ObjectiveTo determine whether intravenous infusion of substance P elicits headache and arterial dilation in healthy adults.MethodsIn a double-blind, placebo-controlled, two-way crossover study, we randomly allocated healthy adults to receive either substance P (1.5 pmol/kg/min) or placebo (isotonic saline) by 20-minute intravenous infusion on separate experiment days. The primary endpoint was the incidence of headache within 12 hours after the infusion. Other endpoints included the area under the curve (AUC) for headache intensity scores over the 12-hour observation period and AUC changes in the superficial temporal artery (STA) diameter from baseline to 120 minutes post-infusion.ResultsTwenty-one participants underwent randomization and completed both experiment days. Headache was reported by 15 (71%) of 21 participants following substance P, compared with two (10%) after placebo (p < 0.001). The AUC for headache intensity scores was significantly higher after substance P infusion than after placebo (p = 0.03). In addition, there was a significant STA diameter increase with substance P, compared with placebo (p = 0.005).ConclusionsAmong healthy adults, substance P infusion elicited headache and arterial dilation. These findings support a role for substance P in headache pathogenesis and encourage further investigation in migraine and other headache disorders. Additional research is also needed to explore new therapeutic strategies targeting substance P or its downstream signaling.Trial Registration:CT identifier: NCT06632080.

Glycyrrhiza uralensis Fisch. (GU) is a pivotal botanical in traditional Chinese medicine (TCM), because of its ability to reconcile various herbs, and its crucial role in numerous formulas. Huanggui Shaogan decoction (HSGD) is an empirical formula, developed by Huangqi Guizhi Wuwu decoction (HGD) and Shaoyao Gancao decoction (SGD), and prepared by adding GU to HGD. However, the mechanisms of GU reconciling medicine remain incompletely characterized.

This study aimed to explain mechanisms of GU reconciling medicine based on the differences of components, pharmacological efficacy, and the existence of the components.

Differential components between HSGD and HGD were systematically identified using LC‒MS/MS coupled with chemometric analysis. The existence states and binding affinities of these differential components were further characterized via ultrafiltration separation. The therapeutic potential of HSGD was validated in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN).

Twenty-two differential chemical components between HSGD and HGD were identified, including flavonoids, saponins, gingerol, and monoglycoside. The transmittance of flavonoids and gingerols increased in HSGD. However, the transmittance of astragalus saponins decreased, which may be due to micelle association and the increase in molecular clusters. HSGD could enhance the mechanical pain threshold, alleviate cold nociceptive hypersensitivity, relieve dorsal root ganglia neuron injury, and decrease the expression of nerve growth factor, 5-hydroxytryptamine, substance P, and calcitonin gene-related peptide better. The differential correlation analysis revealed the relationship between differential components and pharmacological indicators. The above results indicated that different herbs combinations had a greater impact on the dissolution and molecular state of the components of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao.

The study highlights the solubilizing effect of GU within HSGD, and it also improves the efficacy of the treatment of OIPN, which underpins its compatibility rationality. It provided an inspiration for the study of other TCM formulas.

Mice lacking two neuropeptides thought to be essential for processing pain show no change in how they respond to a wide range of harmful stimuli.

Intrathecal morphine pump helps alleviate pain in the advanced stages of cancer, and thus, ensuring safe intrathecal morphine pump infusion is important. In this study, we investigated the effect of healthcare failure mode and effects analysis (HFMEA) in the management of patients with intrathecal morphine pump implantation.

We included 112 cancer patients with severe pain who met the inclusion criteria for intrathecal morphine pump implantation treatment in the pain department of our hospital from November 2021 to October 2022. We analyzed the severity, likelihood, and crisis of potential failure modes, causes, and results of intrathecal morphine pumps during this period, compiled the records, and formulated the appropriate improvement measures based on the results of the analysis. From November 2022 to October 2023, the HFMEA model was applied to 125 patients in the department, and the effectiveness of the model was evaluated by assessing the patients' VAS (visual analog scale) score, SAS (self-rating anxiety scale) score, SDS score, PSQI (Pittsburgh Sleep Quality Index) score and quality of life (QOL) (self-rating depression scale) score.

The occurrence of adverse events (6 cases vs. 2 cases, p < .05), and the total incidence of adverse events (8.9% vs. 1.6%, X2= 6.600, p = .010) was significantly different before and after HFMEA was applied. For patients who received intrathecal morphine pump implantation, the VAS scores and the related pain indices were significantly lower after HFMEA than before. Additionally, the score of SAS (48.91 ± 6.03 vs. 47.02 ± 6.77), PSQI (37.30 ± 5.78 vs. 39.63 ± 5.64), and QOL (9.93 ± 3.04 vs. 8.98 ± 2.31) of patients improved significantly.

With the application of the HFMEA model, a multidisciplinary team assessed the risks associated with the use of intrathecal morphine pumps and prioritized measures to reduce them. By implementing the improvement measures, potential errors decreased significantly during the intrathecal morphine pump process. It allowed nursing managers to change the safety incidents related to drug administration using an intrathecal morphine pump from negative treatment after the event to active prevention before the event, greatly improved the level of drug use safety management, reflected the continuous improvement of nursing quality, and ensured nursing safety.

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed, we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.

The lateral parabrachial nucleus (PBN) is critically involved in neuropathic pain modulation. However, the cellular and molecular mechanisms underlying this process remain largely unknown. Here, we report that in mice, the right-sided, but not the left-sided, PBN plays an essential role in the development of hyperalgesia following nerve injury, irrespective of the injury side. Spino-parabrachial pathways targeting the right-sided PBN display short-term facilitation, and right-sided PBN neurons exhibit an increase in the excitability and activity after nerve injury. Inhibiting Tacr1-positive neurons, blocking Tacr1-encoding tachykinin 1 receptor (NK1R), or knocking down the Tacr1 gene in the right-sided, rather than left-sided, PBN alleviates neuropathic pain-induced sensory hypersensitivity. Additionally, the right-sided PBN plays a critical role in the development of hyperalgesia during the early phase of neuropathic pain. These results highlight the essential role of NK1R in the lateralized modulation of neuropathic pain by the PBN, providing new insights into the mechanisms underlying neuropathic pain.

