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Background: Neurokinin-1 receptor (NK-1R) and normal T cell expressed and secreted (RANTES) have been shown to play important roles in allergic rhinitis (AR). However, whether the regulating effect of NK-1R in AR is achieved via RANTES remains unknown. Methods: In the present study, Sprague-Dawley rats were sensitized and challenged with ovalbumin to make AR models. During the challenge period, the rats were treated intranasally with NK-1R-specific small interfering RNA (siRNA) for NKR group, negative siRNA for NCS group, rats in NSAR group and NS group were given saline. The amount of nasal secretion and the numbers of nose rubs and sneezes were measured in each rat. The levels of NK-1R and RANTES in the nasal mucosal tissues were determined through real-time fluorescence quantitative RT-PCR and immunohistochemical staining. The numbers of eosinophils in the collected nasal lavage fluid (NLF) were counted, and the concentration of RANTES in NLF was determined by enzyme-linked immunosorbent assay. Results: Compared with that in the NS group, the expression of NK-1R and RANTES was significantly higher in the nasal mucosa of NSAR and NCS group rats. The sneezing and nose rubbing counts and the amount of nasal secretions were increased significantly in the NSAR and NCS groups. Rats in the NKR group experienced greater relief from AR symptoms than rats in the NSAR and NCS groups. Furthermore, knockdown of NK-1R expression also significantly eliminated RANTES expression and eosinophil infiltration in the nasal mucosa of NKR group rats. Conculsion: For the first time, we show that intranasal treatment with NK-1R-specific siRNA can significantly decrease RANTES expression, AR-related symptoms, and eosinophil inflammation, suggesting that the regulating effect of NK-1R in the development of AR occurs via alteration of RANTES expression. [ABSTRACT FROM AUTHOR]

To compare the intensity, location, and short-term impact of the periodontal discomfort/pain, as well as the related functional parameters of bite force and masticatory efficiency, between self-ligating and conventional orthodontic appliances. In 20 patients referred for orthodontic treatment, samples were collected from the gingival sulcus to evaluate the level of substance P using enzyme-linked immunosorbent assay. Orthodontic devices were randomly bonded, with self-ligating appliances on one side and conventional brackets on the contralateral side. Pain threshold (PT), maximal bite force (MBF), and masticatory efficiency (ME) were assessed using standard validated techniques at the beginning of the treatment and 24 hours post–orthodontic activation with an 0.016-inch nickel-titanium wire. There were no significant differences (P >.05) in the substance P levels, PT, MBF, and ME between the self-ligating and conventional orthodontic appliances. There was no difference between conventional and self-ligating appliances in the parameters of pain: substance P and pressure. Functional aspects, such as pain, discomfort, and masticatory efficiency, should not be considered when making a therapeutic decision regarding the use of self-ligating vs conventional orthodontic appliances. [ABSTRACT FROM AUTHOR]

One of the causes of endodontic flare-ups is overinstrumentation during canal preparation. In general, to reduce the level of pain and swelling that is caused by endodontic flare-ups, patients it has taken analgesics and antibiotics after treatment. However, some patients have been reported to have allergic reactions to nonsteroidal anti-inflammatory drugs. Lasers have been reported to be significantly effective in reducing pain and inflammation after root canal treatment. Low-level laser therapy (LLLT) 650 nm pre- or post-conditioning is widely used as a therapy. This study investigated the effect of pre- or post-conditioning with a 650 nm diode laser to reduce pain caused by overinstrumentation Thirty incisor teeth from Wistar rats were overinstrumented and exposed to a 650 nm diode laser before or after overinstrumentation and then divided into six groups. Groups I and II were control groups (30 and 120 min), groups III and IV were precondition groups (30 and 120 min) and Groups V and VI were postcondition groups (30 and 120 min). Immunohistochemical analysis was conducted to check the expression of substance P and interleukin-10 (IL-10) The expression of substance P in the precondition LLLT groups was significantly lower than that in the control and postcondition groups. On the other hand, the expression of IL-10 in the precondition LLLT groups was significantly higher than that in the control and postcondition groups. There was a decrease in pain after preconditioning laser diode 650 nm exposure. [ABSTRACT FROM AUTHOR]

Substance P (SP) is a neuropeptide released from the nervous fibers in response to injury. In addition to its association with pain and reactions to anxiety and stress, SP exerts various physiological functions by binding to the neurokinin-1 receptor (NK1R). However, the expression and role of SP in reparative dentinogenesis remain elusive. Here, we explored whether SP is involved in odontoblastic differentiation during reparative dentinogenesis. Dental pulp stem cells (DPSCs) were isolated from healthy human dental pulp tissues and subjected to odontoblastic differentiation. The expression of SP and NK1R during odontoblastic differentiation was investigated in vitro. The effects of SP on odontoblastic differentiation of DPSCs were evaluated using alizarin red staining, alkaline phosphatase staining, and real-time polymerase chain reaction. After direct pulp capping with mineral trioxide aggregate, the expression of SP and NK1R during reparative dentin formation in rats were identified using histological and immunohistochemical staining. SP and NK1R expression increased during the odontoblastic differentiation of DPSCs. SP translocated to the nucleus when DPSCs were exposed to differentiation medium. NK1R was always present in the nuclei of DPSCs and odontoblast-like cells. Additionally, we discovered that 10−8 M SP marginally enhanced the odontoblastic differentiation of DPSCs, and that these effects could be impaired by the NK1R antagonist. Furthermore, SP and NK1R were expressed in odontoblast-like and dental pulp cells during reparative dentin formation in vivo. SP contributes to odontoblastic differentiation during reparative dentin formation by binding to the NK1R. [ABSTRACT FROM AUTHOR]

Introduction: Although acute mountain sickness (AMS) can be a life-threatening condition, early diagnosis is difficult due to vague and non-specific symptoms. The aim of this study is to investigate biochemical markers that can detect high-altitude diseases in advance. Eight different biomarkers (BNP, HIF-1α, NGAL, MMP-3, MMP-9, SESN2, substance P (SP), and U-II) were studied, and their relationship with AMS was investigated.Methods: Of the 84 mountaineers who participated in the mountaineering training organized by the Turkish Mountaineering Federation in the Rize Kaçkar Mountains in 2018, 52 volunteered to participate in the study. Twelve hours after the participants reached an altitude of 2200 m (exposed to moderate hypoxia), their vital parameters were measured, and blood samples were taken for biochemistry tests. Vital signs and Lake Louise (LL) AMS scores were recorded every 24 h during the following 72 h. The participants were divided into two groups according to their LL scores: those with AMS and those without (AMS+ and AMS -), and the vital parameters and biomarker levels of both groups were compared and evaluated.Results: Of the volunteers participating in the study, 35 (67.3%) were male and 17 (32.7%) were female, although there was no gender difference in terms of susceptibility to AMS. Among the investigated markers in the AMS + group, MMP-9 and SP were statistically significantly higher (p = 0.037 and p = 0.038, respectively). There were no statistical differences between AMS- and AMS+ groups with regard to heart rate, oxygen saturation, and systolic and diastolic blood pressure values (p = 0.507, p = 0.929, p = 0.955, p = 0.572, respectively).Conclusion: There were significant differences between the AMS- and AMS+ groups in terms of MMP-9 and SP. However, differences in physical indexes between the groups were not statistically significant. This could provide objective indexes for scanning and screening individuals susceptible to AMS in the early stages of rapid ascending. [ABSTRACT FROM AUTHOR]

