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Efficient data processing is heavily reliant on prioritizing specific stimuli and categorizing incoming information. Within human biological systems, dorsal root ganglions (particularly nociceptors situated in the skin) perform a pivotal role in detecting external stimuli. These neurons send warnings to our brain, priming it to anticipate potential harm and prevent injury. In this study, we explore the potential of using a ferroelectric memristor device structured as a metal–ferroelectric–insulator–semiconductor as an artificial nociceptor. The aim of this device is to electrically receive external damage and interpret signals of danger. The TiN/HfAlOx (HAO)/HfSiOx (HSO)/n+ Si configuration of this device replicates the key functions of a biological nociceptor. The emulation includes crucial aspects, such as threshold reactivity, relaxation, no adaptation, and sensitization phenomena known as "allodynia" and "hyperalgesia." Moreover, we propose establishing a connection between nociceptors and synapses by training the Hebbian learning rule. This involves exposing the device to injurious stimuli and using this experience to enhance its responsiveness, replicating synaptic plasticity. [ABSTRACT FROM AUTHOR]

To evaluate the P2X3 receptor antagonist, gefapixant, for treating moderate-to-severe endometriosis-related pain. Randomized, double-blind, phase 2, and proof-of-concept trial. Premenopausal women age 18–49 years with moderate-to-severe endometriosis-related pain who were not using hormonal treatment. Gefapixant (45-mg twice daily) or placebo over two menstrual cycles. Participants rated peak pelvic pain severity daily on a 0 (no pain) – 10 (extremely severe pain) scale. The primary endpoint was change from baseline in average daily peak pelvic pain severity during treatment cycle 2. All 187 participants randomized (gefapixant, N = 94; placebo, N = 93) took ≥1 dose of investigational treatment and all but six in each treatment group completed the trial. The model-based least-squares mean reduction from baseline in average daily peak pelvic pain severity during treatment cycle 2 was –2.2 for gefapixant and –1.7 for placebo (difference, –0.5; 95% confidence interval, –1.01 to 0.03). In secondary analyses, the difference between gefapixant and placebo in peak pelvic pain severity reduction from baseline on menstrual days was –0.6 (95% confidence interval, –1.18 to –0.06) and –0.5 (95% confidence interval, –1.04 to 0.03) on nonmenstrual days. Taste-related adverse events were reported in 31.9% of participants for gefapixant vs. 4.3% for placebo. Pharmacokinetic assessments at months 1 and 2 clinic visits indicated that of the 94 participants in the gefapixant group, 39 had detectable levels of gefapixant in the blood for both assessments although 38 had no detectable levels for ≥1 assessment. Gefapixant (45-mg twice daily) was not shown to be superior to placebo in reducing endometriosis-related pain, although the results directionally favored gefapixant. This trial result should be considered inconclusive given possible issues with treatment compliance. NCT03654326. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. This in vivo calcium imaging study shows that spinal cord stimulation inhibited the activation of superficial neurokinin 1 receptor–positive neurons, unraveling a new mechanism for spinal cord stimulation–induced analgesia. Spinal cord stimulation (SCS) is an effective modality for pain treatment, yet its underlying mechanisms remain elusive. Neurokinin 1 receptor–positive (NK1R+) neurons in spinal lamina I play a pivotal role in pain transmission. To enhance our mechanistic understanding of SCS-induced analgesia, we investigated how different SCS paradigms modulate the activation of NK1R+ neurons, by developing NK1R-Cre;GCaMP6s transgenic mice and using in vivo calcium imaging of superficial NK1R+ neurons under anesthesia (1.5% isoflurane). Neurokinin 1 receptor–positive neurons in the lumbar spinal cord (L4-5) showed a greater activation by electrical test stimulation (TS, 3.0 mA, 1 Hz) at the hindpaw at 2 weeks after tibia-sparing nerve injury (SNI-t) than in naïve mice. Spinal cord stimulation was then delivered through a bipolar plate electrode placed epidurally at L1-2 level. The short-term 50-Hz high-intensity SCS (80% motor threshold [MoT], 10 minutes) induced robust and prolonged inhibition of NK1R+ neuronal responses to TS in both naïve and SNI-t mice. The 30-minute 50-Hz and 900-Hz SCS applied at moderate intensity (50% MoT) also significantly inhibited neuronal responses in SNI-t mice. However, at low intensity (20% MoT), the 30-minute 900-Hz SCS only induced persistent neuronal inhibition in naïve mice, but not in SNI-t mice. In conclusion, both 10-minute high-intensity SCS and 30-minute SCS at moderate intensity inhibit the activation of superficial NK1R+ neurons, potentially attenuating spinal nociceptive transmission. Furthermore, in vivo calcium imaging of NK1R+ neurons provides a new approach for exploring the spinal neuronal mechanisms of pain inhibition by neuromodulation pain therapies. [ABSTRACT FROM AUTHOR]

• Mechanical allodynia was ameliorated by inhibition of IL-33/ST2 signaling in the TG. • Fibroblast ablation in the TG caused the loss of IL-33 expression after IONI. • Fibroblast ablation in the TG inhibited the development of mechanical allodynia after IONI. • IL-33 enhanced TRPA1 membrane translocation and TRPA1 mediated Ca2+ influx. Damage to the peripheral nerves of trigeminal ganglion (TG) neurons leads to intractable orofacial neuropathic pain through the induction of neuroinflammation. However, the details of this process are not yet fully understood. Here, we found that fibroblast-derived interleukin (IL)-33 was required for the development of mechanical allodynia in whisker pad skin following infraorbital nerve injury (IONI). The amount of IL-33 in the TG increased after IONI when the mice exhibited mechanical allodynia. Neutralization of IL-33 in the TG inhibited the development of IONI-induced mechanical allodynia. Conversely, intra-TG administration of recombinant human IL-33 (rhIL-33) elicited mechanical allodynia in naïve mice. IL-33 and its receptor were exclusively expressed in fibroblasts and neurons, respectively, in the TG. Fibroblast ablation caused the loss of IL-33 in the TG and delayed the development of mechanical allodynia after IONI. rhIL-33 elicited an increase in intracellular Ca2+ concentration and subsequent enhancement of Ca2+ influx via transient receptor potential ankyrin 1 (TRPA1) in primary cultured TG neurons. Additionally, rhIL-33 facilitated membrane translocation of TRPA1 in the TG. Mechanical allodynia caused by intra-TG administration of rhIL-33 was significantly inhibited by pharmacological blockade or gene silencing of TRPA1 in the TG. Inhibition of protein kinase A abrogated TRPA1 membrane translocation and delayed mechanical allodynia after IONI. Substance P stimulation caused upregulation of IL-33 expression in primary cultured fibroblasts. Preemptive administration of a neurokinin-1 receptor antagonist in the TG attenuated mechanical allodynia and IL-33 expression following IONI. Taken together, these results indicate that fibroblast-derived IL-33 exacerbates TG neuronal excitability via suppression of tumorigenicity 2 (ST2)-TRPA1 signaling, ultimately leading to orofacial neuropathic pain. [ABSTRACT FROM AUTHOR]