Resveratrol (RV-3, 5, 4'-trihydroxystilbene) is a natural compound found in plants like red grapes, berries, and peanuts, with promising effects on dental health. It helps strengthen tooth enamel by promoting remineralization, making the teeth more resistant to decay caused by acid-producing bacteria. RV also shields dentin, a vulnerable layer beneath the enamel, from erosion and sensitivity. Its anti-inflammatory properties can reduce inflammation associated with dental conditions such as pulpitis and endodontic diseases. Moreover, RV's antimicrobial activity inhibits the growth of bacteria involved in dental plaque and biofilm formation, preventing their accumulation on the tooth surface. This contributes to a healthier oral environment and prolongs the lifespan of dental restorative materials. However, the research on RV's impact on dental health is in its early stages, and further studies are needed to confirm potential benefits. Important factors such as determining the optimal dosage, understanding its bioavailability, and assessing potential side effects require further investigation. This review focuses on the important role of RV in promoting dental health. It delves into various aspects, including its impact on root health, maintenance of the dental pulp, care for tooth enamel, effectiveness of dental restorative materials, and health of dentin.

Cigarette smoking has been linked to severe and persistent sleep disturbances alongside notable fluctuations in neuropeptide levels. Substance P (SubP), influenced by smoking, also impacts sleep-wake cycles. However, its specific role in smoking-induced sleep disorders remains unclear. This study aimed to explore the connection between cigarette smoking and sleep quality by examining SubP levels in cerebrospinal fluid (CSF) and identifying potential treatment avenues for sleep disorders.

A total of 146 Chinese men (93 nonsmokers, 53 active smokers) undergoing lumbar puncture before anterior cruciate ligament reconstruction were enrolled. Clinical data and Pittsburgh Sleep Quality Index (PSQI) scores were assessed, followed by CSF sample collection and CSF SubP level measurement.

Active smokers exhibited significantly higher PSQI scores (4.02 ± 2.27 vs. 2.60 ± 2.46, p < 0.001) and CSF SubP levels (2111 ± 212 vs. 1821 ± 289, p < 0.001) compared to nonsmokers. A negative correlation (r = -0.434, p < 0.001) between SubP levels and PSQI scores was observed in all participants and nonsmokers, while no correlation (r = -0.044, p = 0.72) was found in active smokers. Logistic regression analysis across different dimensions of sleep disorders indicated associations between CSF SubP levels and sleep quality as well as daytime dysfunction (OR = 0.439 (0.211-0.891), p = 0.025; OR = 0.308 (0.152-0.608), p = 0.001). Mediation analysis suggested that CSF SubP levels mediated the relationship between smoking and sleep.

CSF SubP levels are elevated in active smokers and appear to play a mediating role in the relationship between smoking and sleep regulation, as evidenced by a negative correlation between CSF SubP levels and PSQI scores.

In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.

Several data indicate that Substance P (SP) neurokinin type 1 receptor (NK1R) is at the center of the interaction between cancer cells and peripheral sensory neurons. Selecting the appropriate cancer cell line and its susceptibility to being modulated by NK1 antagonists are critical to studying this complex interaction. In the current study, we have focused on this selection by comparing several aspects of the triple-negative breast cancer (TNBC) cell line (MDA-MB-231LUC+) with a modified murine cell line (E0771LUC+), both expressing luciferase. This comparison was made using several methods, SP stimulation and 3D cell culture models, to better reproduce the heterogenous microenvironment of solid tumors observed in vivo. Furthermore, the susceptibility of the murine cell line (E0771LUC+) to NK1R antagonist (Aprepitant) was tested. Our results indicate that E0771LUC+ recapitulates several essential aspects of the human cell line, rendering this murine line ideal to be used on immune-competent animals during in vivo studies. We have also found that both cell lines are susceptible to SP stimulation, and their proliferation is disrupted by NK1R antagonists (Aprepitant). In vivo studies are required to verify and refine these findings.

Capsaicin (CAP) induces transient pain sensation by activating transient receptor potential vanilloid-1 (TRPV1). However, the initial neuronal excitation induced by CAP is followed by a prolonged refractory period, resulting in long-lasting analgesia. Although the effects of CAP on microglia in the dorsal root ganglion of neuropathic pain disorders have been reported, the regulatory pathways of CAP on microglia remain poorly defined.

A chronic pain model was established via plantar injection of complete Freund's adjuvant (CFA), and different doses of CAP were administered to rats. Pain behavior, expression of pain-related factors, protein expression of TRPV1 in nerve cells, and the inflammatory activation of microglia were evaluated. In vitro experiments were conducted to explore the activation and migration ability of microglia, expression of inflammatory cytokines and pathway proteins, TRPV1 expression in nerve cells, and intracellular calcium concentration under different doses of CAP.

Different doses of CAP alleviated chronic pain in rats, reduced TRPV1 expression in nerve cells, and inhibited the activation of microglia; however, high doses of CAP were particularly effective in improving chronic pain. In vitro experiments confirmed that CAP reduces the secretion of inflammatory cytokines by microglia via inhibition of the TLR4/AKT/NF-κB signaling pathway. This mechanism reduced the injury and apoptosis of nerve cells, the expression of TRPV1, and the influx of calcium ions in nerve cells.

CAP reduced inflammatory responses in microglia in a dose-dependent manner by inhibiting the TLR4/AKT/NF-κB signaling pathway, which consequently reduced TRPV1 expression on neuronal cells and reduced chronic pain.