Glioma is a primary aggressive brain tumor with high recurrence rate. The poor efficiency of chemotherapeutic drugs crossing the blood‒brain barrier (BBB) is well-known as one of the main challenges for anti-glioma therapy. Moreover, massive infiltrated tumor-associated macrophages (TAMs) in glioma further thwart the drug efficacy. Herein, a therapeutic nanosystem (SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera (PROTAC) ARV-825 into the complex micelle (SPP) composed of substance P (SP) peptide-modified poly(ethylene glycol)-poly(d , l -lactic acid)(SP-PEG-PDLLA) and methoxy poly(ethylene glycol)-poly(d , l -lactic acid) (mPEG-PDLLA, PP), which could penetrate BBB and target brain tumor. Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future. This work introduces a targeting drug delivery system (SPP-ARV-825) consisting of mPEG-PDLLA, SP-PEG-PDLLA and BRD4 PROTAC drug ARV-825 for glioma therapy. The SPP-ARV-825 efficiently induces BRD4 degradation and attenuates glioma tumor growth. The antitumor mechanisms of SPP-ARV-825 involve cells proliferation inhibition, apoptosis induction and M2 macrophages reduction. [Display omitted] [ABSTRACT FROM AUTHOR]

What textbooks usually call the sublingual gland in humans is in reality a tissue mass of two types of salivary glands, the anteriorly located consisting of a cluster of minor sublingual glands and the posteriorly located major sublingual gland with its outlet via Bartholin's duct. Only recently, the adrenergic and cholinergic innervations of the major sublingual gland was reported, while information regarding the neuropeptidergic and nitrergic innervations is still lacking. Bioptic and autoptic specimens of the human major sublingual gland were examined by means of immunohistochemistry for the presence of vasoactive intestinal peptide (VIP)-, neuropeptide Y (NPY)-, substance P (SP)-, calcitonin gene related-peptide (CGRP)-, and neuronal nitric oxide synthase (nNOS)-labeled neuronal structures. As to the neuropeptidergic innervation of secretory cells (here in the form of mucous tubular and seromucous cells), the findings showed many VIP-containing nerves, few NPY- and SP-containing nerves and a lack of CGRP-labeled nerves. As to the neuropeptidergic innervation of vessels, the number of VIP-containing nerves was modest, while, of the other neuropeptide-containing nerves under study, only few (SP and CGRP) to very few (NPY) nerves were observed. As to the nitrergic innervation, nNOS-containing nerves were very few close to secretory cells and even absent around vessels. The various innervation patterns may suggest potential transmission mechanisms involved in secretory and vascular responses of the major sublingual gland. • Neuropeptidergic nerves are mostly around acini. • Neuropeptidergic innervation of vessels is modest to rare. • Vasoactive intestinal peptide is the dominating neuropeptide. • Nitrergic innervation is poor. • Non-adrenergic, non-cholinergic innervations may regulate secretory and vascular functions. [ABSTRACT FROM AUTHOR]

The biology of immediate post-extraction implant osseointegration is mediated by a coordinated cascade of osteoblast-osteoclast interactions. The aim of this study was to develop a dual-delivery system that allowed sequential release of substance P (SP) to promote bone regeneration and alendronate (ALN) to reduce bone resorption, which will improve the implant osseointegration. We used coaxial electrospinning to fabricate the core-shell poly lactic-co-glycolic acid (PLGA)/gelatin nanofibers, which consists of SP in the shell and ALN in the core. This programmed delivery system was shown to release SP and ALN sequentially to match the spatio-temporal specificity of bone healing. The migration assay demonstrated that the SP-ALN dual-delivery system increased bone marrow mesenchymal stem cells (BMSCs) transmigration. Besides, the expression of osteogenic/osteoclastic markers, Alizarin Red staining, tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining and bone resorption experiment showed that the dual-delivery system can render a microenvironment favorable for osteogenic differentiation and adverse to osteoclastogenesis. Using a rat immediate implant model, we validated the promoted osteogenic property and osseointegration around the implants of SP-ALN dual-delivery system by micro-computed tomography (micro-CT) and histological analysis. These findings suggest that the dual-delivery system with time-controlled release of SP and ALN by core-shell nanofibers provides a promising strategy to facilitate immediate implant osseointegration through favorable osteogenesis. Immediate implant placement is potentially challenged by the difficulties in achieving primary implant stability and early osteogenesis. Initial period of osteointegration is regulated by osteoblastic/osteoclastic cells resulting in a coordinated healing process. To have an efficient bone regeneration, the coaxial electrospinning was used to fabricate a programmed dual-delivery system. The SP released rapidly and favored for BMSCs migration and osteogenic differentiation, while the sustained release of ALN can reduce the bone resorption. The rat immediate implant model indicated that the SP-ALN dual-delivery system could present the promoted peri‑implant osteogenic property and osseointegration through modulating the osteogenesis-osteoclastogenesis balance. This work highlights the sequential dual delivery of SP and ALN has a promising potential of achieving enhanced osseointegration for immediate implant placement. [Display omitted] [ABSTRACT FROM AUTHOR]

Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific FcεR1γ knockdown (TRPV1Cre::FcεR1γfl/fl) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor FcεR1, the levels of which increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies T H 2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre::FcεR1γfl/fl mice and in FcεR1α–/– mice into which bone marrow has been transplanted. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell–derived nociceptors. Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1-expressing vagal sensory neurons, and T H 2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, FcεR1γ expressed by nociceptors. [ABSTRACT FROM AUTHOR]

Objective: To systematically review the literature to identify controlled clinical trials evaluating the effectiveness of deep dry needling (DDN) in the treatment of patients with chronic masticatory myofascial pain (MMP).Methods: The sample size for a clinical trial was calculated and involved five patients who consecutively presented for treatment of MMP. The percentage of change in the means of three consecutive measurements of the pressure pain threshold (PPT) of myofascial trigger points (MTPs) was calculated and the statistical significance of this difference evaluated using the Wilcoxon test.Results: Twenty-five studies were considered for inclusion based on title and abstract. Only 2 studies met the inclusion criteria and were used to calculate the sample size. DDN significantly increased (p = 0.04) the PPT in MTP (44.6%) compared with sham procedure (-5.5%).Conclusion: Patients with chronic MMP treated with DDN of MTPs showed an increase in PPT measurements on the experimental side.Abbreviations: CGRP: calcitonin gene-related peptide; DC/TMD: diagnostic criteria for temporomandibular disorders; DDN: deep dry needling; DN: dry needling; LILACS: Latin American and Caribbean Health Sciences; MMP: masticatory myofascial pain; MTP: myofascial trigger point; MTPs: myofascial trigger points; PPT: pressure pain threshold; RCTs: randomized clinical trials; SciELO: Scientific Electronic Library Online; SP: Substance P; TMD: temporomandibular disorders. [ABSTRACT FROM AUTHOR]

The Mas-related G protein–coupled receptor X2 (MRGPRX2) is a multiligand receptor responding to various exogenous and endogenous stimuli. Being highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of proinflammatory mediators, and it promotes multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are upregulated in the serum and/or skin of patients with inflammatory and pruritic skin diseases, such as chronic spontaneous urticaria or atopic dermatitis. Therefore, MRGPRX2 and its agonists might be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment. In addition, they may represent promising targets for prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions. To assess this possibility, this review explores the role and relevance of MRGPRX2 and its activators in cutaneous inflammatory disorders and chronic pruritus. [ABSTRACT FROM AUTHOR]