The present study has investigated whether circulating estrogen level variations in the pro-estrus and estrus phases of the intact rats and estrogen depletion in the ovariectomized animals (OVX) adjust the formalin-induced nociceptive behaviors. During the pro-estrus and estrus phases of rats' estrus cycle and in the OVX rats, 17β-estradiol and ICI 182,780 (estrogen receptor antagonist) were administered into the right paragigantocellularis lateralis (LPGi) nucleus. Then, the formalin-induced flexing and licking responses were recorded for 60 min. The findings of this study revealed that intra-LPGi administration of 17β-estradiol (0.8 μmol) reduced the formalin-induced flexing and licking duration in pro-estrus and estrus rats (P < 0.001), suggesting an analgesic effect. 17β-Estradiol injection into the LPGi nucleus of OVX rats increased the flexing duration (P < 0.05) while decreasing the licking duration (P < 0.05) of the formalin test. The pain modulatory effect of 17β-estradiol on the flexing response was reversed by ICI 182,780 (15 nmol) in the pro-estrus (P < 0.001) and estrus rats (P < 0.001) but not in the OVX rats. Also, pretreatment of LPGi nucleus with ICI 182,780 reversed the analgesic effect of 17β-estradiol on the licking response in the pro-estrus (P < 0.05), estrus (P < 0.001), and OVX rats (P < 0.001). These results suggest that the pain threshold in intact female rats is modulated independently of the estrus state. Still, the basal level of plasma estrogen and the activation of its receptors are necessary for pain modulation. [ABSTRACT FROM AUTHOR]

Introduction: The paraventricular thalamic nucleus (PVT) is recognized for its critical role in pain regulation, yet the precise molecular mechanisms involved remain poorly understood. Here, we demonstrated an essential role of the microglial adenosine A2A receptor (A2AR) in the PVT in regulating pain sensation and non-opioid analgesia. Method and results: Specifically, A2AR was predominantly expressed in ionized calcium binding adapter molecule 1 (Iba1)-positive microglia cells within the PVT, with expression levels remaining unchanged in mice experiencing persistent inflammatory pain induced by complete Freund's adjuvant (CFA). Pharmacological activation of local PVT A2AR with its agonist CGS21680 induced significantly decreased 50% paw withdrawal threshold (50%PWTs) and paw withdrawal latency (PWLs), as measured by the Von Frey test and Hargreaves test in adult mice. Conversely, intra-PVT infusion of A2AR antagonist SCH58261 increased 50%PWTs and PWLs in mice; a robust analgesic effect was also observed in CFA mice with inflammatory pain. Importantly, these analgesic effects of A2AR antagonist SCH58261 were not affected by adjunctive intraperitoneal administration of naloxone or rimonabant, inhibitors of opioid receptor and cannabinoid CB1 receptor (CB1R), respectively. Discussion: Overall, these pharmacological experiments underscore an essential role of microglia-expressed A2AR with in PVT in pain sensation while revealing a novel analgesic action independent of opioid and cannabinoids receptors. Thus, these findings highlight PVT microglial adenosine A2A receptor as a promising target for novel approaches to pain modulation and future analgesic development. [ABSTRACT FROM AUTHOR]

Background/Objectives: Ketamine offers effective pain relief with fewer side effects than traditional analgesics, making it a promising alternative for acute pain treatment. However, further research is needed to fully assess its role in perioperative care. This umbrella review aimed to compile the highest-quality evidence available regarding the application of ketamine in managing acute pain. Methods: A thorough search of the literature was carried out in PubMed, Scopus, and the Cochrane Library, including systematic reviews that focused on the application of ketamine in managing acute pain. The data extraction included the research type, analgesics used, number of studies and patients per review, pain types, scoring methods, ketamine doses, administration routes, and reporting guidelines. Results: Of the 807 records identified, 20 studies met the inclusion criteria. In accordance with the AMSTAR-2 evaluation, most of the systematic reviews were rated as critically low quality. Intravenous ketamine administered during the perioperative period was found to reduce the pain intensity of acute pain within 15–30 and 60 min following treatment, and decrease postoperative opioid consumption by 14–50% at both 24 and 48 h after surgery. Conclusions: Evidence shows that intravenous ketamine reduces the pain intensity, postoperative opioid use, and the risk of vomiting and nausea while improving analgesia, making it a valuable adjunct in perioperative pain management. [ABSTRACT FROM AUTHOR]

Introduction: Neuropathic pain is a debilitating neurological disorder and is on the rise. Since no effective treatment has been so far approved to combat the complex pathological mechanisms behind neuropathic pain, finding new therapeutic candidates is of great importance. Astaxanthin (AST) is a carotenoid with strong antioxidant, and anti-inflammatory activities. Purpose: The present research aimed to evaluate the ameliorative effects of AST on a rat model of neuropathic pain. Methods: To induce neuropathic pain, a chronic constriction injury (CCI) model was employed. Accordingly, Wistar rats were divided into nine groups of six including sham, negative control group (CCI), positive control group gabapentin (100 mg/kg), AST (5, 10 mg/kg), flumazenil (0.5 mg/kg), naloxone (0.1 mg/kg), AST (10 mg/kg) + flumazenil (0.5 mg/kg), and AST (10 mg/kg) + naloxone (0.1 mg/kg) were administered intraperitoneally on days 1, 3, 5, 7, 10, and 14. To check the experimental signs of neuropathic pain and motor dysfunction, hot plate, acetone drop, and open field tests were used at the same time points. Additionally, biochemical assay and zymography were done on days 7 and 14 to assess the changes in catalase, glutathione and nitrite, as well as matrix metalloproteinases (MMP-2 and MMP-9). Besides, histological evaluations were performed for tissue damages on days 7 and 14. Results and discussion: Results indicated that intraperitoneal injection of AST improved allodynia, hyperalgesia, and locomotor activity after CCI. AST also increased catalase and glutathione while suppressing nitrite, MMP-2, and MMP-9 activity through opioid/benzodiazepine receptors. Conclusion: The results highlighted AST as a promising candidate against neuropathic pain with beneficial effects on motor function by suppressing inflammatory mediators, and augmenting antioxidant factors, passing through opioid/benzodiazepine receptors. [ABSTRACT FROM AUTHOR]

Background: Chronic pain poses a clinical challenge due to its associated costly disability and treatment needs. Determining how pain transitions from acute to chronic is crucial for effective management. Upregulation of the chemokine C-X-C motif ligand 12 (CXCL12) in nociceptive pathway is associated with chronic pain. Our previous study has reported that elevated plasma CXCL12 mediates intracerebral neuroinflammation and the comorbidity of cognitive impairment in neuropathic pain, but whether it is also involved in the pathogenesis of pathologic pain has not been investigated. Methods: Intravenous or intrathecal injection (i.v. or i.t.) of recombinant mouse CXCL12, neutralizing antibody (anti-CXCL12) or AMD3100 [an antagonist of its receptor C-X-C chemokine receptor type 4 (CXCR4)] was used to investigate the role of CXCL12 signaling pathway in pain chronicity. Two behavioral tests were used to examine pain changes. ELISA, immunofluorescence staining, Western blot, quantitative Real Time-PCR and Cytokine array were applied to detect the expressions of different molecules. Results: We found that increased plasma CXCL12 was positively correlated with pain severity in both chronic pain patients and neuropathic pain model in mice with spared nerve injury (SNI). Neutralizing plasma CXCL12 mitigated SNI-induced hyperalgesia. A single i.v. injection of CXCL12 induced prolonged mechanical hyperalgesia and activation of the nociceptive pathway. Multiple intravenous CXCL12 caused persistent hypersensitivity, enhanced structural plasticity of nociceptors and up-regulation of the CXCL12/CXCR4 axis in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH). However, intrathecal blocking of CXCL12/CXCR4 pathway by CXCL12 antibody or CXCR4 antagonist AMD3100 significantly alleviated CXCL12-induced pain hypersensitivity and pathological changes. Conclusions: Our study provides strong evidence that a sustained increase in plasma CXCL12 contributes to neuropathic pain through a positive feedback loop that enhances nociceptor plasticity, and suggests that targeting CXCL12/CXCR4 axis in plasma or nociceptive pathways has potential value in regulating pain chronicity. Highlights: 1) Plasma CXCL12 in neuropathic pain states were positively correlated with pain severity. 2) A sustained increase in plasma CXCL12 contributes to pain chronicity. 3) Elevated plasma CXCL12 enhances spinal synaptic structural plasticity of pain through positive feedback. [ABSTRACT FROM AUTHOR]