Chronic headaches and pain are prevalent in those who are exposure to blast events, yet there is a gap in fundamental data that identifies the pathological mechanism for the chronification of pain. Blast-related post-traumatic headaches (PTH) are understudied and chronic pain behaviors in preclinical models can be vital to help elucidate PTH mechanisms. The descending pain modulatory system controls pain perception and involves specific brain regions such as the cortex, thalamus, pons, and medulla. In this study, male rats were exposed to repeated blast events to induce traumatic brain injury (bTBI) and subsequently assessed for the development of PTH by testing for chronic pain behaviors and examining the neuropathology of the descending pain pathway. The results demonstrated that facial hypersensitivity developed as early as week two following bTBI and persisted throughout the study (12 weeks). Depressive-like behaviors were observed at 12 weeks following bTBI, and these behaviors were associated with neuropathologies such as microglia ramification and neuropeptide elevation (Calcitonin Gene-Related Peptide, CGRP; Substance P, SP). Overall, these findings support the hypothesis that bTBI causes the activation of microglia and elevation of neuropeptides, which contribute to the development of chronic PTH behaviors.

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.

Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.

Chronic pain is a major global health issue, yet effective treatments are limited by poor translation from preclinical studies to humans. To address this, we developed a high-content screening (HCS) platform for analgesic discovery using hiPSC-derived nociceptors. These cells were cultured on multi-well micro-electrode arrays to monitor activity, achieving nearly 100% active electrodes by week two, maintaining stable activity for at least two weeks. After maturation (28 days), we exposed the nociceptors to various drugs, assessing their effects on neuronal activity, with excellent assay performance (Z' values >0.5). Pharmacological tests showed responses to analgesic targets, including ion channels (Nav, Cav, Kv, TRPV1), neurotransmitter receptors (AMPAR, GABA-R), and kinase inhibitors (tyrosine, JAK1/2). Transcriptomic analysis confirmed the presence of these drug targets, although expression levels varied compared to primary human dorsal root ganglion cells. This HCS platform facilitates the rapid discovery of novel analgesics, reducing the risk of preclinical-to-human translation failure.

Chronic pain affects approximately 1.5 billion people worldwide, yet effective treatments remain elusive. A significant barrier to progress in analgesic drug discovery is the limited translation of preclinical findings to human clinical outcomes. Traditional rodent models, although widely used, often fail to accurately predict human responses, while human primary tissues are limited by scarcity, technical difficulties, and ethical concerns. Recent advancements have identified human induced pluripotent stem cell (hiPSC)-derived nociceptors as promising alternatives; however, current differentiation protocols produce cells with inconsistent and physiologically questionable phenotypes.To address these challenges, our study introduces a novel high-content screening (HCS) platform using hiPSC-derived nociceptors cultured on multi-well micro-electrode arrays (MEAs). The "Anatomic" protocol, used to generate these nociceptors, ensures cells with transcriptomic profiles closely matching human primary sensory neurons. Our platform achieves nearly 100% active electrode yield within two weeks and demonstrates sustained, stable activity over time. Additionally, robust Z' factor analysis (exceeding 0.5) confirms the platform's reliability, while pharmacological validation establishes the functional expression of critical analgesic targets. This innovative approach improves both the efficiency and clinical relevance of analgesic drug screening, potentially bridging the translational gap between preclinical studies and human clinical trials, and offering new hope for effective pain management.

A significant quantity of substance P (SP) and its receptor, the neurokinin 1 (NK1) receptors are found in the brain. SP is a neuropeptide distributed in the central nervous system and functions as a neurotransmitter, neuromodulator, and neurotrophic factor. The concentrations of SP in the brain and cerebrospinal fluid fluctuate in individuals with Alzheimer's disease (AD). SP is an endogenous ligand for NK1 receptor, enhancing the expression of toll-like receptors (TLR) and vice versa. So, both pathways are interconnected, where activation of one pathway activates the second pathway. Researchers have observed the interaction of TLR with SP in the pathophysiology of AD. Thus, this review discusses various TLRs involved in regulating amyloid processing and its interaction with SP in AD. Further, in AD pathology, SP can regulate the non-amyloidogenic pathway. Recent studies have also demonstrated the capacity of SP in regulating voltage-gated potassium channel currents, emphasizing SP's neuroprotective ability. Therefore, we corroborate the findings linking the SP, NK1R, and TLRs in AD.

Cancer neuroscience is an emerging field that investigates the intricate relationship between the nervous system and cancer, gaining increasing recognition for its importance. The central nervous system governs the development of the nervous system and directly affects brain tumors, and the peripheral nervous system (PNS) shapes the tumor microenvironment (TME) of peripheral tumors. Both systems are crucial in cancer initiation and progression, with recent studies revealing a more intricate role of the PNS within the TME. Tumors not only invade nerves but also persuade them through remodeling to further promote malignancy, creating a bidirectional interaction between nerves and cancers. Notably, immune cells also contribute to this communication, forming a triangular relationship that influences protumor inflammation and the effectiveness of immunotherapy. This review delves into the intricate mechanisms connecting the PNS and tumors, focusing on how various immune cell types influence nerve‒tumor interactions, emphasizing the clinical relevance of nerve‒tumor and nerve‒immune dynamics. By deepening our understanding of the interplay between nerves, cancer, and immune cells, this review has the potential to reshape tumor biology insights, inspire innovative therapies, and improve clinical outcomes for cancer patients.