Background: Scalding burn injuries can occur in everyday life but occur more frequently in young children. Therefore, it is important to develop more effective burn treatments. Objectives: This study examined the effects of bee venom (BV) stimulation on scalding burn injury-induced nociception in mice as a new treatment for burn pain. Methods: To develop a burn injury model, the right hind paw was immersed temporarily in hot water (65°C, 3 seconds). Immediately after the burn, BV (0.01, 0.02, or 0.1 mg/kg) was injected subcutaneously into the ipsilateral knee area once daily for 14 days. A von Frey test was performed to assess the nociceptive response, and the altered walking parameters were evaluated using an automated gait analysis system. In addition, the peripheral and central expression changes in substance P (Sub P) were measured in the dorsal root ganglion and spinal cord by immunofluorescence. Results: Repeated BV treatment at the 2 higher doses used in this study (0.02 and 0.1 mg/kg) alleviated the pain responses remarkably and recovered the gait performances to the level of acetaminophen (200 mg/kg, intraperitoneal, once daily), which used as the positive control group. Moreover, BV stimulation had an inhibitory effect on the increased expression of Sub P in the peripheral and central nervous systems by a burn injury. Conclusions: These results suggest that a peripheral BV treatment may have positive potency in treating burn-induced pain. [ABSTRACT FROM AUTHOR]

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The aim of this study was to compare levels of neurokinin A (NKA), substance P (SP), interleukin (IL)-8, and matrix metalloproteinase-8 (MMP-8) in pulp tissue and gingival crevicular fluid (GCF) samples of healthy and symptomatic irreversible pulpitis teeth. Forty patients diagnosed with healthy and symptomatic irreversible pulpitis teeth were included in this study. NKA, SP, IL-8, and MMP-8 levels were measured using the enzyme-linked immunosorbent assay test after pulp and GCF samples were obtained from healthy (n = 20) and symptomatic irreversible pulpitis teeth (n = 20). GCF sampling of 40 teeth was repeated 1 week later. Routine root canal treatment procedures of the teeth were performed, and the treatment process was completed. As a control group, GCF samples were taken from the contralateral teeth in both groups. Statistical analysis was performed using dependent and independent t tests, analysis of variance, Kruskal-Wallis, Mann-Whitney U tests, and Pearson correlation analysis. Comparing the groups, all mediator levels were significantly higher in the pulp samples in the pulpitis group compared with the healthy group (NKA: P <.001, SP: P =.005, IL-8: P <.001, and MMP-8: P <.001). Likewise, in the pulpitis group, all mediator levels were significantly higher in the first GCF samples compared with the healthy group (NKA: P =.01, SP: P <.001, IL-8: P =.001, and MMP-8: P <.001). It was observed that NKA, SP, IL-8, and MMP-8 increased significantly in pulp tissue and GCF specimens of symptomatic irreversible pulpitis teeth compared with pulp tissue and GCF specimens of healthy teeth. Second, it was determined that NKA, SP, IL-8, and MMP-8 levels decreased significantly in GCF samples in teeth diagnosed with symptomatic irreversible pulpitis 1 week after the removal of inflamed pulp. Finally, SP, IL-8, and MMP-8 levels were found to be higher in pulp tissue samples of the patients with symptomatic irreversible pulpitis with higher pain scores than those with low pain scores. [ABSTRACT FROM AUTHOR]

Background: One of the hallmarks of bullous pemphigoid (BP) is moderate to severe chronic itch. Managing this is difficult because little is known about the mechanisms of itch in BP.Objective: We sought to elucidate the pathophysiologic mechanisms of itch in BP.Methods: The expression of itch mediators in lesions of 24 patients with BP and 6 healthy individuals were examined through immunofluorescence staining. Furthermore, the expression of itch mediators and itch severity was correlated.Results: Itch severity was correlated with eosinophils, substance P, neurokinin 1R, interleukin (IL) 31 receptor A, oncostatin M receptor-β, IL-13, periostin, and basophils. There was also a trend between itch severity and IL-31 expression. Most of the cells expressing IL-31 or neurokinin 1R were identified as eosinophils. Intraepidermal nerve fiber density was decreased. Other itch mediators, including mast cells, IL-4, thymic stromal lymphopoietin, transient receptor potential vanilloid 1 and ankyrin 1, and protease activated receptor 2 were not significantly correlated with itch severity.Limitations: The relatively small sample size, the examination of protein expression exclusively through immunofluorescent analysis, and lack of functional assays in patients are the limitations.Conclusions: Multiple factors are involved in BP-associated itch, including eosinophils, substance P, neurokinin 1R, IL-31, IL-31 receptor A, oncostatin M receptor-β, IL-13, periostin, and basophils. They could be useful therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch.Objective: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639).Methods: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening.Results: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients.Limitations: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded.Conclusion: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population. [ABSTRACT FROM AUTHOR]

Background: Chronic pruritus causes major morbidity in epidermolysis bullosa (EB). The substance P-neurokinin 1 receptor (SP-NK1) pathway is a promising target for treating EB-related pruritus.Objective: To evaluate the safety and efficacy of the oral NK1 receptor antagonist serlopitant in treating moderate-severe pruritus in EB.Methods: The study randomized 14 patients to serlopitant or placebo for 8 weeks, followed by a 4-week washout and optional open-label extension. The primary end point was change in itch as measured by the Numeric Rating Scale. Secondary end points were change in itch during dressing changes and wound size.Results: We observed greater itch reduction with serlopitant, equivalent to a 0.64-point comparative reduction on the 11-point Numeric Rating Scale by week 8, although this failed to meet statistical significance (P = .11). More serlopitant patients achieved ≥3-point reduction compared with placebo (43% vs 14%, P = .35). In post hoc analysis excluding 1 patient with a concurrent seborrheic dermatitis flare, serlopitant achieved significantly greater median itch reduction from baseline by week 4 (-2 points vs 0, P = .01). We observed no statistically significant differences in secondary end points. Serlopitant was well-tolerated.Limitations: Small sample size due to disease rarity.Conclusion: The potential itch reduction with serlopitant observed in this trial will be pursued by a larger powered trial (NCT03836001). [ABSTRACT FROM AUTHOR]

This study is conducted to determine effects of manual acupuncture (MA) in patients with a diagnosis of major depressive disorder (MDD) and comorbid insomnia. A total of 67 participants who met the inclusion criteria were randomly enrolled in a two-arm randomized, placebo controlled, patients-blind trial and allocated to a real-MA group (patients = 34) and a sham-MA group (patients = 33). Patients in the real-MA group were treated on 'Five-shen acupoints', including Sìshéncōng (四神聪 EX-HN 1), Shéntíng (神庭 GV 24), Shéndào (神道 GV 11), bilateral Běnshén (本神 GB 13), and bilateral Shénmén (神门 HT 7). Though being punctured on the same acupoints, patients in the sham-MA group were treated by a placebo acupuncture approach (Streitberger Placebo-needle). Each group received corresponding interventions every other day, three times a week for total eight weeks. Both polysomnography (PSG) and testing of serum biological markers such as neuropeptide Y (NPY) and substance P (SP) were performed at pre- and post-treatment. Additionally, the global scores of Pittsburgh sleep quality index (PSQI) and the global scores of 17-items Hamilton Depression Rating Scale (HAMD17) were used for assessing the subjective sleep and emotion experience of patients, respectively. Meanwhile, adverse effects were monitored and recorded. After eight-week treatment, the global scores of PSQI and global scores of HAMD17 declined significantly (both P < 0.05) in the real-MA group but not in the sham-MA group (both P > 0.05). According to the parameters of PSG, striking decline were observed in sleep latency (SL) and wake after sleep onset (WASO) and striking climb were observed in total sleep time (TST) and sleep efficiency (SE) in the real-MA group after treatment (P < 0.05, respectively) but not in the sham-MA group (P > 0.05, respectively). Additionally, there were no significant differences in awakening times (ATs) and rapid eyes movement sleep latency (REM-SL) in both two groups after treatment (both P > 0.05). Meanwhile, the expression of NPY increased significantly and the expression of SP decreased significantly in the real-MA group after interventions (both P < 0.05) while those indicators only slightly fluctuated in the sham-MA group (P > 0.05). No serious adverse event was reported in either real- or sham- MA group. (1) MA may be a potential alternative therapy for improving MDD and comorbid insomnia (particularly in extending total sleep time and shortening wake-up duration and sleep latency) via upregulating the expression of NPY and downregulating the expression of SP; more importantly, this efficacy of acupuncture can not be replaced by sham-acupuncture acting on the same acupoints with the same treatment frequency. (2) There is insufficient evidence to prove that MA can effectively reduce the number of arousals. [ABSTRACT FROM AUTHOR]

