRP from dura mater or TG in male or female rats when compared to the vehicle control. However, pre-treated with 10 µM progesterone weakly enhanced capsaicin induced CGRP release observed in the dura mater of male rats. Similarly, in male basilar arteries, progesterone significantly amplified the dilation in response to capsaicin. Conclusions: In conclusion, these results highlight the potential for progesterone to modulate sensory neurotransmission and vascular responses in a complex manner, with effects varying by sex, tissue type, and the nature of the stimulus. Further investigations are needed to elucidate the underlying mechanisms and physiological implications of these findings. [ABSTRACT FROM AUTHOR]

Macrophages, which are part of the mononuclear phagocytic system, possess sensory receptors that enable them to target cancer cells. In addition, they are able to engulf large amounts of particles through phagocytosis, suggesting a potential "Trojan horse" drug delivery approach to tumors by facilitating the engulfment of drug-hidden particles by macrophages. Recent research has focused on the development of macrophage-based microrobots for anticancer therapy, showing promising results and potential for clinical applications. In this review, we summarize the recent development of macrophage-based microrobot research for anticancer therapy. First, we discuss the types of macrophage cells used in the development of these microrobots, the common payloads they carry, and various targeting strategies utilized to guide the microrobots to cancer sites, such as biological, chemical, acoustic, and magnetic actuations. Subsequently, we analyze the applications of these microrobots in different cancer treatment modalities, including photothermal therapy, chemotherapy, immunotherapy, and various synergistic combination therapies. Finally, we present future outlooks for the development of macrophage-based microrobots. [ABSTRACT FROM AUTHOR]

Background: Regional anaesthesia has the benefit of reducing the need for systemic analgesia and therefore, potentially reducing undesired side effects. With the end of the sensory nerve block however, many patients report severe pain that requires therapy with opioids and often compromise the initial opioid sparing effect. This study aimed to characterise the postoperative pain profile and the phenomenon of rebound pain after axillary brachial plexus anaesthesia (RA) compared to general anaesthesia (GA). Design: Single‐centre observational, stratified cohort study. Setting: The study was conducted at University Hospital Marburg from May 2020 until September 2022. Participants: One hundred thirty‐two patients receiving elective hand and forearm surgery were enrolled in this study. Interventions: Group RA received ultrasound‐guided brachial plexus anaesthesia via the axillary approach with 30 mL of prilocaine 1% and 10 mL ropivacaine 0.2%. Group GA received balanced or total intravenous general anaesthesia. Main Outcome Measures: Primary endpoint were integrated pain scores (IPS) within 24 h postoperatively. Secondary endpoints were pain scores (NRS 0–10), morphine equivalents, patient satisfaction, quality of recovery and opioid‐related side effects. Results: One hundred thirty‐two patients were analysed of which 66 patients received brachial plexus block and 66 patients received general anaesthesia. Following RA significantly lower IPS were seen directly after surgery (p <.001) and during the post‐anaesthesia care unit interval (p <.001) but equalised after 3 h at the ward. No overshoot in pain scores or increased opioid consumption could be detected. Patient satisfaction and postoperative recovery were comparable between both groups. Conclusion: The IPS and NRS was initially lower in the RA group, increased with fading of the block until equal to the GA group and equal thereafter. Although various definitions of rebound pain were met during this phase, the opioid sparing effect of regional anaesthesia was not counteracted by it. The incidence of episodes with uncontrolled, severe pain did not differ between groups. We found no clinical implications of rebound pain in this setting, since the RA group did not show higher pain scores than the GA group at any time point. Trial Registration: German Clinical Trials Register (DRKS00021764). [ABSTRACT FROM AUTHOR]

Objective: Throughout our existence, the skin senses and analyses the mechanical forces imposed by the environment. In response to these environmental forces, skin can deform itself and achieve a biological response. The subsequent cutaneous plasticity emerges from mechanical properties arising from the collective action of the skin cells, particularly keratinocytes, that govern the tensile strength via cell‐to‐cell adhesions and via cell–matrix adhesion structures. In addition to serving as force‐bearing entities, keratinocytes respond to forces by activating signalling pathways to control their own fate and function. To detect and adapt to mechanical signals, keratinocytes possess a panel of sensory receptors and junctional intercellular structures. Mechanically activated ion channel Piezo1 has been described as a force sensor and as being involved in pleasant touch perception. In this study, relationships between Piezo1 modulation and oxytocin synthesis were investigated. Methods: The expression of Piezo1 in the skin was studied and compared with the expression of TRPV1. Dooku1 antagonist and Jedi1 agonist were used to modulate Piezo1. The level of E‐cadherin and oxytocin was monitored in ex vivo skin biopsies by immunodetection. Results: Taken together, our results illustrate the major role of mechanosensitive ion channel Piezo1 in skin barrier integrity, and in peripheral oxytocin synthesis in the skin. Conclusion: In conclusion, this study highlights the relationships between pleasant touch, soft touch and local oxytocin synthesis. [ABSTRACT FROM AUTHOR]