The role of nociceptive nerves in modulating immune responses to harmful stimuli via pain or itch induction remains controversial. Compared to conventional surgery, various implant surgeries are more prone to infections even with low bacterial loads. In this study, an optogenetic technique is introduced for selectively activating peripheral nociceptive nerves using a fully implantable, wirelessly rechargeable optogenetic device. By targeting nociceptors in the limbs of awake, freely moving mice, it is found that activation induces anticipatory immunity in the innervated territory and enhances the adhesion of various host cells to the implant surface. This effect mediates acute immune cell‐mediated killing of Staphylococcus aureus on implants and enables the host to win "implant surface competition" against Staphylococcus aureus. This finding provides new strategies for preventing and treating implant‐associated infections. [ABSTRACT FROM AUTHOR]

Purpose: Pregnancy-induced analgesia develops in late pregnancy, but its mechanisms are unclear. The anterior cingulate cortex (ACC) plays a key role in the pathogenesis of neuropathic pain. The authors hypothesized that pregnancy-induced analgesia ameliorates neuropathic pain by suppressing activation of microglia and the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and by upregulating opioid receptors in the ACC in late-pregnant mice. Methods: Neuropathic pain was induced in non-pregnant (NP) or pregnant (P) C57BL/6JJmsSlc female mice by partial sciatic nerve ligation (PSNL). The nociceptive response was evaluated by mechanical allodynia and activation of microglia in the ACC was evaluated by immunohistochemistry. The expressions of phosphorylated AMPA receptors and opioid receptors in the ACC were evaluated by immunoblotting. Results: In von Frey reflex tests, NP-PSNL-treated mice showed a lower 50% paw-withdrawal threshold than NP-Naïve mice on experimental day 9. No difference in 50% paw-withdrawal threshold was found among the NP-Naïve, NP-Sham, P-Sham, and P-PSNL-treated mice. The number of microglia in the ACC was significantly increased in NP-PSNL-treated mice compared to NP-Sham mice. Immunoblotting showed significantly increased expression of phosphorylated AMPA receptor subunit GluR1 at Ser831 in NP-PSNL-treated mice compared to NP-Sham mice. Immunoblotting also showed significantly increased δ-opioid receptor in the ACC in P-Sham and P-PSNL-treated mice compared to NP-Sham mice. Conclusion: Pregnancy-induced analgesia ameliorated neuropathic pain by suppressing activation of microglia and the expression of phosphorylated AMPA receptor subunit GluR1 at Ser831, and by upregulation of the δ-opioid receptor in the ACC in late-pregnant mice. [ABSTRACT FROM AUTHOR]

The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurons from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurons from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurons from a female macaque monkey. Critically, neurons recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurons. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurons and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurons. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted. [ABSTRACT FROM AUTHOR]

Ozone (O3) is an unstable, highly oxidative gas that rapidly decomposes into oxygen. The therapeutic use of O3 dates back to the beginning of 20th century and is currently based on the application of low doses, inducing moderate oxidative stress that stimulates the antioxidant cellular defences without causing cell damage. In recent decades, experimental investigations allowed the establishment of some basic mechanisms accounting for the therapeutic effects of eustress-inducing low-dose O3. In this review, special attention was given to the impact of O3 administration on the cell oxidant–antioxidant status, O3 anti-inflammatory and analgesic properties, efficacy in improving tissue regeneration, and potential anticancer action. Low O3 concentrations proved to drive the cell antioxidant response mainly by activating nuclear factor erythroid 2-related factor 2. The anti-inflammatory effect relies on the downregulation of pro-inflammatory factors and the modulation of cytokine secretion. The painkilling action is related to anti-inflammatory processes, inhibition of apoptosis and autophagy, and modulation of pain receptors. The regenerative potential depends on antioxidant, anti-inflammatory, anti-apoptotic, and pro-proliferative capabilities, as well as fibroblast activation. Finally, the anticancer potential is based on oxidant and anti-inflammatory properties, as well as the inhibition of cell proliferation, invasion, and migration and the induction of apoptosis. [ABSTRACT FROM AUTHOR]

Sensitization of primary afferents is essential for the development of pain, but the molecular events involved in this process and its reversal are poorly defined. Recent studies revealed that acid-sensing ion channels (ASICs) control the excitability of nociceptors in the urinary bladder. Using genetic and pharmacological tools we show that ASICs are functionally coupled with voltage-gated Ca2+ channels to mediate Ca2+ transients evoked by acidification in sensory neurons. Genetic deletion of Asic3 of these sensory neurons does not alter the mechanical response of bladder afferents to distension in naïve mice. Both control and sensory neuron conditional Asic3 knockout (Asic3-KO) mice with chemical cystitis induced by cyclophosphamide (CYP) administration exhibit frequent low volume voiding events. However, these changes are transient and revert over time. Of major significance, in Asic3-KO mice, CYP treatment results in the sensitization of a subset of bladder afferents and pelvic allodynia that persist beyond the resolution of the inflammatory process. Thus, ASICs function is necessary to prevent long-term sensitization of visceral nociceptors. [ABSTRACT FROM AUTHOR]

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2–3.375 μg/kg, 15‐min infusion) and different infusion durations (0.2 and 1 μg/kg, 2‐ or 15‐min infusion). The area under the plasma concentration‐time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose‐linear among 0.2–3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half‐life (t1/2) of 1.5 h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1–2 h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2 h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions. [ABSTRACT FROM AUTHOR]

In vivo analysis of protein function in nociceptor subpopulations using antisense oligonucleotides and short interfering RNAs is limited by their non-selective cellular uptake. To address the need for selective transfection methods, we covalently linked isolectin B4 (IB4) to streptavidin and analyzed whether it could be used to study protein function in IB4(+)-nociceptors. Rats treated intrathecally with IB4-conjugated streptavidin complexed with biotinylated antisense oligonucleotides for protein kinase C epsilon (PKCε) mRNA were found to have: (a) less PKCε in dorsal root ganglia (DRG), (b) reduced PKCε expression in IB4(+) but not IB4(-) DRG neurons, and (c) fewer transcripts of the PKCε gene in the DRG. This knockdown in PKCε expression in IB4(+) DRG neurons is sufficient to reverse hyperalgesic priming, a rodent model of chronic pain that is dependent on PKCε in IB4(+)-nociceptors. These results establish that IB4-streptavidin can be used to study protein function in a defined subpopulation of nociceptive C-fiber afferents.

Artificial nociceptors demonstrate significant potential in emerging fields such as intelligent prosthetics, humanoid robotics, and electronic skin, capable of transducing external noxious stimuli to the central nervous system. Unlike common sensory neurons, nociceptors exhibit unique characteristics, including "no adaptation," "relaxation," "threshold firing," and "sensitization of allodynia/hyperalgesia." This study presents a forming-free volatile transparent ITO/AlN/ITO memristor that emulates biological nociceptor behaviors. Leveraging this artificial nociceptor, an artificial mechano-nociceptive system is developed by integrating the ITO/AlN/ITO memristor into a piezoelectric force sensor system for pain sensing and noxious stimuli warning. This research contributes to the advancement of human cognitive capability emulation and artificial intelligence systems, particularly in the domain of pain perception and response. [ABSTRACT FROM AUTHOR]

Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor‐specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects. [ABSTRACT FROM AUTHOR]

Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier frequency is thought to be less painful than conventional pulsed currents by reducing the sensitivity of pain receptors. However, no purported benefit has been shown unequivocally. We compared the effects of carrier‐frequency stimulation and conventional stimulation on pain tolerance and the thresholds for sensory and motor axons in twelve participants. The ulnar nerve was stimulated transcutaneously with a conventional single pulse and 5 and 10 kHz carrier‐frequency waveforms that had 5 and 10 pulses, respectively, when delivered in bursts of ∼1 ms duration. Phase durations were adjusted across waveform types to match the total charge for a given current amplitude. Single bursts of stimulation were delivered from 1 mA up until no longer tolerable. This was repeated with repetitive bursts of stimulation at 20 Hz for 1 s. Participants tolerated higher current amplitudes with both carrier‐frequency waveforms than conventional stimulation, with repetitive bursts more painful than single bursts. However, compared to conventional stimulation, carrier‐frequency waveforms required more current to produce sensory and motor‐threshold responses and to obtain a maximal motor response (Mmax). When the current at pain tolerance was normalised to the current at Mmax, participants tolerated lower stimulus intensities with carrier‐frequency waveforms than conventional stimulation. These findings indicate that there is little to no benefit in using carrier‐frequency waveforms to minimise the discomfort from electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in the activation of sensory and motor axons. Key points: Transcutaneous electrical stimulation with repetitive bursts of a kilohertz carrier‐frequency waveform is thought to be less painful than conventional pulsed currents.For ulnar nerve stimulation, when stimulus waveforms were matched for total phase charge, participants tolerated higher current amplitudes with carrier‐frequency stimulation than conventional stimulation.However, compared to conventional stimulation, carrier‐frequency waveforms required more current to produce a threshold response in both sensory and motor axons and to produce a maximal motor response (Mmax).When current at pain tolerance was normalised to current at Mmax, participants tolerated lower stimulus intensities with carrier‐frequency waveforms than conventional stimulation.Carrier‐frequency waveforms provide little to no benefit in minimising the discomfort from transcutaneous electrical stimulation as the increase in stimulus intensity at pain tolerance is more than offset by reduced effectiveness in activating sensory and motor axons. [ABSTRACT FROM AUTHOR]

Background: Sciatica and low back pain are prevalent clinical types of neuropathic pain that significantly impair patients' quality of life. Conventional therapies often lack effectiveness, making these conditions challenging to treat. Electroacupuncture (EA) is an effective physiotherapy for pain relief. Prior research has demonstrated a relationship between the frequency of neuropathic pain and the analgesic impact of EA stimulation. This work aimed to assess the analgesic effects of EA in a rat model of chronic compression of the dorsal root ganglion (CCD) and to understand the underlying processes. Methods: We established a rat CCD model to simulate sciatica and low back pain. EA was applied to rats with CCD at various frequencies (2 Hz, 100 Hz, and 2/100 Hz). The paw withdrawal threshold (PWT) was measured to assess analgesic effects. Additionally, protein levels of the purinergic receptor P2X3 (P2X3) and the expression of nociceptive neuronal markers were analyzed using immunohistochemistry and western blot (WB) techniques. The study also measured levels of proinflammatory cytokines TNF-α and IL-1β in the dorsal root ganglion (DRG). The involvement of P2X3 receptors was further investigated using the P2X3 agonist, α,β-methylene ATP (α,β-meATP). Results: CCD rats developed pronounced mechanical allodynia. EA stimulation at all tested frequencies produced analgesic effects, with 2/100 Hz showing superior efficacy compared to 2 Hz and 100 Hz. The expression of P2X3 was increased in ipsilateral DRG of CCD model rats. P2X3 were co-labeled with isolectin B4 (IB4) and transient receptor potential vanilloid (TRPV1), indicating their role in nociception. 2/100 Hz EA treatment significantly reduced mechanical allodynia and inhibited the overexpression of P2X3, TRPV1, substance P (SP), and calcitonin gene-related peptide (CGRP) in the ipsilateral DRG of CCD model rats. Additionally, EA reduced the levels of proinflammatory cytokines TNF-α and IL-1β in the ipsilateral DRG, indicating an anti-inflammatory effect. The P2X3 agonist α,β-me ATP attenuated the analgesic effect of 2/100 Hz EA in CCD rats. The WB and immunofluorescence results consistently demonstrated P2X3 inhibition contributed to the analgesic effects of 2/100 Hz EA on CCD-induced neuropathic pain. Conclusions: Our findings suggest that 2/100 Hz EA alleviates neuropathic pain in rats by inhibiting the upregulation of P2X3 receptors in the ipsilateral DRG. This study backs up EA as a viable treatment option for sciatica and low back pain in clinical settings. [ABSTRACT FROM AUTHOR]

Study objective was to evaluate whether the application of a lip twitch could be proposed as conditioning stimulus in the context of a novel Conditioned Pain Modulation (CPM) assessment paradigm for use in horses. The study was a prospective, experimental, randomized trial. Twelve healthy horses were evaluated in two experimental sessions. The lip twitch was used as the conditioning stimulus in both sessions; electrical stimulation was used as the test stimulus in one session, while mechanical and thermal stimulations were used in the other. Differences between thresholds recorded before and during twitching (Δ) as well as their percent (%) change were computed for each stimulation modality as a measure of CPM. Heart rate and respiratory rate were recorded throughout the experiments to monitor physiological reactions, while the general level of stress and aversiveness toward twitching were scored using ad hoc behavioural scales. Based on these scores, interruption criteria were defined. Ten and seven horses completed the electrical and mechanical/thermal experimental sessions respectively. For electrical stimulation, median (IQR) Δ was −2.8 (−3.9, −1.1) mA and% change 87.9 (65.7–118.2)%; for mechanical stimulation, Δ was −18.2 (−6.4, −21.4) N and% change 343.5 (140, 365.3)%; for thermal stimulation, Δ was −3.1 (−9.2, −2.1)°C, while% change was not calculated. Heart rate and respiratory rates varied significantly over time, with higher values recorded during twitching. Median stress and aversion scores did not differ between the two sessions. As lip twitching consistently affected thresholds to all stimulation modalities, it can be proposed as effective conditioning method for CPM assessment in horses. The exclusion of subjects due to severe aversion shows that this paradigm cannot be indistinctively applied to all horses and that stringent interruption criteria are necessary to guarantee adequate welfare during testing. [ABSTRACT FROM AUTHOR]

Simple Summary: Nociceptors detect damaging stimuli and send signals to the central nervous system (CNS) about potential injury, which can give rise to pain. Crustaceans, such as shore crabs, are widely used in science and aquaculture. Understanding whether they can experience pain is essential for improving their welfare. One key criterion for assessing pain is the presence of nociceptors. This study investigated the existence of nociceptors in shore crabs by examining the CNS response to two types of potentially noxious stimuli, i.e., mechanical and chemical or acetic acid. Using electrophysiological equipment, the crabs' CNS activity was measured when different parts of its body, such as the soft tissues of the claws, antennae, and legs were stimulated. The results suggest that the crabs responded to both mechanical and chemical stimuli, indicating the existence of putative nociceptors in these areas. Interestingly, responses to physical stimuli were shorter and more intense than the chemical stimuli, which elicited a longer response. The antennae responded only to the chemical stimuli with no discernable response to touch. Although further research is needed to fully understand pain in crustaceans, this study provides important information on the perception of tissue damage in a crustacean. Nociceptors are receptors that detect injurious stimuli and are necessary to convey such information from the periphery to the central nervous system. While nociception has been extensively studied in various taxa, there is relatively little electrophysiological evidence for the existence of nociceptors in decapod crustaceans. This study investigated putative nociceptive responses in the shore crabs, specifically their response to mechanical and noxious chemical stimuli. Extracellular multi-unit electrophysiological recordings were conducted from the anterior ganglion and the circumesophageal connective ganglia to assess nociceptive responses. Soft tissues at the joints of the chelae, antennae, and walking legs were stimulated using acetic acid (noxious stimulus) and von Frey hairs (mechanical stimulus), while nearby ganglion activity was recorded. The results indicate the existence of nociceptors in the tested areas, with mechanical stimuli eliciting shorter, more intense neural activity compared with acetic acid. Although acetic acid triggered responses in all areas, the antennae and antennules did not respond to mechanical stimuli. Though we acknowledge the challenges of conducting in vivo electrophysiological recordings, future research should focus on further characterizing nociceptor activity because the results suggest the presence of nociceptors. [ABSTRACT FROM AUTHOR]