The substance P (SP) and neurokinin-1 receptor (NK-1R) axis is crucial in numerous pathological processes, including inflammation, stress responses, pain perception, and vomiting. Consequently, aprepitant, an NK-1R blocker, is used as an antiemetic in chemotherapy, including the use of doxorubicin (DOX), but whether aprepitant can also assuage DOX-mediated chemobrain remains to be unveiled. Here, we scrutinized the potential neuroprotective effect and underlying mechanisms of aprepitant using DOX-induced chemobrain model, where rats were allocated into 4 groups (control, aprepitant, DOX, and DOX+ aprepitant). Cognitive deficits were assessed through behavioral tests and hippocampal structural alterations were determined by H&E and toluidine blue staining. Biochemical measurements were performed using ELISA, real-time quantitative PCR, western blotting, and immunohistochemical methods. Aprepitant improved cognitive responses, and hippocampal morphology, enhancing the presence of intact neurons. At the molecular tier, aprepitant significantly reduced hippocampal contents of SP and the inflammatory markers NF-κB and IL-1β. Additionally, it signified its antioxidant and antiapoptotic capacities by downregulating cleaved caspase-3 protein expression and curbing the content of malondialdehyde but boosted those of glutathione and Bcl-2. Aprepitant also downregulated the expression of miR-146a and turned off the endoplasmic reticulum (ER) stress cascade PERK/eIF-2α/ATF-4/CHOP. To recapitulate, aprepitant demonstrates a neuroprotective effect against DOX-mediated chemobrain by alleviating inflammatory, oxidative, and apoptotic responses, partly by reducing SP, ER stress, and miR-146a. These findings not only underscore the potential of aprepitant as a neuroprotective agent but also offer new understanding of the mechanisms behind chemobrain, leading to better therapeutic strategies for cancer patients.

An extensive network of cutaneous nerves, neuropeptides, and specific receptors richly innervates the skin and influences a variety of physiological and pathological processes. The sensory and autonomic nerve fibers secrete a variety of neuropeptides that are essential to the different phases of wound healing. In addition to initiating a neurogenic inflammatory response in the early stages of healing, neuropeptides also control wound healing by influencing immune cells, repair cells, and the growth factor network. However, the precise mechanism by which they accomplish these roles in the context of cutaneous wound healing is still unknown. Investigating the mechanisms of action of neuropeptides in wound healing and potential therapeutic applications is therefore urgently necessary. The present review discusses the process of wound healing, types of neuropeptides, potential mechanisms underlying the role of neuropeptides in cutaneous wound healing, as well as some neuropeptide-derived treatment strategies, such as hydrogels, new dressings, electro stimulation, and skin-derived precursors. Future in-depth mechanistic studies of neuropeptides in cutaneous wound healing may provide opportunities to develop therapeutic technologies that harness the roles of neuropeptides in the wound healing process.

Numerous lines of evidence suggest that neuropeptide Y (NPY) is critically involved in the modulation of neuropathic pain. Postherpetic neuralgia (PHN) is characterized by prolonged duration, severe pain, and significant treatment resistance, substantially impairing patients' quality of life. This study aims to evaluate the potential of plasma NPY levels in patients with PHN as a predictive biomarker for the development of this condition.

Between February 2022 and December 2023, 182 patients with herpes zoster (HZ) were recruited. Thirty-eight volunteers with no history of HZ were also recruited as controls. Clinical factors, NPY, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) were assessed within 3 days of healing. Logistic regression analysis was used to predict the development of PHN.

NPY levels were lower and BDNF and NGF were higher in HZ patients than those in controls. Only NPY levels were lower in patients with PHN (n = 59) compared with those without PHN (n = 123). Age, acute pain severity, and rash area were independent predictors of PHN, as were NPY levels. The area under the curve (AUC) to predict the development of PHN based on the combination of NPY levels and clinical factors was 0.873 (95% CI: 0.805 to 0.940), and the AUC was 0.804 based on only clinical factors (AUC: 0.804, 95% CI: 0.728 to 0.881).

Low plasma NPY levels are a predictor of developing PHN in patients with HZ. Combining clinical predictors with NPY levels may improve predictive accuracy.

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come. SIGNIFICANCE STATEMENT: Pharmacological research at Karolinska Institutet has a long and successful history. Given the 75-year anniversary of the Department of Physiology and Pharmacology, this perspective provides an overview of recent departmental achievements and future trajectories. For these developments, interdisciplinary and intersectoral collaborations and a clear focus on result translation are key elements to continue its legacy of world-leading pharmacological research.

To investigate the tear proteomic and neuromediator profiles, in vivo confocal microscopy (IVCM) imaging features, and clinical manifestations in neuropathic corneal pain (NCP) patients.

Cross-sectional study.

A total of 20 NCP patients and 20 age-matched controls were recruited. All subjects were evaluated by corneal sensitivity, Schirmer test, tear break-up time, and corneal and ocular surface staining, Ocular Surface Disease Index and Ocular Pain Assessment Survey questionnaires were administered, as well as IVCM examinations for corneal nerves, microneruomas, and epithelial and dendritic cells. Tears were collected for neuromediator and proteomic analysis using enzyme-linked immunosorbent assay and data-independent acquisition mass spectrometry.

Burning and sensitivity to light were the 2 most common symptoms in NCP. A total of 188 significantly dysregulated proteins, such as elevated metallothionein-2, creatine kinases B-type, vesicle-associated membrane protein 2, neurofilament light polypeptide, and myelin basic protein, were identified in the NCP patients. The top 10 dysregulated biological pathways in NCP include neurotoxicity, axonal signaling, wound healing, neutrophil degradation, apoptosis, thrombin signaling mitochondrial dysfunction, and RHOGDI and P70S6K signaling pathways. Compared to controls, the NCP cohort presented with significantly decreased corneal sensitivity (P < .001), decreased corneal nerve fiber length (P = .003), corneal nerve fiber density (P = .006), and nerve fiber fractal dimension (P = .033), as well as increased corneal nerve fiber width (P = .002), increased length, total area and perimeter of microneuromas (P < .001, P < .001, P = .019), smaller corneal epithelial size (P = .017), and higher nerve growth factor level in tears (P = .006).

These clinical manifestations, imaging features, and molecular characterizations would contribute to the diagnostics and potential therapeutic targets for NCP.