Glottal incompetence, i.e., reduced ability to produce effective glottal closure, is a problem often associated with aging. The study protocol is presented to determine whether blood substance P (SP) serves as an indicator of glottal closure function among the elderly. SP is involved in the neuromuscular mechanisms of cough; reduced concentration of SP may be a marker for increased risk of aspiration pneumonia. The antihypertensive angiotensin-converting enzyme inhibitor, which also inhibits degradation of SP, has been found to be effective in preventing aspiration pneumonia by strengthening the cough reflex. In this study, we will employ National Hospital Organization self-controlled vocal exercise (NHOEx), which has been shown to improve glottal closure by strengthening the laryngeal adduction muscles. We hypothesize that improved glottal closure by NHOEx may lead to the increase in the plasma concentration of SP, which reflects effective cough reflex. Maximum phonation time (MPT), an indicator of glottal closure, will be measured to assess improvement of glottis-closing function. The study will include 180 patients over 65 years old with dysphonia, dysphagia, or MPT of less than 15 seconds. Based on the speculation that the improved MPT may be associated with changes in SP expression, we will measure the plasma SP before and after 6-month treatment of glottal incompetence using NHOEx. The goal is to verify the reliability of SP as an indicator for glottal closure and swallowing function. Measurement of plasma SP may be helpful for earlier detection of subjects with higher risk of aspiration pneumonia among the elderly. [ABSTRACT FROM AUTHOR]

• Substance P (SP) did not correlate with the pain grade in horses with colic • Cortisol and lactate were correlated with the Equine Acute Abdominal Pain Scale • Individual horses had constant SP concentrations over the 4 hr post admission Equine colic is an important condition associated with acute abdominal pain and one of the leading causes of death in horses. As such, objectively evaluating pain is of interest for attending veterinarians. Pain scales for assessment are present, but no single pain-specific biomarker has been reported. The aim of this study was to determine if substance P (SP) could be a reliable biomarker to reflect pain and serve as a parameter to predict outcome in equine colic. The hypothesis was that horses displaying severe colic signs present with higher values of SP in contrast to those with mild colic signs. Thirty warmblood horses, aged between 3 and 20 years were recruited; evenly distributed (10 horses each) in three colic groups (mild, moderate, severe). To classify the colic signs, the horses were graded by the Equine Acute Abdominal Pain Scale (EAAPS). Clinical examination and EAAPS were performed at arrival in the hospital. Blood samples were collected four times in hourly intervals commencing from arrival. For comparison, already established parameters for prognosticating equine colic (heart rate, serum cortisol, and blood lactate concentration) were also measured. The assumption of increasing SP concentrations along with pain could not be confirmed. SP did not show any association with heart rate, cortisol, lactate, or EAAPS. Whereas the established parameters increased according to the EAAPS, SP remained stable in individual horses regardless of clinical signs, treatment, and disease progression. Consequently, SP was not a reliable parameter to reflect painful conditions or to predict outcome in equine colic. [ABSTRACT FROM AUTHOR]

Mast cells are highly versatile in terms of their mode of activation by a host of stimuli and their ability to flexibly release a plethora of biologically highly active mediators. Within the immune system, mast cells can best be designated as an active nexus interlinking innate and adaptive immunity. Here we try to draw an arc from initiation of acute inflammatory reactions to microbial pathogens to development of adaptive immunity and allergies. This multifaceted nature of mast cells is made possible by interaction with multiple cell types of immunologic and nonimmunologic origin. Examples for the former include neutrophils, eosinophils, T cells, and professional antigen-presenting cells. These interactions allow mast cells to orchestrate inflammatory innate reactions and complex adaptive immunity, including the pathogenesis of allergies. Important partners of nonimmunologic origin include cells of the sensory neuronal system. The intimate association between mast cells and sensory nerve fibers allows bidirectional communication, leading to neurogenic inflammation. Evidence is accumulating that this mast cell/nerve crosstalk is of pathophysiologic relevance in patients with allergic diseases, such as asthma. [ABSTRACT FROM AUTHOR]

Background and aims: Substance P (CSF-SP) is known to be elevated in females with fibromyalgia syndrome (FMS). The aims of this study were to evaluate the effect of cognitive behaviour therapy (CBT) on plasma SP levels in women with FMS and to find possible clinical behavioural correlates to plasma SP level changes. Methods: Forty-eight women with FMS were randomly allocated into two groups. Group 1 received the CBT treatment intervention over the course of 6 months while group 2 was waitlisted. CBT was given with a protocol developed to diminish stress and pain. After 6 months, group 2 was given the same CBT treatment as well. All were followed up 1 year after the start of CBT treatment. This approach allowed for two analytical designs – a randomised controlled trial (RCT) (n=24 vs. n=24) and a before-and-after treatment design (n=48). All women were repeatedly evaluated by the West Haven-Yale Multidimensional Pain Inventory (MPI) and three other psychometric questionnaires and plasma SP was analysed. Results: In the RCT design, the plasma SP level was 8.79 fmol/mL in both groups at the start of the trial, after adjustment for initial differences. At the end of the RCT, the plasma SP level was 5.25 fmol/mL in the CBT intervention group compared to 8.39 fmol/mL in the control group (p=0.02). In the before-and-after design, the plasma SP was reduced by 33% (p<0.01) after CBT, but returned to the pre-treatment level at follow-up 1 year after the start of CBT treatment. Plasma SP was associated with the MPI dimensions experienced "support from spouses or significant others" and "life control". Conclusions: Plasma SP might be a marker of the effect of CBT in FMS associated with better coping strategies and reduced stress rather than a biochemical marker of pain. [ABSTRACT FROM AUTHOR]

Background: Therapeutic ultrasound (TU) alleviates nerve injury-associated pain, while the molecular mechanisms are less clear. This is an investigator-initiated experimental study to evaluate the mechanisms and effects of ultrasound on prolonged post-thoracotomy pain in a rodent model.Methods: The rats were randomly separated into four groups (n=8 per group): sham-operation (sham; group 1), thoracotomy and rib retraction (TRR; group 2), and TRR procedure followed by TU (TRR+TU-3; group 3) or TU with the ultrasound power turned off (TRR+TU-0; group 4). TU was delivered daily, beginning on postoperative day 11 (POD 11) for the next 2 weeks. Mechanical sensitivity, subcutaneous tissue temperature, and spinal substance P and interleukin-1 beta (IL-1β) were evaluated on PODs 11 and 23.Results: Group 3, which received ultrasound treatment (3 MHz; 1.0 W/cm2) for 5 min each day, demonstrated higher mechanical withdrawal thresholds when compared with the group without ultrasound intervention (group 2) or sham ultrasound (group 4). Ultrasound treatment also inhibited the upregulation of spinal substance P and IL-1β measured from spinal cord dorsal horns extract and increased subcutaneous temperature.Conclusions: The results of this study suggest an increase in mechanical withdrawal thresholds and subcutaneous temperature, as well as a downregulation of spinal substance P and IL-1β, in the group which received ultrasound treatment. The regulation of spinal substance P and IL-1β may mediate potential effects of this non-invasive treatment. [ABSTRACT FROM AUTHOR]