Multimodal analgesia is defined as using several drugs or techniques simultaneously to target different pain pathways or receptors to avoid pain propagation. This study evaluated the pharmacokinetic profile and comparative bioavailability of etoricoxib 90 mg and tramadol 50 mg dosing alone (reference drugs) or in a novel fixed‐dose combination (test drug) under fasting conditions in Mexican healthy volunteers. This was a randomized, open‐label, 3‐way, crossover, single‐dose, prospective, and longitudinal study with a 14‐day washout period. Eligible subjects were healthy Mexican adult volunteers. The drugs were dosing orally, according to the randomization sequence, after 10 hours of fasting and 4 hours before breakfast with 250 mL of water at room temperature. Serial blood samples were collected before and after dosing, both drugs were quantified using high‐performance liquid chromatography coupled with tandem mass spectrometry. Forty‐two subjects were enrolled and 38 completed the study (28 men and 14 women, mean age 25.2 years, mean weight 66.6 kg). Test products were considered to have comparative bioavailability if confidence intervals of natural log‐transformed for (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration‐time curve form 0 up to last sampling time (AUC0‐t), and (area under the plasma drug concentration‐time curve from 0 up to infinity (AUC0‐∞) data were within the range of 80%‐125%. Non‐serious adverse events were observed. The results demonstrate that the pharmacokinetic profile and bioavailability of the etoricoxib/tramadol fixed‐dose combination are comparable to those of the reference products. [ABSTRACT FROM AUTHOR]

The artificial nociceptor is a device that simulates the biological nociception system, which has a wide range of applications in the fields of medicine, rehabilitation, and robotics. Multimodal nociceptors can respond to diverse stimuli, including visual, mechanical, and thermal, and so on, and then convert them into neural signals for processing by the brain. Herein, a back‐gate optoelectronic transistor based on 2D InSe/MoS2 heterostructure is demonstrated. By employing energy band alignment of the heterojunction, the device exhibits high sensitivity (106) and high responsivity (330 AW−1) to harmful UV irradiation, which can be exploited to emulate the key features of nociceptors, including "threshold," "relaxation," "no adaptation," and "sensitization." Moreover, the device can be operated in a two‐terminal mode, memristive characteristics are obtained through applying source–drain voltages. Then, artificial nociceptive behaviors responding to external electrical pulses have been successfully emulated. Finally, the modulation of nociceptive sensitivity can be achieved through the controlling gate bias, which fully demonstrates the potential of our device for the application of biomimetic multimodal artificial nociceptors in future neuromorphic sensory system. [ABSTRACT FROM AUTHOR]

Aim: This investigation addresses Piezo1's expression and mechanistic role in dorsal root ganglion (DRG) neurons and delineates its participation in mechanical and inflammatory pain modulation. Methods: We analyzed Piezo1's expression patterns in DRG neurons and utilized Piezo1‐specific shRNA to modulate its activity. Electrophysiological assessments of mechanically activated (MA) currents in DRG neurons and behavioral analyses in mouse models of inflammatory pain were conducted to elucidate Piezo1's functional implications. Additionally, we investigated the excitability of TRPV1‐expressing DRG neurons, particularly under inflammatory conditions. Results: Piezo1 was preferentially expressed in DRG neurons co‐expressing the TRPV1 nociceptor marker. Knockdown of Piezo1 attenuated intermediately adapting MA currents and lessened tactile pain hypersensitivity in models of inflammatory pain. Additionally, silencing Piezo1 modified the excitability of TRPV1‐expressing neurons under inflammatory stress. Conclusion: Piezo1 emerges as a key mediator in the transmission of mechanical and inflammatory pain, indicating its potential as a novel target for pain management therapies. Our finding not only advances the understanding of nociceptive signaling but also emphasizes the therapeutic potential of modulating Piezo1 in the treatment of pain. [ABSTRACT FROM AUTHOR]

Persistent activation and increased mechanical responsiveness of nociceptive neurons that innervate the cranial meninges are considered to be the key processes underlying migraine pain genesis. Meningeal neurogenic inflammation involving neuropeptide-driven neurovascular and neuroimmune interactions likely drives meningeal nociceptors in migraine. Meningeal arteries may directly activate sensitized meningeal nociceptors during vasodilatation or indirectly via local elaboration of pro-nociceptive mediators. In migraine with aura, nociceptive molecules generated in the cortex in response to cortical spreading depolarization (CSD) could activate and sensitize meningeal nociceptors directly or indirectly via an axon reflex and neurogenic inflammation. Migraine treatments target sensory neuropeptides and receptors located in meningeal vascular, immune, neuronal, and glial cells. Migraine is a highly prevalent and disabling pain disorder that affects >1 billion people worldwide. One central hypothesis points to the cranial meninges as a key site underlying migraine headache genesis through complex interplay between meningeal sensory nerves, blood vessels, and adjacent immune cells. How these interactions might generate migraine headaches remains incompletely understood and a subject of much debate. In this review we discuss clinical and preclinical evidence supporting the concept that meningeal sterile inflammation, involving neurovascular and neuroimmune interactions, underlies migraine headache genesis. We examine downstream signaling pathways implicated in the development of migraine pain in response to exogenous events such as infusing migraine-triggering chemical substances. We further discuss cortex-to-meninges signaling pathways that could underlie migraine pain in response to endogenous events, such as cortical spreading depolarization (CSD), and explore future directions for the field. [ABSTRACT FROM AUTHOR]

Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa. A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the potential antinociception and mechanism of these Cannabis terpenes in a mouse model of chronic pain. We first tested for antinociception by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with mouse models of chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal antinociception to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs either alone. We then used the adenosine A2A receptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord–specific CRISPR knockdown of the A2AR to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A2AR agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain and identify a receptor mechanism for this activity. [ABSTRACT FROM AUTHOR]

The neurotransmitter glycine is an agonist at the strychnine‐sensitive glycine receptors. In addition, it has recently been discovered to act at two new receptors, the excitatory glycine receptor and metabotropic glycine receptor. Glycine's neurotransmitter roles have been most extensively investigated in the spinal cord, where it is known to play essential roles in pain, itch, and motor function. In contrast, less is known about supraspinal glycinergic functions, and their contributions to pain circuits are largely unrecognized. As glycinergic neurons are absent from cortical regions, a clearer understanding of how supraspinal glycine modulates pain could reveal new pharmacological targets. This review aims to synthesize the published research on glycine's role in the adult brain, highlighting regions where glycine signaling may modulate pain responses. This was achieved through a scoping review methodology identifying several key regions of supraspinal pain circuitry where glycine signaling is involved. Therefore, this review unveils critical research gaps for supraspinal glycine's potential roles in pain and pain‐associated responses, encouraging researchers to consider glycinergic neurotransmission more widely when investigating neural mechanisms of pain. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis. [ABSTRACT FROM AUTHOR]

Synovitis is a widely accepted sign of osteoarthritis (OA), characterised by tissue hyperplasia, where increased infiltration of immune cells and proliferation of resident fibroblasts adopt a pro-inflammatory phenotype, and increased the production of pro-inflammatory mediators that are capable of sensitising and activating sensory nociceptors, which innervate the joint tissues. As such, it is important to understand the cellular composition of synovium and their involvement in pain sensitisation to better inform the development of effective analgesics. Studies investigating pain sensitisation in OA with a focus on immune cells and fibroblasts were identified using PubMed, Web of Science and SCOPUS. In this review, we comprehensively assess the evidence that cellular crosstalk between resident immune cells or synovial fibroblasts with joint nociceptors in inflamed OA synovium contributes to peripheral pain sensitisation. Moreover, we explore whether the elucidation of common mechanisms identified in similar joint conditions may inform the development of more effective analgesics specifically targeting OA joint pain. The concept of local environment and cellular crosstalk within the inflammatory synovium as a driver of nociceptive joint pain presents a compelling opportunity for future research and therapeutic advancements. [ABSTRACT FROM AUTHOR]