The objectives of this prospective, randomized, blinded, crossover, experimental study were to detect the potential anaesthetic- and analgesic-sparing effects of classical music provided to dogs undergoing skin surgery, and to investigate the role of substance P as an intraoperative pain indicator. Twenty dogs were included, each subjected to three different treatments: Chopin music, Mozart music and no music. They were premedicated with acepromazine, butorphanol and meloxicam and anaesthetized with propofol and isoflurane. Fentanyl was used as rescue analgesia. The anaesthetic depth was monitored by using the bispectral index along with standard anaesthetic monitoring, and autonomic nervous system responses were used to monitor the adequacy of analgesia. Furthermore, measurements of substance P serum concentration were carried out. Dogs exposed to music required less isoflurane and fentanyl. Furthermore, a statistically significant effect of time on substance P concentration was observed regardless of exposure to music, and there was a significant interaction effect between different timepoints and the type of acoustic stimulus. Classical music seems to have an isoflurane and fentanyl sparing effect on dogs undergoing minor surgery. Following surgical stimulation, the serum substance P concentration increases rapidly, and thus appears to be a potentially useful pain indicator.

The most prevalent hip disease in neonates is developmental dysplasia of the hip (DDH). A timely and accurate diagnosis is required to provide the most effective treatment for pediatric patients with DDH. Heredity and gene variation have been the subject of increased attention and research worldwide as one of the factors contributing to the pathogenesis of DDH. Genome-wide association studies (GWAS), genome-wide linkage analyses (GWLA), and exome sequencing (ES) have identified variants in numerous genes and single-nucleotide polymorphisms (SNPs) as being associated with susceptibility to DDH in sporadic and DDH family patients. Furthermore, the DDH phenotype can be observed in animal models that exhibit susceptibility genes or loci, including variants in CX3CR1, KANSL1, and GDF5. The dentification of noncoding RNAs and de novo gene variants in patients with DDH-related syndrome has enhanced our understanding of the genes implicated in DDH. This article reviews the most recent molecular mechanisms and genetic factors that contribute to DDH.

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol.

The aim of this study was to investigate the potential therapeutic applications of (+)-catechin in the treatment of neuropathic pain. In vivo study, 32 SD rats were randomly divided into four groups: sham group, chronic constriction injury (CCI) group, CCI + ibuprofen group and CCI+ (+)-catechin group. They were subjected to behavioural tests, ELISA, immunohistochemistry and Western blotting. The mechanisms involved were investigated using specific inhibitors in cell experiments. Results of in vivo experiments showed that (+)-catechin could reduce the cold sensitivity pain in a rat model of CCI; ELISA and immunohistochemistry results showed that (+)-catechin could decrease the levels of IL-8, IL-6, TNF-α, CCL2 and CCL5 in serum and the expression levels of nNOS, COX2, IL6, TNF-α, IBA-1 and CSF1R in DRG of CCI rats. Finally, western blot confirmed that (+)-catechin could diminish the levels of IL-34/CSF1R/JAK2/STAT3 signalling pathway in DRG of CCI rats. In vitro studies showed that (+)-catechin reduced IL-34 secretion in LPS-induced RSC96 cells. Meanwhile, (+)-catechin administration in LPS-induced Schwann cell-conditioned medium (L-CM) significantly inhibited the proliferation and migration of RAW264.7 cells; in addition, L-CM+(+)-catechin reduced the activation of the CSF1R/JAK2/STAT3 signalling pathway. (+)-Catechin attenuated the Schwann cell-macrophage cascade response in the DRG by modulating the IL34/CSFIR axis and inhibiting activation of the JAK2/STAT3 pathway, thereby attenuating CCI-induced neuropathic pain in rats.

The spinal cord is a key structure involved in the transmission and modulation of pain. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP), are expressed in the spinal cord. These peptides activate G protein-coupled receptors (PAC1, VPAC1 and VPAC2) that could provide targets for the development of novel pain treatments. However, it is not clear which of these receptors are expressed within the spinal cord and how these receptors signal.

Dissociated rat spinal cord cultures were used to examine agonist and antagonist receptor pharmacology. Signalling profiles were determined for five signalling pathways. The expression of different PACAP and VIP receptors was then investigated in mouse, rat and human spinal cords using immunoblotting and immunofluorescence.

PACAP, but not VIP, potently stimulated cAMP, IP1 accumulation and ERK and cAMP response element-binding protein (CREB) but not Akt phosphorylation in spinal cord cultures. Signalling was antagonised by M65 and PACAP6-38. PACAP-27 was more effectively antagonised than either PACAP-38 or VIP. The patterns of PAC1 and VPAC2 receptor-like immunoreactivity appeared to be distinct in the spinal cord.

The pharmacological profile in the spinal cord suggested that a PAC1 receptor is the major functional receptor subtype present and thus likely mediates the nociceptive effects of the PACAP family of peptides in the spinal cord. However, the potential expression of both PAC1 and VPAC2 receptors in the spinal cord highlights that these receptors may play differential roles and are both possible therapeutic targets.

The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.

Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis and limited treatment options. Aprepitant, a selective NK-1R antagonist, can inhibit the growth of various tumours in vitro and in vivo. However, it remains unclear whether aprepitant has cytotoxic effects on iCCA.

We measured the expression of SP/NK-1R in clinical samples of iCCA by immunohistochemistry. Then, we detected the cytotoxic effects of aprepitant on iCCA cells via MTT, EdU and colony formation assay. We constructed a subcutaneous xenograft model of BALB/c nude mice by using HCCC-9810 and RBE cell lines to explore the effects of aprepitant in vivo. To elucidate the potential mechanisms, we explored the pro-apoptotic effect of aprepitant by flow cytometric, western blotting, ROS detection and JC-1 staining. Furthermore, we detected the autophagic level of HCCC-9810 and RBE by western blotting, mRFP-eGFP-LC3 adenovirus transfection and electron microscope.

SP/NK-1R is significantly expressed in iCCA. Aprepitant inhibited human iCCA xenograft growth and dose-dependently decreased the viability of RBE and HCCC-9810 cells. Aprepitant-induced mitochondria-dependent apoptosis through ROS/JNK pathway. Additionally, pretreatment with z-VAD-fmk partly reversed the effect of aprepitant on cell viability, while NAC completely attenuated the cytotoxic effects of aprepitant in vitro. Furthermore, we observed the dynamic changes of autophagosome in RBE and HCCC-9810 cells treated with aprepitant.

