Plasma Substance P Levels Research Articles

The Effect of Group Training or Spinal Orthosis on Quality of Life and Potential Plasma Markers of Pain in Older Women With Osteoporosis. A Randomized Controlled Trial

ObjectivePrimary purpose was to examine the effects of exercise and use of a spinal orthosis on quality of life (QoL). Secondary, to explore the effects of above-mentioned interventions on plasma levels of potential markers of pain: substance P (SP), calcitonin gene-related peptide (CGRP), and interleukin-6 (IL-6). DesignRandomized controlled trial. SettingCommunity-dwelling women in Stockholm. ParticipantsA total of 113 women aged 60-93 years suffering from back pain and self-reported osteoporosis (n=113). InterventionsThe randomized controlled trial was 3-armed: participation in an equipment exercise group, treatment with an activating spinal orthosis or controls. The intervention time was 6 months. Main Outcome Measure(s)QoL (QUALEFFO-41 and SF-36), plasma levels of SP, CGRP, and IL-6 measured at baseline and after 6 months in all 3 arms. ResultsNo improvement of QoL was found. Comparing change in mobility (QUALEFFO-41), the effect in least squares means was lower in the spinal orthosis group compared with controls. In the exercise group, the role emotional score (SF-36) deteriorated during the intervention. Effect size varied between 0.02 and 0.6. There was no change in the levels of CGRP or SP, while IL-6 levels were lower at 6 months in the spinal orthosis group compared with the other groups. At least 1 previous vertebral fracture was verified by X-ray in 46 women. ConclusionThe interventions showed none or negative effect on QoL, which was unexpected. The modest effect size may prompt a cautious interpretation. We found a lowering of IL-6 levels in the spinal orthosis group, but more studies are needed.

Role of Substance P in the Pathophysiology of Inflammatory Bowel Disease and Its Correlation With the Degree of Inflammation.

Inflammatory bowel disease (IBD) is a multi-factorial, chronic inflammation of the gastrointestinal tract, containing ulcerative colitis (UC) and Crohn's disease (CD). In UC, inflammation and sores are confined morphologically and microscopically to the mucosa, the innermost surface of the colon and the rectum. Although, in CD, the infection is granulomatous and transmural, affecting the entire gastrointestinal tract from the mouth to the anus, with the skip area in-between. A Neuropeptide, substance P (SP), which acts as a neurotransmitter and as a neuromodulator, plays a vital role in the brain-gut axis under stress. Owing to the pro-inflammatory effects of SP, neuropeptide dysregulation induces inflammation in the intestine. There are variations in the distribution of substance P immunoreactive fibres in the various intestinal layers. The highest concentration of SP is in the mucosa and the lowest concentration in the lamina propria of the intestinal muscular membrane. Reduced vasoactive intestinal peptide (VIP) levels and elevated SP levels observed in the colonic mucosa of IBD by using immunohistochemistry and immunoassay. This literature review aims to find out the correlations between the level of substance P (SP) and disease activity. We conducted a literature review on IBD, SP, and we searched PubMed and Google Scholar for relevant articles in English. The result of the study supports a positive relationship between the level of substance P (SP) and disease activity, with increased concentration of substance p in the colon and rectum of CD and UC patients. It is concluded that patients with active CD, along with inflammatory changes, had elevated plasma SP levels and immunoreactivity of SP in the colon than those seen in control and inactive cases. These alterations are more prevalent in ulcerative colitis than Crohn's disease and are more prevalent in the moderately infected area than the least affected area of the intestine.

Cough Suppression during Flexible Bronchoscopy Using Transcutaneous Electric Acupoint Stimulation: A Randomized Controlled Study.

Background and Objective. Transcutaneous electric acupoint stimulation (TEAS) is recommended for its sedative and analgesic effects. We sought to evaluate the effect of TEAS on cough suppression during flexible bronchoscopy (FB) and explore the underlying mechanism. Methods. In this single-center, randomized, single-blind, parallel-controlled study, we randomized 100 patients scheduled for FB into two equal groups treated with or without TEAS (TEAS group and control group). Patients in the TEAS group received 30 min of stimulation at the Hegu (LI4), Neiguan (PC6), and Lieque (LU7) points before FB. The control group underwent the same procedure, but without stimulation. The primary outcome was the intraoperative cough score determined by the bronchoscopist. The secondary outcomes were patient-reported discomfort scores and other procedural parameters. Results. Compared with the controls, patients who received TEAS preconditioning had lower cough scores (P=0.0027) and requirement of lidocaine and fentanyl (P < 0.05) and significantly higher postprocedural plasma β-endorphin levels (P=0.0367). There were no intergroup differences in discomfort scores, midazolam dosage, rate of premature termination, oxygen requirement, sedation level, airway assistance, oxygen saturation, lowest oxygen saturation level, heart rate, plasma substance-P levels, and rate of complications after 24 h. The total procedure duration, time for passage of the bronchoscope through the vocal cords, and systolic and diastolic blood pressure levels were less in the TEAS group than in the control group (P=0.033, 0.039 and <0.05, respectively). Conclusion. The combination of midazolam and TEAS was superior to midazolam alone for cough suppression during FB, probably due to increased plasma β-endorphin levels. This trial is registered with ChiCTR1800016612 at chictr.org.cn/index.aspx.