Itch is a sensation in the skin which provokes the desire to scratch. In the past few decades there has been a significant elucidation of the immune and neural pathways which underly the sensation of itch. An interesting divergence in the itch pathway relates to the type of stimulation used to evoke an itchy sensation. Commonly, chemical mediators of itch such as histamine are injected into the skin where they activate their cognate receptors on sensory neurons. Another way to evoke itch, particularly in patients with chronic itch, is to use light mechanical stimulation. Investigation into these pathways utilizing the mouse model have shown that the neuronal pathways which underly chemical itch are distinct from those which mediate itch in response to mechanical stimulation. Specific populations of primary sensory neurons, spinal interneurons and transmission neurons have been identified which suggests a labeled line for itch transmission. Additionally, Piezo channels, which underly mechanosensation, were discovered to play an important role in the mechanical itch pathway. Given these novel findings relating to the mechanical itch pathway, the purpose of this review is to summarize the reports from human subjects and animal studies to highlight the advances in our understanding of mechanical itch and alloknesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Zinc oxide nanoparticles (ZnO-NPs) can exert toxic effects on living organisms. The fish olfactory epithelium is considered the first organ affected by ZnO-NPs, and we demonstrated that a 60-day exposure to ZnO-NPs induced significant malformations of the olfactory rosettes at histological, ultrastructural, and genetic levels in zebrafish, affecting the cellular repairing mechanisms. The present study shows that ZnO-NPs can mediate the cellular oxidative stress and arrest cell growth that induces apoptosis without the ability of cellular regeneration, damaging the olfactory epithelium and affecting fish smell and appetite. Nanotechnology has gained tremendous attention because of its crucial characteristics and wide biomedical applications. Although zinc oxide nanoparticles (ZnO-NPs) are involved in many industrial applications, researchers pay more attention to their toxic effects on living organisms. Since the olfactory epithelium is exposed to the external environment, it is considered the first organ affected by ZnO-NPs. Herein, we demonstrated the cytotoxic effect of ZnO-NPs on the olfactory organ of adult zebrafish after 60 days post-treatment. We opted for this period when fishes stop eating their diet from the aquarium, appear feeble, and cannot swim freely. Our study demonstrated that ZnO-NPs induced significant malformations of the olfactory rosettes at histological, ultrastructural, and genetic levels. At the ultrastructure level, the olfactory lamellae appeared collapsed, malformed, and twisted with signs of degeneration and loss of intercellular connections. In addition, ZnO-NPs harmed sensory receptor and ciliated cells, microvilli, rodlet, crypt, and Kappe cells, with hyper-activity of mucous secretion from goblet cells. At the genetic level, ZnO-NPs could activate the reactive oxygen species (ROS) synthesis expected by the down-regulation of mRNA expression for the antioxidant-related genes and up-regulation of DNA damage, cell growth arrest, and apoptosis. Interestingly, ZnO-NPs affected the odor sensation at 60 days post-treatment (60-dpt) more than at 30-dpt, severely damaging the olfactory epithelium and irreparably affecting the cellular repairing mechanisms. This induced a dramatically adverse effect on the cellular endoplasmic reticulum (ER), revealed by higher CHOP protein expression, that suppresses the antioxidant effect of Nrf2 and is followed by the induction of apoptosis via the up-regulation of Bax expression and down-regulation of Bcl-2 protein. [ABSTRACT FROM AUTHOR]

Empoasca onukii Matsuda is a primary pest of the tea plant Camellia sinensis (L.) O. Ktze that severely influences the production and quality of tea products. Gustatory receptors (GRs) are an indispensable part of the E. onukii chemosensory machinery as members of the G-protein coupled receptor family. Insect odor and gustatory receptors are consumingly sensitive and selective sensory receptors to search for foraging, mates, and spawning sites. In this study, the gustatory receptor EonuGR1 was cloned and analyzed bioinformatically, and the expression levels of EonuGR1 in diverse tissues of E. onukii were tested via qRT-PCR. The behavioral response of E. onukii to volatile compounds was determined via RNA interference and Y-tube olfactometer assays to investigate the role of EonuGR1 in the olfactory recognition of E. onukii. The coding sequence length of EonuGR1 was 1062 bp, and the length of the protein encoded by EonuGR1 was 40.52 kD. The highest interference efficiency was observed after 3 h of dsEonuGR1 treatment via root soak treatment. Moreover, the response rates to phenylacetaldehyde at concentrations of 10 and 0.1 µL/mL were significantly downregulated in E. onukii. The responses to phenylacetaldehyde at concentrations of 10 and 100 µL/mL showed a significant decrease after dsEonuGR1 treatment for 12 h in E. onukii. In conclusion, EonuGR1 was highly expressed in the abdomen and functioned in olfactory recognition of the tea plant volatile phenylacetaldehyde by E. onukii. Overall, EonuGR1 has the potential as a gene target for the design of effective control strategies against E. onukii. [ABSTRACT FROM AUTHOR]