Highlights • For the first time, the Merkel cells (MCs) have been characterized in the dolphin skin. • Merkel cells (MCs) are specialized skin receptors. • Merkel cells (MCs) participate in skin disorders through the release of neuropeptides and hormones. Abstract Cetacean mechanical senses, such as hearing, echolocation, active touch and the perception of water movements, are essential for their survival. Dolphins skin possesses dense packing of dermal papillae associated with the cutaneous ridges that suggests a sensory function, furthermore they are well innervated and very sensitive to touch. This is mediated by mechanoreceptors, abundant in the region of the head and in the dorsal part of the body. Most odontocetes possess vibrissae (i.e., sensory hair) that have been well described in literature and present a microanatomy similar to that of terrestrial mammals. The aim of this study was to characterize Merkel cell through use of specific antibodies: Substance P, Anti-calbindin DK28, Anti-5HT, Leu- enkephalin, Protein Gene Product 9.5 (PGP9.5) and Anti-Human Neuronal Protein, for the first time. Merkel cells (MCs) in the dolphin skin are specialized skin receptors, characterized by their particular location and close association with nerve terminals. The presence of neuroendocrine markers and different neuropeptides confirms that MCs play also neuroendocrine function and are considered as part of the diffuse neuroendocrine system. Furthermore, the presence of Leu-enkephalin in Merkel cells could involve these cells in inflammatory responses in the skin. [ABSTRACT FROM AUTHOR]

Capsaicin, the chemical that causes heat and burning sensations when consuming chilli peppers, is generally not thought of as a medicament. However, it provides a dual role. The initial pain experience is via activation of specific nociceptor ion channels on the sensory terminal known as Transient Receptor Potential VI (TRPV1), causing the release of neurotransmitters (in particular substance P). The pain elicited by capsaicin is reproducible and is used as a reliable method within oral pain models. Furthermore, repeated exposure to capsaicin causes the enhanced release of substance P and inhibited uptake. This creates a period of "desensitisation" preventing noxious stimuli from activating the neurone and providing an analgesic role. Within dentistry this property has been utilised and investigated (e.g. by topical application) in the treatment of conditions such as trigeminal neuralgia, pain in the temporomandibular joint area and atypical odontalgia. Advantages over other analgesics are namely that of avoidance of certain side effects and ability to be used for those with complex medical histories. Providing action at the start of the pain pathway allows for future drug treatments to use possible targeted delivery systems with potentially enhanced properties. Nonetheless, placebo effects and capsaicin's associated side effects should not be overlooked. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Cutaneous innervation is increasingly recognized as a major element of skin physiopathology through the neurogenic inflammation driven by neuropeptides that are sensed by endothelial cells and the immune system. To investigate this process in vitro, models of innervated tissue-engineered skin (TES) were developed, yet exclusively with murine sensory neurons extracted from dorsal root ganglions. In order to build a fully human model of innervated TES, we used induced pluripotent stem cells (iPSC) generated from human skin fibroblasts. Nearly 100% of the iPSC differentiated into sensory neurons were shown to express the neuronal markers BRN3A and β3-tubulin after 19 days of maturation. In addition, these cells were also positive to TRPV1 and neurofilament M, and some of them expressed Substance P, TrkA and TRPA1. When stimulated with molecules inducing neuropeptide release, iPSC-derived neurons released Substance P and CGRP, both in conventional monolayer culture and after seeding in a 3D fibroblast-populated collagen sponge model. Schwann cells, the essential partners of neurons for function and axonal migration, were also successfully differentiated from human iPSC as shown by their expression of the markers S100, GFAP, p75 and SOX10. When cultured for one additional month in the TES model, iPSC-derived neurons seeded at the bottom of the sponge formed a network of neurites spanning the whole TES up to the epidermis, but only when combined with mouse or iPSC-derived Schwann cells. This unique model of human innervated TES should be highly useful for the study of cutaneous neuroinflammation. Statement of Significance The purpose of this work was to develop in vitro an innovative fully human tissue-engineered skin enabling the investigation of the influence of cutaneous innervation on skin pathophysiology. To reach that aim, neurons were differentiated from human induced pluripotent stem cells (iPSCs) generated from normal human skin fibroblasts. This innervated tissue-engineered skin model will be the first one to show iPSC-derived neurons can be successfully used to build a 3D nerve network in vitro. Since innervation has been recently recognized to play a central role in many human skin diseases, such as psoriasis and atopic dermatitis, this construct promises to be at the forefront to model these diseases while using patient-derived cells. [ABSTRACT FROM AUTHOR]

Trichothecene mycotoxins commonly contaminate cereal grains and are often linked to human and animal food poisoning. The rapid onset of anorexia is a common hallmark of trichothecenes-induced toxicity. Although the neurotransmitters 5-hydroxytryptamine (5-HT) and substance P (SP) are known to regulate appetite, it remains unknown whether these two neurotransmitters are involved in type A trichothecenes-induced anorectic response. The goal of this study is to relate plasma 5-HT and SP to anorectic responses induced by type A trichothecenes T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS) and neosolaniol (NEO). These four toxins evoked robust anorectic response and secretion of plasma 5-HT and SP at 1 mg/kg bw. Following oral exposure, plasma 5-HT and SP were elevated and all peaked at 2 h for T-2, HT-2, DAS and NEO. Following intraperitoneal (IP) administration, plasma 5-HT and SP were peaked at 6 h, 6 h, 2 h, 2 h and 2 h, 6 h, 2 h, 2 h for T-2, HT-2, DAS and NEO, respectively. Elevations of plasma 5-HT and SP markedly corresponded to anorexia induction by T-2, HT-2, DAS and NEO. Altogether, the results presented herein indicated that 5-HT and SP play contributory roles in anorectic responses induced by T-2, HT-2, DAS and NEO. [ABSTRACT FROM AUTHOR]

Epidemiological studies show female predominance in the prevalence of non- allergic rhinitis (NAR) and local allergic rhinitis (LAR). Experimental studies show female patients with allergic rhinitis (AR) demonstrate higher levels of sensitivity to irritants and airway hyperresponsiveness than males. Bronchial asthma shows female predominance in post-puberty patients, and gender interaction with severe asthma endotypes. Fibromyalgia, chronic fatigue syndrome, migraine and chronic cough, syndromes, which are commonly related to neurokinin substance P (SP) in the literature, also show strong female predominance. Studies have demonstrated that sex hormones, primarily oestrogens, affect mast cell activation. Mast cell proteases can amplify neurogenic inflammatory responses including the release of SP. Based on human epidemiological data and animal experimental data we hypothesized that female patients have different interaction between mast cell activation and neurogenic inflammation, i.e. substance P release, resulting in a different nasal symptom profile. To test the hypothesis we performed allergen and non-specific nasal challenges in patients with seasonal allergic rhinitis (SAR) out of season and looked for gender differences in subjective and objective responses. The interaction between subjective and objective reactivity was evaluated through the comparison of subjective symptom scores, concentrations of neurokinin substance P (SP) and cellular markers in nasal lavages after low doses of nasal allergen challenges. Female allergic subjects tended to have higher substance P (SP) concentrations both before and after non-specific challenges. The difference between post-allergen and post - hypertonic saline (HTS) challenge was highly significant in female patients (p = 0.001), while insignificant in male subjects (p = 0.14). Female patients had significantly stronger burning sensation after HTS challenge than male. These data indicate difference in the interaction between inflammatory cells and the neurogenic response, which is gender- related, and which may affect symptom profiles after challenges. Different regulation of neurogenic inflammation in females may have impact on symptoms and endotyping in respiratory disorders, not only in allergic rhinitis, but also asthma, chronic rhinosinusitis and irritant -induced cough. [ABSTRACT FROM AUTHOR]