Fibroblast-like synoviocytes (FLSs) are among the main disease-driving players in most cases of monoarthritis (MonoA), oligoarthritis, and polyarthritis. In this review, we look at the characteristics and therapeutic challenges at the onset of arthritis and during follow-up management. In some cases, these forms of arthritis develop into autoimmune polyarthritis, such as rheumatoid arthritis (RA), whereas local eradication of the RA synovium could still be combined with systemic treatment using immunosuppressive agents. Currently, the outcomes of local synovectomies are well studied; however, there is still a lack of a comprehensive analysis of current local intra-articular treatments highlighting their advantages and disadvantages. Therefore, the aim of this study is to review local intra-articular therapy strategies. According to publications from the last decade on clinical studies focused on intra-articular treatment with anti-inflammatory molecules, a range of novel slow-acting forms of steroidal drugs for the local treatment of synovitis have been investigated. As pain is an essential symptom, caused by both inflammation and cartilage damage, various molecules acting on pain receptors are being investigated in clinical trials as potential targets for local intra-articular treatment. We also overview the new targets for local treatment, including surface markers and intracellular proteins, non-coding ribonucleic acids (RNAs), etc. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the pharmacological effects of topical trans-anethole, a natural compound found in anise, star anise, and fennel essential oils, and its relationship with the transient receptor potential of ankyrin 1 (TRPA1). Methods: The effects of topical anethole were assessed by eye wiping, nociceptive behaviour, and ear oedema in mice. Histological evaluations were performed on the ears of the animals topically treated with anethole. Results: Anethole caused less eye irritation than capsaicin (a TRPV1 agonist) and allyl isothiocyanate (a TRPA1 agonist). Anethole (250 and 500 nmol/20 µL/paw) promoted neurogenic nociception in the paw (20.89 ± 3.53 s and 47.56 ± 8.46 s, respectively) compared with the vehicle (0.88 ± 0.38 s). HC030031 (56.1 nmol/20 µL/paw), a TRPA1 antagonist, abolished this nociceptive response. Anethole (4, 10, and 20 µmol/20 µL/ear) induced ear oedema (30.25 ± 4.78 μm, 78.00 ± 3.74 μm, and 127.50 ± 27.19 μm, respectively) compared with the vehicle (5.00 ± 0.5 μm). HC030031 (56.1 nmol/20 µL/ear) inhibited the oedema induced by anethole (10 µmol/20 µL/ear). Ears pre-treated with anethole or allyl isothiocyanate on the first day and re-exposed to these compounds on the third day showed a reduction in oedema (68.16 ± 6.04% and 38.81 ± 8.98.9%, respectively). Cross-desensitisation between anethole and allyl isothiocyanate was observed. Histological analysis confirmed the beneficial effects of anethol. Conclusion: As repeated topical applications of anethole induce the desensitisation of TRPA1, we suggest its clinical application as a topical formulation for treating skin diseases or managing pain associated with this receptor. Anethole may also have advantages over capsaicin and allyl isothiocyanate because of its low pungency and pleasant aroma. [ABSTRACT FROM AUTHOR]

Background: In addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors. Methods: In a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague–Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration. Results: Both doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP. Conclusions: The findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine. [ABSTRACT FROM AUTHOR]

Memristors have emerged as a promising candidate to mimic the human behavior and thus unlocking the potential for bio‐inspired computing advancement. However, these devices operate at a voltages which are still far from the energy‐efficient biological counterpart, which uses an action potential of 50–120 mV to process the information. Here, a diffusive memristor is reported from synthetic WSe2 fabricated in Ag/WSe2/Au vertical device geometry. The devices operate at bio‐voltages of 40–80 mV with Ion/Ioff ratio of 106 and steep switching turn ON and OFF slopes of 0.77 and 0.88 mV per decade, respectively. The power consumption in standby mode and power per set transition are found to be 10 fW and 64 pW, respectively. Further, the diffusive memristors are utilized to emulate the nociceptor, a special receptor for sensory neurons that selectively responds to noxious stimuli. Nociceptor in turn imparts a warning signal to the central nervous system which then triggers the motor response to take precautionary actions to prevent the body from injury. The key features of a nociceptor including “threshold”, “relaxation”, “no‐adaptation” and “sensitization” are demonstrated using artificial nociceptors. These illustrations imply the feasibility of developing low‐power diffusive memristors for bio‐inspired computing, humanoid robots, and electronic skins. [ABSTRACT FROM AUTHOR]

GABAergic neurons and GABAA receptors (GABAARs) are critical elements of almost all neuronal circuits. Most GABAARs of the CNS are heteropentameric ion channels composed of two α, two β, and one γ subunits. These receptors serve as important drug targets for benzodiazepine (BDZ) site agonists, which potentiate the action of GABA at GABAARs. Most GABAAR classifications rely on the heterogeneity of the α subunit (α1--α6) included in the receptor complex. Heterogeneity of the γ subunits (γ1--γ3), which mediate synaptic clustering of GABAARs and contribute, together with α subunits, to the benzodiazepine (BDZ) binding site, has gained less attention, mainly because γ2 subunits greatly outnumber the other γ subunits in most brain regions. Here, we have investigated a potential role of non-γ2 GABAARs in neural circuits of the spinal dorsal horn, a key site of nociceptive processing. Female and male mice were studied. We demonstrate that besides γ2 subunits, γ1 subunits are significantly expressed in the spinal dorsal horn, especially in its superficial layers. Unlike global γ2 subunit deletion, which is lethal, spinal cord-specific loss of γ2 subunits was well tolerated. GABAAR clustering in the superficial dorsal horn remained largely unaffected and antihyperalgesic actions of HZ-166, a nonsedative BDZ site agonist, were partially retained. Our results thus suggest that the superficial dorsal horn harbors functionally relevant amounts of γ1 subunits that support the synaptic clustering of GABAARs in this site. They further suggest that γ1 containing GABAARs contribute to the spinal control of nociceptive information flow. [ABSTRACT FROM AUTHOR]

Background and objective: Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of a sigma-1 receptor (σ1R) antagonist in managing neuropathic pain. Methods: A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084. Results: (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction (GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain. Conclusions: This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention. [ABSTRACT FROM AUTHOR]

Background: Inflammation leads to a decrease in the excitation threshold and the sensitization of peripheral nociceptors. However, little is known about the effect of inflammation on the sensing of regional (CRegP) and widespread chronic pain (CWP) in older adults. This analysis aimed to characterize the prevalence and associates of both types of chronic pain in a population-based cohort. Methods: Our analysis was based on the Polish nationwide PolSenior study database. We excluded participants with moderate-to-severe dementia. Respondents answered questions concerning the occurrence of pain in 10 regions. CWP was defined as chronic pain present in the axial region (neck, upper back, lower back) and any part of both the lower (lower leg, hip, knee, foot) and upper (shoulder, hand) extremities. Inflammatory status was divided into three subgroups: no inflammation (CRP < 3 mg/dL), mild inflammation (CPR 3–10 mg/dL and IL-6 < 10 ng/mL), and significant inflammation (CRP ≥ 10 mg/dL or IL-6 ≥ 10 ng/mL). Results: CRegP was more frequent (33.9%) than CWP (8.8%). The occurrence of CWP was more frequent in subgroups with significant inflammation than in both subgroups with mild or no inflammation (11.4% vs. both 8.4%). Women (OR 3.67; 95% CI: 2.58–5.21) and subjects with major depression symptoms were more likely to experience CWP (OR 2.85; 95% CI: 1.68–4.82), while, malnourished participants were more likely to report CRegP (OR 2.00; 95% CI: 1.52–2.62). Conclusions: Significant inflammation is associated with increased occurrence of CWP in older adults. Female sex and major depression are the most significant associates of CWP, while malnutrition is the most significant associate of CRegP. [ABSTRACT FROM AUTHOR]