Introduction: Spinal Anaesthesia (SA) is frequently associated with hypotension, which is due to sympathectomy causing vasodilation, leading to relative hypovolemia. This decrease in venous return to the heart causes a decrease in left ventricular filling pressure, leading to the activation of the Bezold-Jarisch Reflex (BJR), which causes bradycardia. This response is mediated by mechanoreceptors and chemoreceptors present on the heart walls. These chemoreceptors are mediated through serotonin (5-HT). Therefore, the activation of 5-HT3 receptors at sensory vagal nerve endings in the heart causes hypotension and bradycardia. Aim: To assess the efficacy of Palonosetron in attenuating spinal anaesthesia-induced hypotension and bradycardia. Materials and Methods: The trial was a parallel-design, randomised, double-blind controlled trial conducted over two years, from February 2021 to August 2022 in the Department of Anaesthesiology, Kalinga Institution of Medical Sciences (KIMS), Bhubaneswar, Odisha, India, among patients undergoing spinal anaesthesia for various surgeries. The patients were divided into two groups based on the type of medication received: Group A-Palonosetron group and Group B- the saline group. Computer-generated random number generator software was used for randomisation. At a 1:1 ratio, 150 patients were chosen (75 in each group). Baseline assessment of haemodynamic parameters was performed, followed by continuous monitoring. The drug was administered 10 minutes prior to spinal anaesthesia, and the haemodynamic parameters (Heart Rate [HR], Systolic Blood Pressure [SBP], Diastolic Blood Pressure [DBP], and Mean Arterial Pressure [MAP]) were monitored. Continuous variables are expressed as mean±Standard Deviation (SD). The Student's t-test was used to compare the difference between the two groups, and categorical variables are expressed as frequency and percentage, with comparisons done using the Chi-square test. A p-value of <0.05 was considered statistically significant. Results: The mean age of Group A and Group B was 40.88 and 42.14, respectively. Significant haemodynamic changes (hypotension) were observed following induction in Group B (28 [37.3%]) compared to Group A (9 [12%]). Consumption of vasopressors and intravenous (i.v.) fluids was significantly higher in Group B compared to Group A. The incidence of bradycardia in Group A and Group B was 15 (20%) and 18 (24%), respectively. Postoperative Nausea and Vomiting (PONV) in Group A and Group B were 3 (4%) and 8 (10.7%), respectively. Conclusion: Based on the present study, the prophylactic administration of 0.075 mg Palonosetron 10 minutes before subarachnoid block is effective in attenuating the incidence of spinal anaesthesia-induced hypotension and bradycardia. There is also decreased consumption of vasopressors and a lower incidence of PONV. [ABSTRACT FROM AUTHOR]

The arteries supplying the fingers and sensory nerve are located on the radial and ulnar aspects of the fingers, which are called the digital bundle. Masses can be found on this bundle topographically. This study aimed to investigate whether this mass originates from the neurovascular structure in patients presenting with a mass on the digital bundle topographically between the A1 pulley-distal interphalangeal (DIP)/interphalangeal (IP) joint in the finger. Additionally, it aimed to determine whether tumors originating from neurovascular structures originate from the main digital bundle and the steps involved in their reconstruction. We reviewed 27 cases with mass lesions at the digital bundle trace topographically between the A1 pulley and DIP/IP, which underwent surgery and were confirmed by histopathological examination between October 2014 and April 2022. Each patient requested at least two plane radiographs, US and MRI. All patients underwent surgery under a loupe-magnification or microscope. First, we determined whether the mass lesion originated from a main digital artery or nerve. Thereafter, the relationship of the mass with pulley and tendon structures was evaluated. All patients underwent histopathological examination. Mean follow-up 21 months. The mean age was 39.3 years. The pain was the most common presenting complaint and was observed in 13 patients. The tumors originating from neurovascular structures were found in 10 patients. In 5 patients, the tumor originated from the main digital artery and nerve. Three of them were reconstructed with a nerve graft. The most common non-neurovascular tumors were giant cell tendon sheath tumors and epidermal inclusion cysts. Some of the tumors on the topographically digital bundle are of neurovascular in origin. Reconstruction can be made in tumors originating from the main digital bundle. Again, the protection of pulley and tendon structures in this region is important in terms of morbidity. [ABSTRACT FROM AUTHOR]