Background and aims This study aimed to assess the potential of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory nerves, to induce oedema in orofacial tissue. Experimental approach Wistar rats (150–200 g) anesthetized with isoflurane were injected intraorally with CGRP (100 μl; 8–33 pmol) in the right side of the mouth. The contralateral side was injected with the same volume of physiological saline. Increased cheek thickness (in mm), as a measure of oedema formation, was assayed bilaterally with a digital caliper before ( T  = 0) and up to 24 h following injection of CGRP. Pretreatment with antagonists (CGRP 8–37, 10 nmol; pizotifen, 2 mg/kg) was given by intra-oral or subcutaneous injection, 10 or 30 min, respectively, before the inflammatory stimulus. CGRP and CGRP 8–37 were also injected into the rat hind paw to induce oedema. Data are presented as the mean (±SEM) difference in thickness between the right and the left sides at each time. Results Following intra-oral injection, CGRP induced a rapidly developing (5–15 min) and long-lasting (6 h), dose-dependent oedema in the rat cheek, blocked by pre-treatment with CGRP 8–37 or pizotifen. CGRP induced a smaller oedematogenic effect in the rat hind paw also blocked by the CGRP antagonist. CGRP (16 pmol) potentiated the oedema induced by co-injected substance P (3.7 nmol) and contributed to the oedema following intraoral injection of carrageenan (100 μg). Injection of CGRP 8–37 alone induced an early but short-lasting oedema. Conclusion Local injection of CGRP potently induced oedema in the orofacial tissue of rats which was blocked by a CGRP receptor antagonist. The overall inhibition of carrageenan-induced oedema by CGRP 8–37 suggests that endogenous CGRP contributes to an oedematogenic response in orofacial tissues. [ABSTRACT FROM AUTHOR]

The neurokinin 1 receptor (NK1R) plays an important role in the pathogenesis of acute pancreatitis (AP). Maropitant is an NK1R antagonist that is widely used as an antiemetic in dogs and cats. In the present study, we investigated the anti-inflammatory action of maropitant in a mouse model of AP. AP was induced in BALB/c mice by intraperitoneal administration of cerulein and maropitant was administered subcutaneously at a dose of 8 mg/kg. We assessed the mRNA expression levels of NK1R and substance P (SP) in the pancreatic tissue via real-time reverse transcription polymerase chain reaction. In addition, the effect of maropitant on plasma amylase, lipase, and interleukin-6 (IL-6) levels was measured in each mouse. Inflammatory cell infiltration in the pancreas was assessed by myeloperoxidase (MPO) staining. Our results showed that AP induction significantly elevated the mRNA expression of SP in the pancreatic tissue. Treatment with maropitant significantly lowered plasma amylase and IL-6 levels. In addition, treatment with maropitant inhibited the infiltration of MPO-positive cells in the pancreas. The present study suggests that maropitant possesses an anti-inflammatory activity, in addition to its antiemetic action. [ABSTRACT FROM AUTHOR]

Résumé Les mastocytes sont des cellules granulaires du système immunitaire stratégiquement localisées au sein des tissus connectifs et des muqueuses, où ils participent à la régulation des processus inflammatoires. La caractéristique principale des mastocytes est leur capacité à externaliser rapidement leur contenu granulaire cytoplasmique enrichi en molécules bioactives et immunomodulatrices, en réponse à différent signaux activateur. Mieux comprendre comment ces cellules régulent leur dynamique de sécrétion en fonction du récepteur activé est d’un intérêt majeur pour appréhender les réactions inflammatoires dépendantes des mastocytes. Nous nous sommes particulièrement intéressés à l’activation des mastocytes par deux récepteurs jouant un rôle majeur dans divers processus inflammatoires : le FcɛRI (le récepteur de haute affinité aux IgE) et MRGPRX2 (le récepteur des mastocytes aux substances cationiques). Pour pallier aux contraintes technologiques actuelles, nous avons développé une nouvelle approche permettant de visualiser, en temps réel et à l’échelle cellulaire, la dynamique de dégranulation des mastocytes en utilisant la microscopie confocale in vitro et biphotonique in vivo. Nous avons démontré qu’en réponse à une activation par FcɛRI ou MRGPRX2, les mastocytes mettent en place des stratégies de dégranulation bien spécifiques à chaque récepteur, permettant l’externalisation du contenu granulaires avec des caractéristiques physiques distinctes et le développement de réactions inflammatoire de différentes intensités. Nous proposons ici une synthèse des connaissances nouvelles sur les différentes stratégies de dégranulation des mastocytes. Mast cells are granular immune cells strategically located among connective tissues and mucosa, where they participate to the regulation of diverse inflammatory processes. The principal characteristic of mast cells is their capacity to rapidly exteriorize intracellular granular content enriched in bioactive molecules in response to different activation signals. A better understanding of how these cells regulate their secretion dynamics under different stimulatory conditions is crucial to apprehend mast cell-dependent inflammatory reactions. We particularly focused on mast cell activation via two major receptors involved in diverse pathophysiological processes: FcɛRI (the high affinity receptor for IgE) and MRGPRX2 (the mast cell receptor for cationic molecules). To circumvent existing technical constraints, we developed a new approach that permits to monitor, in real-time and at the single cell level, mast cell degranulation dynamics using in vitro confocal microscopy and in vivo two-photon microscopy. We found that mast cell translate FcɛRI- or MRGPRX2-mediated signals into distinct degranulation strategies leading to the release of granular content with specific physical characteristics and the development of mast cell-dependent reactions of different intensities. Here we propose a synthesis of new concept on how mast cells regulate their degranulation strategy in response to activation via different receptors. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) and the poor ability of many drugs to cross that barrier greatly limits the efficacy of chemotherapies for glioblastoma multiforme (GBM). The present study exploits albumin as drug delivery vehicle to promote the chemotherapeutic efficacy of paclitaxel (PTX) by improving the stability and targeting efficiency of PTX/albumin nanoparticles (NPs). Here we characterize PTX-loaded human serum albumin (HSA) NPs stabilized with intramolecular disulfide bonds and modified with substance P (SP) peptide as the targeting ligand. The fabricated SP-HSA-PTX NPs exhibited satisfactory drug-loading content (7.89%) and entrapment efficiency (85.7%) with a spherical structure (about 150 nm) and zeta potential of −12.0 mV. The in vitro drug release from SP-HSA-PTX NPs occurred in a redox-responsive manner. Due to the targeting effect of the SP peptide, cellular uptake of SP-HSA-PTX NPs into brain capillary endothelial cells (BCECs) and U87 cells was greatly improved. The low IC 50 , prolonged survival period and the obvious pro-apoptotic effect shown by TUNEL analysis all demonstrated that the fabricated SP-HSA-PTX NPs showed a satisfactory anti-tumor effect and could serve as a novel strategy for GBM treatment. [ABSTRACT FROM AUTHOR]

Background: Neuropeptides, such as substance P (SP), have long been seen as mediators of widespread continuous airway inflammation, a process known as neurogenic inflammation. However, this has been difficult to demonstrate clinically, suggesting an alternative role for these signaling molecules. Objectives: We sought to examine the role of SP in nasal infection by assessing the release of SP in response to viral stimulation and characterizing the effects of SP on innate immunity, with the latter reflected in changes in local Toll-like receptor (TLR) expression. Methods: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in the upper airways represented by primary human nasal epithelial cells (HNECs) and murine nasal epithelial cells (MNECs) and isolated murine trigeminal ganglial neurons. SP release from HNECs, MNECs, and trigeminal ganglial neurons was quantified with EIA. The effects of SP on TLR expression on HNECs were determined by using flow cytometry and confocal microscopy. Results: SP was released from the sensory neurons, MNECs, and HNECs within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNECs within 30 minutes through induction of TLR movement within HNECs. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor antagonist aprepitant before SP stimulation. Conclusions: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway. [ABSTRACT FROM AUTHOR]

Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex. [ABSTRACT FROM AUTHOR]

Background: Zymosan is a fungal cell wall protein-carbohydrate complex that is known to activate inflammatory pathways through the Toll-like receptors and is commonly used to induce fever. Nevertheless, the central mediators that are involved in the zymosan-induced febrile response are only partially known. Methods: The present study evaluated the participation of prostaglandins, substance P, endothelin-1 (ET-1), and endogenous opioids (eOPs) in the zymosan-induced febrile response by using inhibitors and antagonists in male Wistar rats. Results: Both nonselective (indomethacin) and selective (celecoxib) cyclooxygenase inhibitors reduced the febrile response induced by an intraperitoneal (i.p.) injection of zymosan. Indomethacin also blocked the increase in the prostaglandin E2 levels in the cerebrospinal fluid. An intracerebroventricular injection of the neurokinin-1, ETB, and μ-opioid receptor antagonists also reduced the febrile response induced by the i.p. injected zymosan. Moreover, the μ-opioid receptor antagonist CTAP also reduced the febrile response induced by intra-articular injection of zymosan. Conclusions: These results demonstrate that prostaglandins, substance P, ET-1, and eOPs are central mediators of the zymosan-induced febrile response. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for preventing chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients receiving CHOP therapy, and to evaluate the relationship between in vivo kinetics of plasma substance P and these adverse events. Patients with malignant lymphoma who received CHOP chemotherapy or THP (THP-ADR)-COP therapy were investigated for CINV and anorexia for 5 days after the start of chemotherapy. With the first course of chemotherapy, all patients received only granisetron on day1 as an antiemetic. Patients who experienced nausea, vomiting, or anorexia exceeding grade 1 in the first course received aprepitant for 3 days in addition to granisetron with the second course of CHOP chemotherapy. Plasma substance P concentrations at 24 and 72 hours after chemotherapy were measured. Nineteen patients were evaluated. Nausea, vomiting, or anorexia was observed with the first course in 7 of 19 patients. During the second course with aprepitant, no patients experienced vomiting, and the toxicity grade of nausea, vomiting, or anorexia was decreased compared with those in the first course. Substance P concentrations showed no differences after chemotherapy, in patients with nausea, vomiting, or anorexia and in patients without. The addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: To determine alterations of circulating levels of hydrogen sulfide and substance P in patients with sepsis compared to non-sepsis patients with similar disease severity and organ dysfunction.Methods: This study included 23 septic and 14 non-septic patients during 2015-16 study period at the Christchurch Hospital Intensive Care Unit, Christchurch, New Zealand. Blood samples were collected from the time of admission to 96 h, with collection at different time points (0 h, 12 h, 24 h, 48 h, 72 h and 96 h) and subjected to measurement of hydrogen sulfide, substance P, procalcitonin, C-reactive protein, interleukin-6 and lactate levels.Results: Patients with sepsis showed higher circulating hydrogen sulfide and substance P levels compared to patients without sepsis. Hydrogen sulfide levels were significantly higher at 12 h (1.45 vs 0.75 μM; p < 0.05) and 24 h (1.11 vs 0.72 μM; p < 0.01), whereas substance P levels were higher at 48 h (0.55 vs 0.31 ng/mL; p < 0.05). Increased hydrogen sulfide and substance P levels in septic patients were associated with increased levels of inflammatory mediators - procalcitonin, C-reactive protein and interleukin-6.Conclusions: These results provide evidence that higher circulating levels of hydrogen sulfide and substance P are associated with increased inflammatory response in patients with sepsis. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that older adults would have a stronger response for substance P (facilitatory) but weaker response to β-endorphin (inhibitory), in magnitude as well as time course. Eight younger and 9 older adults underwent 3 experimental sessions using well validated laboratory pain models: cold pressor task, contact heat pain, and a nonpainful control. Blood was collected through an indwelling catheter at baseline and 3, 15, 30, 45, and 60 minutes after stimuli administration. Older adults had higher baseline levels of both neuropeptides suggesting increased peripheral activity compared with younger adults. After the cold pressor task, older adults demonstrated a quick and strong release of substance P with dramatic recovery, whereas young adults maintained a constant low-grade response. Unlike substance P, β-endorphin increased between 3 and 15 minutes for both groups with the upsurge substantially higher for older adults. After heat pain, younger adults had an immediate surge in circulating substance P and β-endorphin that was more pronounced than among older adults. However, levels of substance P for younger adults slowly tapered whereas they continued to climb for the older adults through 30 minutes. β-endorphin peaked at 30 minutes for both groups and returned to baseline. No changes were observed during the nonpainful control session.Perspective: Older adults had higher baseline levels of substance P and β-endorphin suggesting increased peripheral activity compared with younger adults. After pain evocation, older adults demonstrated a more intense early response for both neuropeptides suggesting peripheral mechanisms involved in the response to pain may change with age. [ABSTRACT FROM AUTHOR]

Background and aims Ketamine+xylazine mixture is a widely used anaesthetic in animal experiments. In rats anaesthetized with this mixture, we have shown that injection of carrageenan, a standard proinflammatory stimulus, into the cheek (intra-oral injection) induced oedema. A likely mediator of this oedema is substance P (SP), a major transmitter of sensory nerves in orofacial tissue. We have assessed the effects of intra-oral injection of SP in rats. Experimental approach SP (50–1 μg per rat) was injected intra-orally in male adult Holtzman or Wistar rats, anaesthetized with ketamine+xylazine. For comparison, histamine (50 μg) and 5-HT (5 μg) were similarly injected. Antagonists of SP (SR140333, 2 mg/kg), of histamine (pyrilamine, 2 mg/kg) or of 5-HT (pizotifen, 2 mg/kg) were subcutaneously (s.c.) injected, 30 min before the corresponding agonist. Oedema in the cheek was assessed by measuring tissue thickness with calipers. Results Intra-oral injection of SP (1–50 μg per rat) in Holtzman or Wistar rats anaesthetized with ketamine+xylazine induced, dose-dependently, death within 15 min, accompanied by signs of excessive salivation. Rats pretreated with SR140333 were protected against SP-induced lethality and the excessive salivation. However, intra-oral injection of either histamine or 5-HT did not induce death, only a characteristic cheek oedema. These doses of SP injected into the hindpaws of conscious Holtzman and Wistar rats only induced oedema with no deaths. In rats anaesthetized with inhaled isoflurane, intra-oral SP (50 μg) induced only cheek oedema, with no deaths or excessive salivation. This oedema was prevented by pre-treating rats with SR140333, pyrilamine and pizotifen. Conclusion It is likely that the deaths were due to excessive salivation induced by the particular combination of ketamine and SP. Our results are presented as a warning to other experimenters who might use these two otherwise non-toxic conditions and the consequent unexpected and needless loss of experimental animals. [ABSTRACT FROM AUTHOR]

The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus. The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK 1 (CP122,721, CP99,994), NK 2 (SR48,968, GR159,897) and NK 3 (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array. Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK 3 had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon. This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms. • Anti-emetic therapy often targets NK 1 receptor, but tachykinin effects on gut motility in an emetic species is unknown • SP-induced larger contractions than NKA in stomach tissue but smaller contractions in intestinal segments • Distinct tachykinin effects were identified in the stomach/colon vs. duodenum/ileum on electrical pacemaker activity • Substance P induced dose-dependent contradictive responses in both mechanical and electrical response in the colon [ABSTRACT FROM AUTHOR]