SP/NK-1R signalling is significantly activated in iCCA and promotes the proliferation of iCCA cells. By contrast, aprepitant can induce autophagy and apoptosis in iCCA cells via ROS accumulation and subsequent activation of JNK.

The 5-hydroxytryptamine-3 receptor (5-HT3R), a subtype of serotonin receptor, is a ligand-gated ion channel crucial in mediating fast synaptic transmission in the central and peripheral nervous systems. This receptor significantly influences various neurological activities, encompassing neurotransmission, mood regulation, and cognitive processing; hence, it may serve as an innovative target for neurological disorders. Multiple studies have revealed promising results regarding the beneficial effects of these phytoconstituents and extracts on conditions such as nausea, vomiting, neuropathic pain depression, anxiety, Alzheimer's disease, cognition, epilepsy, sleep, and dyskinesia via modulation of 5-HT3R in the pathophysiology of neurological disorder. The review delves into a detailed exploration of in silico, in vitro, and in vivo studies and clinical studies that discussed phytoconstituents acting on 5-HT3R and attenuates difficulties in neurological diseases. The diverse mechanisms by which plant-derived phytoconstituents influence 5-HT3R activity offer exciting avenues for developing innovative therapeutic interventions. Besides producing an agonistic or antagonistic effect, some phytoconstituents exert modulatory effects on 5-HT3R activity through multifaceted mechanisms. These include γ-aminobutyric acid and cholinergic neuronal pathways, interactions with neurokinin (NK)-1, NK2, serotonergic, and γ-aminobutyric acid(GABA)ergic systems, dopaminergic influences, and mediation of calcium ions release and inflammatory cascades. Notably, the phytoconstituent's capacity to reduce oxidative stress has also emerged as a significant factor contributing to their modulatory role. Despite the promising implications, there is currently a dearth of exploration needed to understand the effect of phytochemicals on the 5-HT3R. Comprehensive preclinical and clinical research is of the utmost importance to broaden our knowledge of the potential therapeutic benefits associated with these substances.

Osteoarthritis (OA) related pain has affected millions of people worldwide. However, the current pharmacological options for managing OA-related pain have not achieved a satisfactory effect.

This narrative review provides an overview of the current and emerging drugs for OA-related pain. It covers the drugs' mechanism of action, safety, efficacy, and limitations. The National Library of Medicine (PubMed) database was primarily searched from 2000 to 2024.

Current treatment options are limited and suboptimal for OA pain management. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are the recognized and first-line treatment in the management of OA-related pain, and other drugs are inconsistent recommendations by guidelines. Emerging treatment options are promising for OA-related pain, including nerve growth factor (NGF) inhibitors, ion channel inhibitors, and calcitonin gene-related peptide (CGRP) antagonists. Besides, drugs repurposing from antidepressants and antiepileptic analgesics are shedding light on the management of OA-related pain. The management of OA-related pain is challenging as pain is heterogeneous and subjective. A more comprehensive strategy combined with non-pharmacological therapy needs to be considered, and tailored management options to individualized patients.

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP's impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP's diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies.

Chronic pain, a complex and debilitating condition, poses a significant challenge to both patients and healthcare providers worldwide. Conventional pharmacological interventions often prove inadequate in delivering satisfactory relief while carrying the risks of addiction and adverse reactions. In recent years, electric neuromodulation emerged as a promising alternative in chronic pain management. This method entails the precise administration of electrical stimulation to specific nerves or regions within the central nervous system to regulate pain signals. Through mechanisms that include the alteration of neural activity and the release of endogenous pain-relieving substances, electric neuromodulation can effectively alleviate pain and improve patients' quality of life. Several modalities of electric neuromodulation, with a different grade of invasiveness, provide tailored strategies to tackle various forms and origins of chronic pain. Through an exploration of the anatomical and physiological pathways of chronic pain, encompassing neurotransmitter involvement, this narrative review offers insights into electrical therapies' mechanisms of action, clinical utility, and future perspectives in chronic pain management.

Tumor microenvironment infiltration by cells of the T helper cell type 1 (TH1) system, including TH1 cells, M1 macrophages, natural killer cells, and CD8+ T cells, is associated with better cancer prognosis. In contrast, tumor microenvironment infiltration by cells of the TH2 system, including TH2 cells, M2 macrophages, and innate lymphoid cells type 2, as well as immune suppressive myeloid-derived suppressor cells and regulatory T cells, is associated with poorer cancer prognosis. Beyond the tumor itself and a myriad of other modifying factors, such as genetic and epigenetic influences on tumorigenesis, the overall immune state of the patient, termed the macroenvironment, has also been shown to significantly influence cancer outcomes. Alterations in the tricarboxylic acid (TCA) cycle (TCA cycle breaks) involving loss of function of succinate dehydrogenase, isocitrate dehydrogenase, and fumarate hydratase have been shown to be associated with an intracellular metabolic shift away from oxidative phosphorylation and into glycolysis in cells that are transforming into cancer cells. The same loss of function of succinate dehydrogenase and isocitrate dehydrogenase has also been identified as inducing a shift in macrophages toward glycolysis that is associated with M1 macrophage polarization. M1 macrophages make interleukin 12, which stimulates TH1 cells and natural killer cells to produce interferon gamma (IFN-γ), which in turn stimulates M1 macrophage activity, forming an activation loop. IFN-γ also drives activation of CD8+ T cells. Thus, M1 macrophage activation initiates and sustains activation of the TH1 system of cells. In this fashion, TCA cycle breaks at succinate dehydrogenase and isocitrate dehydrogenase that promote cellular transformation into cancer cells are also associated with upregulation of the TH1 system that provides anti-cancer immune surveillance. The TH1 and TH2 systems are known to inhibit each other's activation. It is this author's hypothesis that, in patients whose macroenvironment is sufficiently TH2-dominant, the metabolic shift toward glycolysis induced by TCA cycle breaks that gives rise to mutagenic changes in tissue parenchymal cells is not counterbalanced by adequate activation of M1 macrophages, thus giving rise to cancer cell development. For instance, the atopic TH2-high asthma phenotype, a TH2 dominance-based comorbidity, is associated with a more than doubled incidence of colon, breast, lung, and prostate cancer, compared with non-asthmatics. Failure of TCA cycle breaks to induce M1 polarization of tissue-resident macrophages yields a tissue environment in which the tissue-resident macrophages fail to routinely perform M1-associated functions such as phagocytizing newly developing cancer cells. Failure of M1 phenotypic expression in both tissue-resident macrophages and monocyte-derived macrophages recruited to the tumor microenvironment yields both a loss of direct antitumor M1 macrophage actions and failure of TH1 system activation in general, including failure of CD8+ T cell activation, yielding a cancer-permissive tumor microenvironment and a poorer prognosis in patients with existing cancers. This paper proposes a conceptual framework that connects established elements in the existing research and points to the utility of a patient profiling process, aimed at personalization of treatment through identification and targeting of elements in each patient's tumor microenvironment and macroenvironment that contribute to unfavorable prognosis.