Twelve proline (Pro)/glutamic acid (Glu) dipeptides were synthesized to explore the molecular interaction mechanism between Pro/Glu dipeptides and umami receptors. Based on sensory evaluation, the homology modeling and molecular docking technique were used to assess the structure-activity relationship between Pro/Glu dipeptides and umami receptors, including taste receptor type 1 member 1 (T1R1), taste receptor type 3 member 3 (T1R3) and calcium-sensitive receptor (CaSR). Our results indicated that except for proline-serine (Pro-Ser), valine-proline (Val-Pro), and leucine-glutamic acid (Leu-Glu), the umami threshold of other dipeptides was lower than that of sodium glutamate (0.3 mg/mL). The umami threshold of γ-glutamic acid-methionine (γ-Glu-Met) and glycine-glutamic acid (Gly-Glu) was the lowest (0.07 mg/mL). Notably, Asp147, Thr149, Ser172, and Arg277 were the key binding sites of Pro-Glu dipeptides to T1R1, the key umami receptor of Glu dipeptides. Similarly, Glu45, Ser147, Val277, and His278 were the key binding sites to T1R3, whereas Ser147 was the key binding site between N-γ-Glu dipeptides and the T1R3 receptor. Leu173, Asn176, Gln179, Arg220, Ser244, and Asp275 were the key binding sites to CaSR, with Glu dipeptides had a higher affinity for binding to the CaSR receptor compared to Pro dipeptides. Binding of Pro/Glu dipeptides to receptors was mainly achieved through hydrogen bonds and hydrophobic interaction. During molecular docking, dipeptides with strong umami interactions were predominantly embedded in the depth of the receptor binding pocket, whereas dipeptides with weak umami interactions were located in the shallow position of the binding pocket, with some of their hydrophobic or hydrophilic regions being exposed to the surface of the receptors. This study aided in clarifying the interaction mechanism between Pro-Glu dipeptides and umami receptors, establishing a foundation for further study on the mechanism of action of umami peptides. [ABSTRACT FROM AUTHOR]

Numerous adverse effects on human health have been reported in epidemiological studies of oleoresin capsicum (OC) and other riot control agents (RCAs). Importantly, the daunting risk of such RCAs can be neutralized by optimizing the desired concentration of such agents for mob dispersal. Hence, a nonlethal riot control combinational formulation (NCF) was prepared for dispersing rioters without imparting fatal outcomes. However, for desired utilization of NCF, it is essential to recognize its extent of potential toxicity. Therefore, the current investigation evaluated the dermal toxicity of NCF using experimental animals in compliance with the OECD guidelines. Additionally, few essential metal ions were analyzed and found non -significantly different in the test rats as compared to control rats. Moreover, abnormal dermal morphology and lesions ultrastructural tissue defects were not noticed as evinced by different studies like ultrasonography, histology, and scanning electron microscopy (SEM) respectively. Further, Doppler ultrasonography exhibited non-significantly different blood flow velocity in both groups, whereas miles test demonstrated a significantly increased Evans blue concentration in test rats compared to the control rats, which might be due to an initial increase in blood flow via an instant action of the NCF at the cutaneous sensory nerve endings. However, our results demonstrated NCF can produce initial skin irritating and sensitizing effects in guinea pigs and rabbits without the antecedence of acute toxicity (≤2000 mg/kg) in Wistar rats. [ABSTRACT FROM AUTHOR]

This article discusses the regulation of glucose and energy metabolism through the actions of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are intestinal hormones that promote glucose-dependent insulin secretion. GLP-1 also inhibits glucagon secretion and suppresses appetite, while GIP is involved in obesity and insulin resistance. The article explores the potential benefits of enhancing GLP-1 action for improving obesity and insulin resistance in people with type 2 diabetes. It also discusses the effects of pharmacological GIP action and the differences between physiological and pharmacological actions of GIP. [Extracted from the article]