Effect of anti-reflux treatment on gastroesophageal reflux-associated chronic cough: Implications of neurogenic and neutrophilic inflammation

Objective: Gastroesophageal reflux disease (GERD) is an important cause of chronic cough. Substance P (SP) has been implicated in the pathophysiology of cough. Proton pump inhibitors (PPIs) and prokinetic agents are the current treatment for GER-associated cough. The aim was to evaluate the effects of anti-reflux treatment and its associations with cellular and neurogenic inflammation.Methods: Thirty-seven patients with GER-associated cough suspected based on characteristic symptoms such as heartburn and worsening of cough by phonation and rising were recruited. A PPI, rabeprazole 20 mg daily, and a prokinetic agent, itopride 50 mg t.i.d., were administered for 4 weeks in a prospective, observational manner. Before and after treatment, subjective cough measures [visual analog scale (VAS) and the Japanese version of the Leicester Cough Questionnaire (J-LCQ)], the modified frequency scale for the symptoms of GERD [FSSG, consisting of 2 domains: acid-reflux (AR) and functional dyspepsia symptoms], sputum and plasma SP levels, and sputum cell differentials were examined. Patients with good response to treatment [Δ (decrease of) VAS >15 mm; n = 21) were compared with poor responders (ΔVAS ≤15 mm).Results: Anti-reflux treatment significantly improved the cough VAS, J-LCQ, and AR symptoms, and ΔVAS and ΔAR were significantly correlated. Decreases of plasma and sputum SP levels and sputum neutrophil counts were significantly greater in responders than in poor responders. Both baseline values and post-treatment changes of plasma SP and sputum neutrophils were significantly correlated for all patients.Conclusions: Successful treatment of GER-associated cough may be associated with the attenuation of neurogenic and neutrophilic inflammation.

Effect of Shenling-Baizhu powder on gastrointestinal hormone, digestive enzyme and inflammatory factors in diarrhea-predominant irritable bowel syndrome rats

Objective To investigate the effect of Shenling-Baizhu powder on gastrointestinal hormone, digestive enzyme and inflammatory factors in D-IBS rats. Methods A total of 50 Wistar rats were randomly divided into the normal group, the model group, the Shenling-Baizhu powder large dose group, medium dose group and small dose group, 10 rats in each group. D-IBS rat model was induced by high lactose diet and restraint stress except normal group. At the same time, the Shenling-Baizhu powder groups received Shenling-Baizhu powder (large dose group: 9 g/kg, medium dose group: 3 g/kg, small dose group: 1 g/kg), normal group and model group received equal volume of normal saline. Malate dehydrogenase (MDH), lactate dehydrogenase (LDH) and disaccharidase activities were detected from small intestine of rats in each group. Plasma vasoactive intestinal peptide (VIP) and substance P (SP) activities were measured by radioimmunoassay. TNF-α and IL-10 levels in serum were determined by ELISA. Results Compared with the model group, the model group, the ratio of serum TNF-α/IL-10 (0.31 ± 0.15, 0.34 ± 0.21, 0.41 ± 0.15 vs. 0.74 ± 0.19) significantly decreased in large, medium and low dose groups (P<0.05). The disaccharidase activities in the small intestinal mucosa (38.44 ± 11.30 U/mg, 44.77 ± 16.46 U/mg, 42.58 ± 13.02 U/mg vs. 23.23 ± 6.85 U/mg) significantly increased in the large, medium and low dose groups (P<0.05). LDH activities in the small intestinal mucosa (1 863.61 ± 1 019.28 U/mg, 1 136.13 ± 631.89 U/mg vs. 416.50 ± 223.94U/mg) significantly increased in large, medium dose groups (P<0.05). Plasma SP level (22.88 ± 10.17 pg/mg vs. 31.86 ± 7.81 pg/mg) significantly decreased in large dose group (P<0.05). Conclusions Shenling-Baizhu powder may increase the activities of LDH, MDH and disaccharidase, inhibit the abnormal secretion of SP and regulate of Th1/Th2 immune imbalance to relieve diarrhea. Key words: Irritable bowel syndrome; Shen Ling Bai Zhu San; Gastrointestinal hormones; Digestive enzyme; Inflammation; Rats

The comparison of effects of applications of compound 48/80 and mast cell mediator suspension on inflammation in rats: A methodological study for acute inflammatory pain