Interactions between nociceptors and mammalian immune cells are complex; however, most promote tissue repair and homeostasis, adaptive immune responses, or Type 2 immunity and inflammation. Nociceptors inhibit histotoxic, collateral damage-causing immune responses and promote tissue repair chiefly through the secretion of the calcitonin gene-related peptide (CGRP) neuropeptide. Nociceptors promote adaptive immunity by fine-tuning dendritic cell functions, through innervation of secondary lymphoid organs, and by communicating with B lymphocytes. Nociceptors can regulate Type 2 immunity inflammation by secreting neuropeptides or glutamate. While the primary role of nociceptors is to maintain tissue homeostasis, their actions can promote pathological conditions if unchecked. Nociceptor functions are themselves modulated by immune cell actions, forming numerous feed-forward and feed-back loops. The peripheral nervous system is being increasingly recognized as a regulator of immune responses at steady-state and in response to infections, cancer, tissue injury, and other challenges. In particular, nociceptors, a population of somatosensory neurons that confer the sensation of itch or pain, can exert both pro- and anti-inflammatory effects. Developing a better understanding of nociceptors as conductors of immune responses is at the forefront of neuroimmunology research. Nociceptors have emerged as master regulators of immune responses in both homeostatic and pathologic settings; however, their seemingly contradictory effects on the functions of different immune cell subsets have been a source of confusion. Nevertheless, work by many groups in recent years has begun to identify patterns of the modalities and consequences of nociceptor-immune system communication. Here, we review recent findings of how nociceptors affect immunity and propose an integrated concept whereby nociceptors are neither inherently pro- nor anti-inflammatory. Rather, we propose that nociceptors have the role of a rheostat that, in a context-dependent manner, favors tissue homeostasis and fine-tunes immunity by preventing excessive histotoxic inflammation, promoting tissue repair, and potentiating anticipatory and adaptive immune responses. [ABSTRACT FROM AUTHOR]

In the era of big data, traditional computing architectures face limitations in handling vast amounts of data owing to the separate processing and memory units, thus causing bottlenecks and high‐energy consumption. Inspired by the human brain's information exchange mechanism, neuromorphic computing offers a promising solution. Resistive random access memory devices, particularly those with bilayer structures like Pt/TaOx/TiOx/TiN, show potential for neuromorphic computing owing to their simple design, low‐power consumption, and compatibility with existing technology. This study investigates the synaptic applications of Pt/TaOx/TiOx/TiN devices for neuromorphic computing. The unique coexistence of nonfilamentary and filamentary switching in the Pt/TaOx/TiOx/TiN device enables the realization of reservoir computing and the functions of artificial nociceptors and synapses. Additionally, the linkage between artificial nociceptors and synapses is examined based on injury‐enhanced spike‐time‐dependent plasticity paradigms. This study underscores the Pt/TaOx/TiOx/TiN device's potential in neuromorphic computing, providing a framework for simulating nociceptors, synapses, and learning principles. [ABSTRACT FROM AUTHOR]

PIEZO2 is a trimeric mechanically-gated ion channel expressed by most sensory neurons in the dorsal root ganglia. Mechanosensitive PIEZO2 channels are also genetically required for normal touch sensation in both mice and humans. We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage. Specifically, it is only at very positive voltages that all channels are available for opening by mechanical force. Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials. The physiological function of this unusual biophysical property of PIEZO2 channels, however, remained unknown. We characterized the biophysical properties of three PIEZO2 ion channel mutations at an evolutionarily conserved arginine (R2756). Using genome engineering in mice we generated Piezo2 R2756H/R2756H and Piezo2 R2756K/R2756K knock-in mice to characterize the physiological consequences of altering PIEZO2 voltage sensitivity in vivo. We measured endogenous mechanosensitive currents in sensory neurons isolated from the dorsal root ganglia and characterized mechanoreceptor and nociceptor function using electrophysiology. Mice were also assessed behaviourally and morphologically. Mutations at the conserved Arginine (R2756) dramatically changed the biophysical properties of the channel relieving voltage block and lowering mechanical thresholds for channel activation. Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice that were homozygous for gain-of-function mutations were viable and were tested for sensory changes. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but mechanosensitive currents in most mechanoreceptors that underlie touch sensation were only mildly affected by the same mutations. Single-unit electrophysiological recordings from sensory neurons innervating the glabrous skin revealed that rapidly-adapting mechanoreceptors that innervate Meissner's corpuscles exhibited slightly decreased mechanical thresholds in Piezo2 knock-in mice. Consistent with measurements of mechanically activated currents in isolated sensory neurons essentially all cutaneous nociceptors, both fast conducting Aδ-mechanonociceptors and unmyelinated C-fibre nociceptors were substantially more sensitive to mechanical stimuli and indeed acquired receptor properties similar to ultrasensitive touch receptors in Piezo2 knock-in mice. Mechanical stimuli also induced enhanced ongoing activity in cutaneous nociceptors in Piezo2 knock-in mice and hyper-sensitive PIEZO2 channels were sufficient alone to drive ongoing activity, even in isolated nociceptive neurons. Consistently, Piezo2 knock-in mice showed substantial behavioural hypersensitivity to noxious mechanical stimuli. Our data indicate that ongoing activity and sensitization of nociceptors, phenomena commonly found in human chronic pain syndromes, can be driven by relieving the voltage-block of PIEZO2 ion channels. Indeed, membrane depolarization caused by multiple noxious stimuli may sensitize nociceptors by relieving voltage-block of PIEZO2 channels. [ABSTRACT FROM AUTHOR]

• Nociceptors can directly sense viral nucleic acids, such as dsDNA derived from herpes and vaccinia viruses. • Cytosolic dsDNA causes nocifensive behaviors and mechanical hypersensitivity via STING expression and signaling in nociceptors. • STING agonist induces action potentials and calcium responses in sensory neurons and triggers pain-like behaviors. • Both cytosolic dsDNA and STING agonists rely on TRPV1, hinting at a new non-canonical STING signaling. • Herpetic mechanical allodynia was significantly reduced in mice lacking STING and TRPV1 expression in nociceptors. Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections. [ABSTRACT FROM AUTHOR]

Nociplastic pain, characterized by abnormal pain processing without an identifiable organic cause, affects a significant portion of the global population. Unfortunately, current pharmacological treatments for this condition often prove ineffective, prompting the need to explore new potential targets for inducing analgesic effects in patients with nociplastic pain. In this context, toll-like receptors (TLRs), known for their role in the immune response to infections, represent promising opportunities for pharmacological intervention because they play a relevant role in both the development and maintenance of pain. Although TLRs have been extensively studied in neuropathic and inflammatory pain, their specific contributions to nociplastic pain remain less clear, demanding further investigation. This review consolidates current evidence on the connection between TLRs and nociplastic pain, with a specific focus on prevalent conditions like fibromyalgia, stress-induced pain, sleep deprivation-related pain, and irritable bowel syndrome. In addition, we explore the association between nociplastic pain and psychiatric comorbidities, proposing that modulating TLRs can potentially alleviate both pain syndromes and related psychiatric disorders. Finally, we discuss the potential sex differences in TLR signaling, considering the higher prevalence of nociplastic pain among women. Altogether, this review aims to shed light on nociplastic pain, its underlying mechanisms, and its intriguing relationship with TLR signaling pathways, ultimately framing the potential therapeutic role of TLRs in addressing this challenging condition. [ABSTRACT FROM AUTHOR]