Cyclosporine A (CsA) is used for the treatment of dry eye (DE) with good clinical results, improving tear secretion and decreasing subjective symptoms. These effects are attributed to the improved tear film dynamics, but there are no data on the effect of CsA on the abnormal sensory nerve activity characteristic in DE. Our purpose was to evaluate the CsA effect on the enhanced activity of corneal cold thermoreceptors in a tear-deficient DE animal model using in vitro extracellular recording of cold thermoreceptors nerve terminal impulses (NTIs) before and in the presence of CsA. NTI shape was also analyzed. Blinking frequency and tearing rate were also measured in awake animals before and after topical CsA. CsA increased the tearing and blinking of treated animals. CsA significantly decreased the peak response to cold of cold thermoreceptors. Neither their spontaneous NTIs discharge rate nor their cooling threshold were modified. CsA also seemed to reverse some of the changes in NTI shape induced by tear deficiency. These data suggest that, at least in part, the beneficial clinical effects of CsA in DE can be attributed to a direct effect on sensory nerve endings, although the precise mechanisms underlying this effect need further studies to be fully clarified. [ABSTRACT FROM AUTHOR]

The function of sensory cells has been largely investigated in the field of neuroscience for how they report the physical and chemical changes of the environment ("exteroception") and of internal physiology ("interoception"). Investigations over the last century have largely focused on the morphological, electrical and receptor properties of sensory cells in the nervous system focusing on conscious perception of external cues or homeostatic regulation upon detection of internal cues. Research in the last decade has uncovered that sensory cells can often sense polymodal cues, such as mechanical, chemical, and/ or thermal. Furthermore, sensory cells in the peripheral as well as in the central nervous system can detect evidence associated with the invasion of pathogenic bacteria or viruses. The corresponding neuronal activation associated with the presence of pathogens can impact their classical functions within the nervous system and trigger the release of compounds modulating the response to intruders, either triggering pain to raise awareness, enhancing host defense or sometimes, aggravating the infection. This perspective brings to light the need for interdisciplinary training in immunology, microbiology and neuroscience for the next generation of investigators in this field. [ABSTRACT FROM AUTHOR]

When an inflammatory response is elicited in the dental pulp, internal tissue pressure increases, which mechanically stimulates dental pulp cells, including nerve terminals and odontoblasts [[7]]. The authors developed a model that mimicked the effect of increased tissue pressure on inflammatory responses in the dental pulp, and direct mechanical stimulation was applied to TG neurons. The [cAMP] SB i sb response from the odontoblasts approximating the stimulated TG neurons was measured using an odontoblast-neuron co-culture system. Saito et al. determined the role of the CGRP-CGRP receptor axis in axon reflex occurrence by measuring intracellular cyclic adenosine monophosphate (cAMP) ([cAMP] SB i sb ) levels via G SB s sb protein-coupled CGRP receptor activation in odontoblasts [[8]]. [Extracted from the article]

Chronic neuropathic pain greatly impairs the affected individual's quality of life. Development of effective disease-modifying therapies is imperative to alleviate the ongoing public health issues associated with opioid-based treatments. Natural killer (NK) cells possess the capability to target several candidate pain-inducing factors within the PNS, including hyperexcitable sensory neurons, miswired sensory nerve endings, senescent structural cells, and inflammatory immune cells. Comprehensive understanding of NK cell function in various pain diseases may guide the development of novel therapies for neuropathic pain. Novel disease-modifying treatments for neuropathic pain are urgently required. The cellular immune response to nerve injury represents a promising target for therapeutic development. Recently, the role of natural killer (NK) cells in both CNS and PNS disease has been the subject of growing interest. In this opinion article, we set out the case for NK cell-based intervention as a promising avenue for development in the management of neuropathic pain. We explore the potential cellular and molecular targets of NK cells in the PNS by contrasting with their reported functional roles in CNS diseases, and we suggest strategies for using the beneficial functions of NK cells and immune-based therapeutics in the context of neuropathic pain. [ABSTRACT FROM AUTHOR]

Cyclic nucleotide-gated (CNG) channels transduce chemical signals into electrical signals in sensory receptors and neurons. They are activated by cGMP or cAMP, which bind to the cyclic nucleotide-binding domain (CNBD) to open a gate located 50-60 Å away in the central cavity. Structures of closed and open vertebrate CNG channels have been solved, but the conformational landscape of this allosteric gating remains to be elucidated and enriched. Here, we report structures of the cGMP-activated human cone photoreceptor CNGA3/CNGB3 channel in closed, intermediate, pre-open and open states in detergent or lipid nanodisc, all with fully bound cGMP. The pre-open and open states are obtained only in the lipid nanodisc, suggesting a critical role of lipids in tuning the energetic landscape of CNGA3/CNGB3 activation. The different states exhibit subunit-unique, incremental and distinct conformational rearrangements that originate in the CNBD, propagate through the gating ring to the transmembrane domain, and gradually open the S6 cavity gate. Our work illustrates a spatial conformational-change wave of allosteric gating of a vertebrate CNG channel by its natural ligand and provides an expanded framework for studying CNG properties and channelopathy. Hu et al. present eight cryo-EM structures of the human cone photoreceptor CNGA3/CNGB3 channel in the closed, intermediate, pre-open and open states, all fully bound with cGMP. These structures provide an unprecedented view of the conformational trajectory of CNG channel activation. [ABSTRACT FROM AUTHOR]