Neuropeptide substance P (SP) belongs to a family of bioactive peptides and regulates many human diseases. This study aims to investigate the role and underlying mechanisms of SP in colitis. Here, activated SP-positive neurons and increased SP expression were observed in dextran sodium sulfate (DSS)-induced colitis lesions in mice. Administration of exogenous SP efficiently ameliorated the clinical symptoms, impaired intestinal barrier function, and inflammatory response. Mechanistically, SP protected mitochondria from damage caused by DSS or TNF-α exposure, preventing mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. SP can also directly prevent STING phosphorylation through the neurokinin-1 receptor (NK1R), thereby inhibiting the activation of the TBK1-IRF3 signaling pathway. Further studies revealed that SP alleviated the DSS or TNF-α-induced ferroptosis process, which was associated with repressing the cGAS-STING signaling pathway. Notably, we identified that the NK1R inhibition reversed the effects of SP on inflammation and ferroptosis via the cGAS-STING pathway. Collectively, we unveil that SP attenuates inflammation and ferroptosis via suppressing the mtDNA-cGAS-STING or directly acting on the STING pathway, contributing to improving colitis in an NK1R-dependent manner. These findings provide a novel mechanism of SP regulating ulcerative colitis (UC) disease.

Provoked vulvodynia represents a challenging chronic pain condition, characterized by its multifactorial origins. The inherent complexities of human-based studies have necessitated the use of animal models to enrich our understanding of vulvodynia's pathophysiology. This review aims to provide an exhaustive examination of the various animal models employed in this research domain. A comprehensive search was conducted on PubMed, utilizing keywords such as "vulvodynia", "chronic vulvar pain", "vulvodynia induction", and "animal models of vulvodynia" to identify pertinent studies. The search yielded three primary animal models for vulvodynia: inflammation-induced, allergy-induced, and hormone-induced. Additionally, six agents capable of triggering the condition through diverse pathways were identified, including factors contributing to hyperinnervation, mast cell proliferation, involvement of other immune cells, inflammatory cytokines, and neurotransmitters. This review systematically outlines the various animal models developed to study the pathogenesis of provoked vulvodynia. Understanding these models is crucial for the exploration of preventative measures, the development of novel treatments, and the overall advancement of research within the field.

Accidents caused by Bothrops jararaca (Bj) snakes result in several local and systemic manifestations, with pain being a fundamental characteristic. The inflammatory process responsible for hyperalgesia induced by Bj venom (Bjv) has been studied; however, the specific roles played by the peripheral and central nervous systems in this phenomenon remain unclear. To clarify this, we induced hyperalgesia in rats using Bjv and collected tissues from dorsal root ganglia (DRGs) and spinal cord (SC) at 2 and 4 h post-induction. Samples were labeled for Iba-1 (macrophage and microglia), GFAP (satellite cells and astrocytes), EGR1 (neurons), and NK1 receptors. Additionally, we investigated the impact of minocycline, an inhibitor of microglia, and GR82334 antagonist on Bjv-induced hyperalgesia. Our findings reveal an increase in Iba1 in DRG at 2 h and EGR1 at 4 h. In the SC, markers for microglia, astrocytes, neurons, and NK1 receptors exhibited increased expression after 2 h, with EGR1 continuing to rise at 4 h. Minocycline and GR82334 inhibited venom-induced hyperalgesia, highlighting the crucial roles of microglia and NK1 receptors in this phenomenon. Our results suggest that the hyperalgesic effects of Bjv involve the participation of microglial and astrocytic cells, in addition to the activation of NK1 receptors.

Electrical epilation of unwanted hair is a widely used hair removal method, but it is largely unknown how this affects the biology of human hair follicles (HF) and perifollicular skin. Here, we have begun to explore how mechanical epilation changes selected key biological read-out parameters ex vivo within and around the pilosebaceous unit.

Human full-thickness scalp skin samples were epilated ex vivo using an electro-mechanical device, organ-cultured for up to 6 days in serum-free, supplemented medium, and assessed at different time points by quantitative (immuno-)histomorphometry for selected relevant read-out parameters in epilated and sham-epilated control samples.

Epilation removed most of the hair shafts, often together with fragments of the outer and inner root sheath and hair matrix. This was associated with persistent focal thinning of the HF basal membrane, decreased melanin content of the residual HF epithelium, and increased HF keratinocyte apoptosis, including in the bulge, yet without affecting the number of cytokeratin 15+ HF epithelial stem cells. Sebocyte apoptosis in the peripheral zone was increased, albeit without visibly altering sebum production. Epilation transiently perturbed HF immune privilege, and increased the expression of ICAM-1 in the bulge and bulb mesenchyme, and the number of perifollicular MHC class II+ cells as well as mast cells around the distal epithelium and promoted mast cell degranulation around the suprabulbar and bulbar area. Moreover, compared to controls, several key players of neurogenic skin inflammation, itch, and/or thermosensation (TRPV1, TRPA1, NGF, and NKR1) were differentially expressed in post-epilation skin.