Thermosensation requires the activation of a unique collection of ion channels and receptors that work in concert to transmit thermal information. It is widely accepted that transient receptor potential melastatin 8 (TRPM8) activation is required for normal cold sensing; however, recent studies have illuminated major roles for other ion channels in this important somatic sensation. In addition to TRPM8, other TRP channels have been reported to contribute to cold transduction mechanisms in diverse sensory neuron populations, with both leak- and voltage-gated channels being identified for their role in the transmission of cold signals. Whether the same channels that contribute to physiological cold sensing also mediate noxious cold signaling remains unclear; however, recent work has found a conserved role for the kainite receptor, GluK2, in noxious cold sensing across species. Additionally, cold-sensing neurons likely engage in functional crosstalk with nociceptors to give rise to cold pain. This Review will provide an update on our understanding of the relationship between various ion channels in the transduction and transmission of cold and highlight areas where further investigation is required. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) is a neurotrophic protein that has crucial roles in survival, growth and differentiation. It is expressed in neuronal and non-neuronal tissues. NGF exerts its effects via two types of receptors including the high affinity receptor, tropomyosin receptor kinase A and the low affinity receptor p75 neurotrophin receptor highlighting the complex signaling pathways that underlie the roles of NGF. In pain perception and transmission, multiple studies shed light on the effects of NGF on different types of pain including inflammatory, neuropathic, cancer and visceral pain. Also, the binding of NGF to its receptors increases the availability of many nociceptive receptors such as transient receptor potential vanilloid 1, transient receptor potential ankyrin 1, N-methyl-D-aspartic acid, and P2X purinoceptor 3 as well as nociceptive transmitters such as substance P and calcitonin gene-related peptide. The role of NGF in pain has been documented in pre-clinical and clinical studies. This review aims to shed light on the role of NGF and its signaling in different types of pain. [ABSTRACT FROM AUTHOR]

Nociceptors are key sensory receptors that transmit warning signals to the central nervous system in response to painful stimuli. This fundamental process is emulated in an electronic device by developing a novel artificial nociceptor with an ultrathin, nonstoichiometric gallium oxide (GaOx)‐silicon oxide heterostructure. A large‐area 2D‐GaOx film is printed on a substrate through liquid metal printing to facilitate the production of conductive filaments. This nociceptive structure exhibits a unique short‐term temporal response following stimulation, enabling a facile demonstration of threshold‐switching physics. The developed heterointerface 2D‐GaOx film enables the fabrication of fast‐switching, low‐energy, and compliance‐free 2D‐GaOx nociceptors, as confirmed through experiments. The accumulation and extrusion of Ag in the oxide matrix are significant for inducing plastic changes in artificial biological sensors. High‐resolution transmission electron microscopy and electron energy loss spectroscopy demonstrate that Ag clusters in the material dispersed under electrical bias and regrouped spontaneously when the bias is removed owing to interfacial energy minimization. Moreover, 2D nociceptors are stable; thus, heterointerface engineering can enable effective control of charge transfer in 2D heterostructural devices. Furthermore, the diffusive 2D‐GaOx device and its Ag dynamics enable the direct emulation of biological nociceptors, marking an advancement in the hardware implementation of artificial human sensory systems. [ABSTRACT FROM AUTHOR]

AbstractHerbal plant secondary metabolites such as curcumin, resveratrol, and capsaicin are becoming increasingly popular as natural remedies. These herbal compounds are also known to act on the calcium signaling pathways, and therefore cell calcium assays can be used to study the relative interactions of these compounds with cellular receptors pertaining to natural remedies. To investigate this, Fluo-4, a fluorophore that specifically binds to Ca2+, was used to detect the increase in calcium signaling in human glioblastoma cells treated with curcumin, resveratrol, and capsaicin. The human cells used are U87 MG cells which expresses TRPV1, a pain receptor on the cell membrane. The increases of the fluorescence intensity in the cells treated with the three herbal compounds were measured using a bulk microplate assay, which generates data in a high throughput, and a microfluidic single-cell assay, which allows for the observation of the cell calcium changes in real-time. It was found that all three compounds would increase the intracellular Ca2+ concentrations on the two assays, with curcumin generating the highest increase, which confirms the greatest responses elicited by this herbal compound from the cell. Furthermore, the data obtained by a molecular docking computation study, which has been used to determine the binding affinities of the three compounds with the TRPV1 receptor, corroborate with the experimental finding of the highest cellular response due to curcumin. [ABSTRACT FROM AUTHOR]

Chronic pain is a debilitating condition frequently observed in the elderly, involving numerous pathological mechanisms within the nervous system. Diminished local blood flow, nerve degeneration, variations in fiber composition, alterations in ion channels and receptors, accompanied by the sustained activation of immune cells and release of pro-inflammatory cytokines, lead to overactivation of the peripheral nervous system. In the central nervous system, chronic pain is strongly associated with the activation of glial cells, which results in central sensitization and increased pain perception. Moreover, agerelated alterations in neural plasticity and disruptions in pain inhibitory pathways can exacerbate chronic pain in older adults. Finally, the environmental influences on the development of chronic pain in the elderly must be considered. An understanding of these mechanisms is essential for developing novel treatments for chronic pain, which can significantly improve the quality of life for this vulnerable population. [ABSTRACT FROM AUTHOR]

Peripheral nerve regeneration depends on close interaction between neurons and Schwann cells (SCs). After nerve injury, SCs produce growth factors and cytokines that are crucial for axon re-growth. Previous studies revealed the supernatant of SCs exposed to nuclear magnetic resonance therapy (NMRT) treatment to increase survival and neurite formation of rat dorsal root ganglion (DRG) neurons in vitro. The aim of this study was to identify factors involved in transferring the observed NMRT-induced effects to SCs and consequently to DRG neurons. Conditioned media of NMRT-treated (CM NMRT) and untreated SCs (CM CTRL) were tested by beta-nerve growth factor (ßNGF) ELISA and multiplex cytokine panels to profile secreted factors. The expression of nociceptive transient receptor potential vanilloid 1 (TRPV1) channels was assessed and the intracellular calcium response in DRG neurons to high-potassium solution, capsaicin or adenosine triphosphate was measured mimicking noxious stimuli. NMRT induced the secretion of ßNGF and pro-regenerative-signaling factors. Blocking antibody experiments confirmed ßNGF as the main factor responsible for neurotrophic/neuritogenic effects of CM NMRT. The TRPV1 expression or sensitivity to specific stimuli was not altered, whereas the viability of cultured DRG neurons was increased. Positive effects of CM NMRT supernatant on DRG neurons are primarily mediated by increased ßNGF levels. [ABSTRACT FROM AUTHOR]

The emergence of the artificial intelligence urgently requires novel devices to handle massive data and bionic simulations. As one of new generation memory devices, memristor has great potential in information storage and brain‐like learning due to its merits, such as low energy consumption, high speed and etc. In addition, the randomness for the generation and breakage of the conducting filaments in the memristor can generate the true random numbers and realize the image encryption. In this work, the ITO/Cs2AgBiBr6/Al based devices exhibit prominent resistance variation characteristics and long‐term environmental stability (≥6 months). Additionally, the flexible PET/ITO/Cs2AgBiBr6/Al devices are assembled and measured resistance variation properties, which are adopt to realize the cryptographic processing of image information. The synaptic plasticity of the memristor is also verified, including paired pulse facilitation and spiking timing‐dependent plasticity. Finally, nociceptive responses are also simulated with the memristor via imposing different voltage. Nociceptive characteristics including “threshold,” “relaxation,” and “sensitization” have been successfully determined. The work provides possibility for lead‐free flexible perovskite memristors in information security and biomimicry. [ABSTRACT FROM AUTHOR]