The consequences of sub-lethal levels of ambient air pollution are underestimated for insects, for example, the accumulation of particulate matter on sensory receptors located on their antennae may have detrimental effects to their function. Here we show that the density of particulate matter on the antennae of houseflies (Musca domestica) collected from an urban environment increases with the severity of air pollution. A combination of behavioural assays, electroantennograms and transcriptomic analysis provide consistent evidence that a brief exposure to particulate matter pollution compromises olfactory perception of reproductive and food odours in both male and female houseflies. Since particulate matter can be transported thousands of kilometres from its origin, these effects may represent an additional factor responsible for global declines in insect numbers, even in pristine and remote areas. The consequences for insects of sub-lethal levels of ambient particulate matter pollution exposure have not received much attention. Here, the authors show that accumulation of particulate matter on houseflies severely compromises their olfactory and other key physiological functions. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Wu et al. report that miR-1306-3p might be an endogenous ligand to activate P2X3 receptors, thus enhancing dorsal root ganglion neuron excitability and contributing to visceral pain. Mounting evidence indicates that microRNAs (miRNAs) play critical roles in various pathophysiological conditions and diseases, but the physiological roles of extracellular miRNAs on the disease-related ion channels remain largely unknown. Here, we showed that miR-1306-3p evoked action potentials and induced inward currents of the acutely isolated rat dorsal root ganglion (DRG) neurons. The miR-1306-3p–induced effects were significantly inhibited by A317491, a potent inhibitor of the P2X3 receptor (P2X3R), or disappeared after the knockdown of P2X3Rs in DRG neurons. We further identified R180, K315, and R52 as the miR-1306-3p interaction sites on the extracellular domain of P2X3Rs, which were distinct from the orthosteric ATP-binding sites. Intrathecal injection of miR-1306-3p produced visceral pain but not somatic pain in normal control rats. Conversely, intrathecal application of a miR-1306-3p antagomir and A317491 significantly alleviated visceral pain in a rat model of chronic visceral pain. Together, our findings suggest that miR-1306-3p might function as an endogenous ligand to activate P2X3Rs, eventually leading to chronic visceral pain. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to The aim of the research is to identify the effect of stretching exercises by facilitating the neuromuscular sensory receptors (PNF) in improving the working muscle strength, range of motion, and the degree of pain for people with ankle joint injuries for team and individual sports athletes. The researchers used the experimental approach with a one-group design with two pre and post-tests. The sample was chosen by the intentional method from the players with team and individual games for young people in the National Center for the Care of Sports Talent in Baghdad Governorate, who are injured in the ankle joint and from the second degree, who are (8) players. They were distributed among the games (2 basketball players, 2 volleyball players, 2 handball players, 2 swimmers), as stretching exercises were used by facilitating neuromuscular sensory receptors (PNF) for a period of (6) weeks, with (3) rehabilitation units in the week. The researchers concluded that stretching exercises with neuromuscular facilitation of sensory receptors (PNF) have a positive effect on the rehabilitation of ankle injury for sports athletes (basketball, volleyball, handball, swimming), due to the appearance of an improvement and a clear increase in the muscle strength of the working muscles and the range of motion of the ankle joint, as well as Reducing the degree of pain in the affected area. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the dynamic aspects of elbow stability, we aimed to analyze sensory nerve endings in the ligaments and the capsule of elbow joints. Materials and methods: The capsule with its anterior (AJC) and posterior (PJC) parts, the radial collateral ligament (RCL), the annular ligament (AL), and the ulnar collateral ligament with its posterior (PUCL), transverse (TUCL) and anterior parts (AUCL) were dissected from eleven human cadaver elbow joints. Sensory nerve endings were analyzed in two levels per specimen as total cell amount/ cm2 after immunofluorescence staining with low-affinity neurotrophin receptor p75, protein gene product 9.5, S-100 protein and 4′,6-Diamidin-2-phenylindol, Carbonic anhydrase II and choline acetyltransferase on an Apotome microscope according to Freeman and Wyke's classification. Results: Free nerve endings were the predominant mechanoreceptor in all seven structures followed by Ruffini, unclassifiable, Golgi-like, and Pacini corpuscles (p ≤ 0.00001, respectively). Free nerve endings were observed significant more often in the AJC than in the RCL (p < 0.00002). A higher density of Ruffini endings than Golgi-like endings was observed in the PJC (p = 0.004). The RCL contained significant more Ruffini endings than Pacini corpuscles (p = 0.004). Carbonic anhydrase II was significantly more frequently positively immunoreactive than choline acetyltransferase in all sensory nerve endings (p < 0.05). Sensory nerve endings were significant more often epifascicular distributed in all structures (p < 0.006, respectively) except for the AJC, which had a pronounced equal distribution (p < 0.00005). Conclusion: The high density of free nerve endings in the joint capsule indicates that it has pronounced nociceptive functions. Joint position sense is mainly detected by the RCL, AUCL, PUCL, and the PJC. Proprioceptive control of the elbow joint is mainly monitored by the joint capsule and the UCL, respectively. However, the extreme range of motion is primarily controlled by the RCL mediated by Golgi-like endings. [ABSTRACT FROM AUTHOR]