These data generated in denervated, organ-cultured human scalp skin demonstrate that epilation-induced mechanical HF trauma elicits surprisingly complex biological responses. These may contribute to the delayed re-growth of thinner and lighter hair shafts post-epilation and temporary post-epilation discomfort. Our findings also provide pointers regarding the development of topically applicable agents that minimize undesirable sequelae of epilation.

To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats.

Randomized, blinded, prospective experimental study.

98 male Wistar rats.

Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR.

Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1).

These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Chronic ocular pain, particularly prevalent in patients with dry eye disease and post-femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) surgery, presents with unclear clinical characteristics and an undefined pathogenesis. In this study, we aimed to compare clinical characteristics and tear neuropeptide concentrations in patients with dry eye disease (DED) with and without chronic ocular pain following FS-LASIK, and investigate correlations between ocular pain, clinical characteristics, and tear neuropeptide levels.

Thirty-eight post-FS-LASIK patients with DED were assigned to two groups: those with chronic ocular pain and those without chronic ocular pain. Dry eye, ocular pain, and mental health-related parameters were evaluated using specific questionnaires and tests. The morphology of corneal nerves and dendritic cells (DCs) was evaluated by in vivo confocal microscopy. Function of corneal innervation was evaluated by corneal sensitivity. Concentrations of tear cytokines (interleukin [IL]-6, IL-23, IL-17A, and interferon-γ) and neuropeptides (α-melanocyte-stimulating hormone, neurotensin, β-endorphin, oxytocin, and substance P [SP]) were measured using the Luminex assay.

Most patients with chronic ocular pain experienced mild to moderate pain; the most common types included stimulated pain (provoked by wind and light), burning pain, and pressure sensation. More severe dry eye (P < 0.001), anxiety symptoms (P = 0.026), lower Schirmer I test values (P = 0.035), lower corneal nerve density (P = 0.043), and more activated DCs (P = 0.041) were observed in patients with ocular pain. Tear concentrations of SP and oxytocin were significantly higher in patients with ocular pain (P = 0.001, P = 0.021, respectively). Furthermore, significant correlations were observed among ocular pain severity, SP, and anxiety levels.

Patients with DED after FS-LASIK who have chronic ocular pain show more severe ocular and psychological discomfort and higher tear levels of neuropeptides. Furthermore, ocular pain severity is correlated with tear SP levels.

ClinicalTrials.gov identifier: NCT05600985.

Pathological pain emerges from nociceptive system dysfunction, resulting in heightened pain circuit activity. Various forms of circuitry plasticity, such as central sensitization, synaptic plasticity, homeostatic plasticity, and excitation/inhibition balance, contribute to the malfunction of neural circuits during pain pathogenesis. Recently, a new form of plasticity in the spinal dorsal horn (SDH), named neural circuit polarization (NCP), was discovered in pain models induced by HIV-1 gp120 and chronic morphine administration. NCP manifests as an increase in excitatory postsynaptic currents (EPSCs) in excitatory neurons and a decrease in EPSCs in inhibitory neurons, presumably facilitating hyperactivation of pain circuits. The expression of NCP is associated with astrogliosis. Ablation of reactive astrocytes or suppression of astrogliosis blocks NCP and, concomitantly, the development of gp120- or morphine-induced pain. In this review, we aim to compare and integrate NCP with other forms of plasticity in pain circuits to improve the understanding of the pathogenic contribution of NCP and its cooperation with other forms of circuitry plasticity during the development of pathological pain.

Currently, society and industry generate huge amounts of plastics worldwide. The ubiquity of microplastics is obvious, but its impact on the animal and human organism remains not fully understood. The digestive tract is one of the first barriers between pathogens and xenobiotics and a living organism. Its proper functioning is extremely important in order to maintain homeostasis. The aim of this study was to determine the effect of microplastic on enteric nervous system and histological structure of swine duodenum. The experiment was carried out on 15 sexually immature gilts, approximately 8 weeks old. The animals were randomly divided into 3 study groups (n = 5/group). The control group received empty gelatin capsules once a day for 28 days, the first research group received daily gelatin capsules with polyethylene terephthalate (PET) particles as a mixture of particles of various sizes (maximum particle size 300 µm) at a dose of 0.1 g/animal/day. The second study group received a dose ten times higher-1 g/animal/day.

A dose of 1 g/day/animal causes more changes in the enteric nervous system and in the histological structure of duodenum. Statistically significant differences in the expression of cocaine and amphetamine regulated transcript, galanin, neuronal nitric oxide synthase, substance P, vesicular acetylcholine transporter and vasoactive intestinal peptide between control and high dose group was noted. The histopathological changes were more frequently observed in the pigs receiving higher dose of PET.

Based on this study it may be assumed, that oral intake of microplastic might have potential negative influence on digestive tract, but it is dose-dependent.

The transparent cornea is the most densely innervated tissue in the body, primarily by sensory nerves originating from the trigeminal ganglia (TG). Damage to corneal nerves reduces sensitivity and tear secretion and results in dry eye. Consequently, ocular pain, for which no satisfactory therapies exist, arises in many cases. Treatment of injured corneas with pigment epithelium-derived factor (PEDF) combined with docosahexaenoic acid (DHA) stimulates nerve regeneration in models of refractive surgery, which damages nerves. The mechanism involves the synthesis of a stereoisomer of resolvin D6 (R,R-RvD6) formed after incorporating DHA into membrane lipids. Activation of a PEDF receptor (PEDF-R) with phospholipase activity releases DHA to synthesize the new resolvin isomer, which is secreted via tears. Topical treatment of mice corneas with R,R-RvD6 shows higher bioactivity in regenerating nerves and increasing sensitivity compared to PEDF+DHA. It also stimulates a transcriptome in the TG that modulates genes involved in ocular pain. Our studies suggest an important therapeutic role for R,R-RvD6 in regenerating corneal nerves and decreasing pain resulting from dry eye.