Substance P (SP) is an important neuropeptide regulating the functions of the pancreas and might play a vital role in the onset of diabetes. SP has been shown to express in nerve fibers of the pancreas, but whether SP exists in the intrapancreatic ganglia, which are components of a complex autonomous nervous system to co-ordinate the functions of the pancreas, is unsure. The aim of this study was to systematically investigate rat intrapancreatic ganglia and the expression of SP in intrapancreatic ganglia. After surgical denervation of posterior branches of bilateral T 5 –L 2 dorsal root ganglia, SP expression remained > 60% in the pancreas. Moreover, after high doses of capsaicin were injected to destroy sensory nerves, the remainder of SP protein levels was still > 50% in the pancreas. In the intrapancreatic ganglia, for anti-SP polyclonal antibody, the immunoreactivity to SP was found in 34.0 ± 1.2% of PGP 9.5-positive intrapancreatic neurons (47 ganglia from 13 rats); for anti-SP monoclonal antibody, the immunoreactivity to SP was found in 26.6 ± 1.0% of PGP 9.5-positive intrapancreatic neurons (18 ganglia from 6 rats). In summary, the present molecular and immunocytochemistry studies showed that there existed intrinsic SP expression in the neurons of intrapancreatic ganglia, which constituted around half of SP origins in the pancreas suggesting that intrapancreatic ganglia might play an important role on mechanisms involving SP. [ABSTRACT FROM AUTHOR]

Tachykinins are a family of pronociceptive neuropeptides with a specific role in pain and inflammation. Several mechanisms regulate endogenous tachykinins and Substance P (SP) levels, including the differential expression of protachykinin mRNA and the controlled secretion of tachykinins from neurons. Proteolysis is suspected to regulate extracellular SP concentrations but few studies were conducted on the metabolism of proneuropeptides and neuropeptides. Here, we provide evidence that proteolysis controls SP levels in the spinal cord leading to the formation of active C-terminal fragments. Using high-resolution mass spectrometry, specific tachykinins fragments were characterized and quantified. The metabolic stability of β-Tachykinin 58–71 and SP were very short resulting in half-life of 5.7 and 3.5 min respectively. Several C-terminal fragments were identified, including SP 3–11 , SP 5–11 and SP 8–11 , which conserve affinity for the Neurokinin 1 receptor. Interestingly, the metabolic stability of C-terminal fragments was significantly superior. Two specific Prolyl endopeptidase inhibitors were used and showed a significant reduction in the rate of formation of SP 3–11 and SP 5–11 providing strong evidence that Prolyl endopeptidase is involved into N-terminal processing of SP in the spinal cord. [ABSTRACT FROM AUTHOR]

Calcitonin gene related peptide (CGRP) and substance P (SP) are neuropeptides that are simultaneously released from nociceptive C-fibers. CGRP is a potent vasodilator, inducing a long-lasting increase in superficial skin blood flow, whereas SP induces only a brief vasodilation but a significant plasma extravasation. CGRP and SP may play important roles in the pathophysiology of various pain states but little is known about their interaction. Different concentrations of SP (ranging from 10 − 5 M to 10 − 9 M) were applied to the volar forearm of 24 healthy subjects via dermal microdialysis. SP was applied either alone or in combination with CGRP10 − 9 M and CGRP 10 − 6 M. As expected, SP induced a transient increase in skin blood flow that decayed shortly after application. This transient blood flow peak was blunted with co-application of CGRP 10 − 9 M and inhibited with co-application of CGRP10 − 6 M. SP alone induced plasma protein extravasation (PPE). However, when CGRP10 − 6 M was added, the PPE significantly increased. Our results demonstrate a complex interaction of the neuropeptides CGRP and SP. CGRP10 − 6 M prevented SP-induced early vasodilation but augmented SP-induced PPE. These interactions might explain why vascular symptoms in chronic pain can differ strikingly between individuals. [ABSTRACT FROM AUTHOR]

This article provides an overview of the structure and function of substance P signalling system and its involvement in the cardiovascular regulation. Substance P is an undecapeptide originating from TAC1 gen and belonging to the tachykinin family. The biological actions of substance P are mainly mediated through neurokinin receptor 1 since substance P is the ligand with the highest affinity to neurokinin receptor 1. Substance P is widely distributed within the central and peripheral nervous systems as well as in the cardiovascular system. Substance P is involved in the regulation of heart frequency, blood pressure and in the stretching of vessels. Substance P plays an important role in ischemia and reperfusion and cardiovascular response to stress. Additionally, it has been also implicated in angiogenesis, pain transmission and inflammation. The substance P/neurokinin receptor 1 receptor system is involved in the molecular bases of many human pathological processes. Antagonists of neurokinin receptor 1 receptor could provide clinical solutions for a variety of diseases. Neurokinin receptor 1 antagonists are already used in the prevention of chemotherapy induced nausea and vomiting. [ABSTRACT FROM AUTHOR]

Nine adult geldings were used in three experiments to study the possible role of substance P in the prolactin responses to nondopaminergic stimuli. Experiment 1 was performed as an incomplete Latin square design to determine the secretory responses of prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) to IV administration of substance P. Doses tested and compared to no peptide (0 dose, control) were 62, 125, 250, and 500 μg of substance P. The three highest doses of peptide caused an immediate rise in heart rate, sweating, salivation, rhinorrhea, stretching of hind legs, and defecation. The lowest dose (62 μg) caused minor sweating, some rhinorrhea, and a rise in heart rate. Recovery from these physical responses was complete in approximately 30 minutes. All doses of substance P caused an immediate rise ( P < .01) in plasma prolactin concentrations, with the three highest doses producing similar responses, and the 62 μg dose producing a minimal response ( P < .05). Concentrations of ACTH ( P < .01) and GH ( P = .05) also increased after substance P administration; concentrations of LH, FSH, and TSH were unaffected. Experiment 2 compared the effects of brief exercise on hormonal characteristics. Two minutes of trotting increased ( P < .01) plasma concentrations of GH, ACTH, and prolactin, as well as LH ( P = .055). Experiment 3 determined the relative responses of prolactin to a fixed dose of sulpiride (0.1 mg/kg of body weight). In general, the prolactin responses to substance P were similar to those after exercise, which were both generally less than after sulpiride. These data are consistent with a possible role of substance P in the prolactin response to stressful stimuli. [ABSTRACT FROM AUTHOR]

Objective: A number of promising compounds developed for osteoarthritic pain have failed to demonstrate clinical efficacy. To enhance preclinical translational research for osteoarthritis, a model of knee osteoarthritis pain was developed in Macaca fascicularis and the effects of two distinct pharmacological classes of drugs were tested on pain-related behavior.Design: Behavioral assessments were developed specifically for the macaque. Baseline knee pressure threshold and weight bearing were assessed prior to a unilateral medial meniscectomy (MMx). Fifteen days following MMx, macaques underwent a once daily exercise regimen for 36 days. Sixty-seven days following MMx, macaques were assigned to one of three treatment groups (n = 3/group), either non-steroidal anti-inflammatory drug (NSAID) diclofenac, NK1 receptor antagonist aprepitant or vehicle, and treated for 5 days. Animals were tested 3-4 h after p.o. dosing and testing was performed blinded. Treatment utilized a crossover design-each animal received all treatments-and a 9-day washout period was utilized between treatments.Results: Vehicle-treated macaques consistently demonstrated decreased ipsilateral pressure threshold ("hyperalgesia") and decreased weight bearing. While diclofenac increased weight bearing and pressure threshold, full attenuation of pain was not obtained. No significant improvement of either knee pressure or weight bearing was observed with aprepitant.Conclusions: Unilateral MMx in the macaque evoked pain-related behaviors and knee joint pathology reminiscent of osteoarthritis. The behavioral endpoints were sensitive to NSAID treatment but not sensitive to NK1 receptor block, which parallel clinical findings. The current macaque osteoarthritis model could be used to test potential treatments for osteoarthritis pain. [ABSTRACT FROM AUTHOR]