In 1998, I was asked by the American Physiological Society to review a book written by Dr. Michael de Burgh Daly, Peripheral Arterial Chemoreceptors and Respiratory-Cardiovascular Integration. Inspired by this work, I came to appreciate how researchers in the later stages of their careers and who provide a detailed review of their experimental approach might effectively contribute to science, especially to the benefit of young scientists (Yu J. The Physiologist 41: 231, 1998.). This article is written in that vein. Over several decades of intensive investigation of cardiopulmonary reflexes, focused on the sensory receptors, my colleagues and I advanced a novel multiple-sensor theory (MST) to explain the role of the vagal mechanosensory system. Described here is our research journey through various stages of developing MST and the process of how the problem was identified, approached, and tackled. MST redefines conventional mechanosensor doctrines and is supported by new studies that clarify a century of research data. It entails reinterpretation of many established findings. Hopefully, this article will benefit young scientists, such as graduate and postdoctoral students in the cardiopulmonary sensory research field. [ABSTRACT FROM AUTHOR]

Objective: The skin is a sensory organ, densely innervated with various types of sensory nerve endings, capable of discriminating touch, environmental sensations, proprioception, and physical affection. Neurons communication with skin cells confer to the tissue the ability to undergo adaptive modifications during response to environmental changes or wound healing after injury. Thought for a long time to be dedicated to the central nervous system, the glutamatergic neuromodulation is increasingly described in peripheral tissues. Glutamate receptors and transporters have been identified in the skin. There is a strong interest in understanding the communication between keratinocytes and neurons, as the close contacts with intra‐epidermal nerve fibers is a favorable site for efficient communication. To date, various coculture models have been described. However, these models were based on non‐human or immortalized cell line. Even the use of induced pluripotent stem cells (iPSCs) is posing limitations because of epigenetic variations during the reprogramming process. Methods: In this study, we performed small molecule‐driven direct conversion of human skin primary fibroblasts into induced neurons (iNeurons). Results: The resulting iNeurons were mature, showed pan‐neuronal markers, and exhibited a glutamatergic subtype and C‐type fibers characteristics. Autologous coculture of iNeurons with human primary keratinocytes, fibroblasts, and melanocytes was performed and remained healthy for many days, making possible to study the establishment of intercellular interactions. Conclusion: Here, we report that iNeurons and primary skin cells established contacts, with neurite ensheathment by keratinocytes, and demonstrated that iNeurons cocultured with primary skin cells provide a reliable model to examine intercellular communication. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chemotherapy‐induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. Experimental Approach: Paclitaxel (PTX) was used to establish CINP. Quantitative real‐time polymerase chain reaction (qRT‐PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot‐plate and von Frey tests. Whole‐cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. Key Results: Expression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX‐treated mice. Additionally, OXTR activation up‐regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage‐gated sodium currents, particularly the voltage‐gated sodium channel 1.7 (NaV1.7) current, that plays an indispensable role in PTX‐induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX‐treated mice. Conclusion and Implications: The OXTR in small‐sized DRG neurons is up‐regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of NaV1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP. [ABSTRACT FROM AUTHOR]

Introduction: TRPV1 channels are responsible for detecting noxious stimuli such as heat (>43C), acid, and capsaicin. P2 receptors are involved in numerous functions of the nervous system, including its modulation and specific response to the application of ATP. In our experiments, we investigated the dynamics of calciumtransients in DRG neurons associated with TRPV1 channel desensitization and the effect of activation of P2 receptors on this process. Methods: We used DRG neurons from rats P7-8 after 1-2 days of culture to measure calcium transients by microfluorescence calcimetry using the fluorescent dye Fura-2 AM. Results: We have shown that DRG neurons of small (d < 22µm) and medium (d = 24-35µm) sizes differ in TRPV1 expression. Thus, TRPV1 channels are mainly present in small nociceptive neurons (59% of the studied neurons). Short-term sequential application of the TRPV1 channel agonist capsaicin (100nM) leads to the desensitization of TRPV1 channels by the type of tachyphylaxis. We identified three types of sensory neurons based on responses to capsaicin: (1) desensitized 37.5%, (2) non-desensitized 34.4%, and (3) insensitive 23.4% to capsaicin. It has also been shown that P2 receptors are present in all types of neurons according to their size. So, the responses to ATP were different in different-sized neurons. Applying ATP (0.1 mM) to the intact cell membrane after the onset of tachyphylaxis caused recovery of calcium transients in response to the addition of capsaicin in these neurons. The amplitude of the capsaicin response after reconstitution with ATP was 161% of the previous minimal calcium transient in response to capsaicin. Discussion: Significantly, the restoration of the amplitude of calcium transients under the ATP application is not associated with changes in the cytoplasmic pool of ATP because this molecule does not cross the intact cell membrane, thus, our results show the interaction between TRPV1 channels and P2 receptors. It is important to note that the restoration of the amplitude of calcium transients through TRPV1 channels after application of ATP was observed mainly in cells of 1-2 days of cultivation. Thus, the resensitization of capsaicin transients following P2 receptor activation may be associated with the regulation of the sensitivity of sensory neurons. [ABSTRACT FROM AUTHOR]

Among the cues that a mosquito uses to find a host for blood-feeding, the smell of the host plays an important role. Previous studies have shown that host odors contain hundreds of chemical odorants, which are detected by different receptors on the peripheral sensory organs of mosquitoes. But how individual odorants are encoded by downstream neurons in the mosquito brain is not known. We developed an in vivo preparation for patch-clamp electrophysiology to record from projection neurons and local neurons in the antennal lobe of Aedes aegypti. Combining intracellular recordings with dye-fills, morphological reconstructions, and immunohistochemistry, we identify different sub-classes of antennal lobe neurons and their putative interactions. Our recordings show that an odorant can activate multiple neurons innervating different glomeruli, and that the stimulus identity and its behavioral preference are represented in the population activity of the projection neurons. Our results provide a detailed description of the second-order olfactory neurons in the central nervous system of mosquitoes and lay a foundation for understanding the neural basis of their olfactory behaviors. The human smell that attracts mosquitoes includes many chemical odorants. Here, authors used electrophysiology to probe neurons in the antennal lobe region of the tiny mosquito brain and found that they represent odorants using a combinatorial code. [ABSTRACT FROM AUTHOR]

Odontoblasts are involved in sensory generation as sensory receptor cells and in dentin formation. We previously reported that an increase in intracellular cAMP levels by cannabinoid 1 receptor activation induces Ca2+ influx via transient receptor potential vanilloid subfamily member 1 channels in odontoblasts, indicating that intracellular cAMP/Ca2+ signal coupling is involved in dentinal pain generation and reactionary dentin formation. Here, intracellular cAMP dynamics in cultured human odontoblasts were investigated to understand the detailed expression patterns of the intracellular cAMP signaling pathway activated by the Gs protein-coupled receptor and to clarify its role in cellular functions. The presence of plasma membrane Gαs as well as prostaglandin I2 (IP), 5-hydroxytryptamine 5-HT4 (5-HT4), dopamine D1 (D1), adenosine A2A (A2A), and vasoactive intestinal polypeptide (VIP) receptor immunoreactivity was observed in human odontoblasts. In the presence of extracellular Ca2+, the application of agonists for the IP (beraprost), 5-HT4 (BIMU8), D1 (SKF83959), A2A (PSB0777), and VIP (VIP) receptors increased intracellular cAMP levels. This increase in cAMP levels was inhibited by the application of the adenylyl cyclase (AC) inhibitor SQ22536 and each receptor antagonist, dose-dependently. These results suggested that odontoblasts express Gs protein-coupled IP, 5-HT4, D1, A2A, and VIP receptors. In addition, activation of these receptors increased intracellular cAMP levels by activating AC in odontoblasts. [ABSTRACT FROM AUTHOR]

Cryptochromes constitute an extensive class of blue-light sensory receptors that regulate the processes of development and circadian rhythm in plants. These photoreceptors can also act as magnetoreceptors. As a chromophore, cryptochromes bind the flavin adenine dinucleotide (FAD) in the photolyase homology region (PHR) domain; near the FAD-binding site, a C-terminal extension CCE is attached to it. The cryptochrome activation is initiated by FAD photoreactions with electron/proton transfer and formation of redox forms. During FAD photoreduction, the protein is exposed to a conformational change causing a separation of the PHR domain and CCE, which is accompanied by the formation of functionally active oligomers of cryptochrome molecules. Photooligomerization is considered as a key process required for a signaling activity of cryptochromes. [ABSTRACT FROM AUTHOR]