Objective: Inflammation underlies the pathological basis of most diseases. Substance-P is a key mediator that participates in various inflammatory processes and painful conditions. Mast cells (MCs) have a key role in inflammatory processes via mediators released from their granules. The experimental models for the investigation of pathogenesis and treatment of inflammatory diseases represent merely certain characteristics of inflammatory cases, therefore, more comprehensive models are required. We aimed to compare effects of administrations of the compound-48/80 and mast cell mediator suspension (MCMS) obtained from peritoneal MCs on the inflammation in rats. Methods: Rats were divided into five groups (n=6): Intraperitoneally, Control group received 0.2 ml saline; C-48/80 group received 2 mg/kg compound-48/80; MCMS group received 0.2 ml MCMS; Cr+C-48/80 group received 10 mg/kg cromolyn plus compound-48/80; Cr+MCMS group received cromolyn plus MCMS. Potent inflammatory markers, plasma substance-P levels, and number and degranulation of dural MCs were measured. Data were analyzed using one-way ANOVA followed by Dunnett’s post hoc test. Results: Compound-48/80 increased plasma substance-P levels (p<0.05) and dural MC-degranulation (p<0.001). Likewise, MCMS increased substance-P levels and dural MC-degranulation (p<0.001) as well as number of dural MCs (p<0.01). MC stabilizer cromolyn inhibited increases in the parameters induced by compound-48/80 and MCMS (p<0.01 and p<0.05, respectively). Conclusion: MCMS administration had greater impact to increase the plasma substance-P levels and number and degranulation of dural MCs than that of the compound-48/80 administration. The results demonstrate the potent inflammatory effect of MCMS treatment over the compund-48/80 administration. Administration of MCMS could be a useful tool to study inflammatory conditions.

The association between substance P and white matter integrity in medication-naive patients with major depressive disorder

Substance P (SP) has been implicated in major depressive disorder (MDD), with SP antagonists being studied as potential antidepressants. Although impaired neural plasticity is considered a key mechanism in MDD pathophysiology, the association between SP and brain structural changes in depression has not been investigated. We investigated the correlations between SP levels and white matter (WM) integrity in 42 medication-naive patients with MDD and 57 healthy controls (HCs). Plasma levels of SP were determined, and diffusion tensor imaging (DTI) was performed to investigate microstructural changes in WM tracts. In patients, negative correlations between SP levels and fractional anisotropy (FA) values of the forceps minor of the corpus callosum, and positive correlations between SP levels and radial diffusivity (RD) and mean diffusivity (MD) values of the right corticospinal tract (CST) were observed, with no significant correlations in HCs. Linear regression analyses showed SP levels to significantly predict FA values of the forceps minor, and RD and MD values of the right CST in patients, but not in HCs. We consider our findings to contribute to the neurobiological evidence on the association between SP and brain structural changes in depression, which may be related with the pathophysiology and treatment of MDD.

Up-regulated expression of substance P in CD8+ T cells and NK1R on monocytes of atopic dermatitis

BackgroundLarge numbers of CD8+ T cells were observed in atopic dermatitis (AD) skin, and monocytes from AD patients showed increased prostaglandin E2 production. However, little is known about the expression of substance P (SP) and its receptor NK1R in blood leukocytes of patients with AD.ObjectiveTo explore the expression of SP and NK1R in leukocytes of AD and the influence of allergens on SP and NK1R expression.MethodsThe expression levels of SP and NK1R in patients with AD were examined by flow cytometry, ELISA and a mouse AD model.ResultsThe plasma SP level was 4.9-fold higher in patients with AD than in HC subjects. Both the percentage of SP expression in the population and mean fluorescence intensity (MFI) of SP expression were elevated in CD8+ T cells in the blood of AD patients. However, both the CD14+NK1R+ population and MFI of NK1R expression on CD14+ cells were enhanced in the blood of AD patients. Allergens ASWE, HDME and PPE failed to up-regulate SP expression in CD8+ T cells. However, allergens ASWE and HDME both enhanced NK1R expression on CD14+ blood leukocytes regardless of AD or HC subjects. OVA-sensitized AD mice showed an elevated proportion and MFI of SP-expressing CD8+ T cells in the blood, which agrees with the SP expression situation in human AD blood. Injection of SP into mouse skin did not up-regulate NK1R expression on monocytes.ConclusionsAn elevated plasma SP level, up-regulated expression of SP and NK1R indicate that the SP/NK1R complex is important in the development of AD. Therefore, SP and NK1R antagonist or blocker agents may help to treat patients with AD.Trial registration Registration number: ChiCTR-BOC-16010279; Registration date: Dec., 28, 2016; retrospectively registered

Upregulated expression of substance P (SP) and NK1R in eczema and SP-induced mast cell accumulation

Substance P (SP) was reported to be associated with eczema and acts as a potent skin mast cell secretagogue. However, little is known of its expression in inflammatory cells in eczema and its ability in induction of mast cell accumulation. In the present study, we investigated expression of SP and neurokinin-1 receptor (NK1R) on peripheral blood leukocytes and mast cells from patients with eczema and influence of SP on mast cell accumulation by using flow cytometry analysis, trans-epithelial cell migration assay and mouse peritoneal model. The results showed that plasma SP and IL-17A levels in eczema patients were higher than that in healthy control subject. The percentages of SP+ and NK1R+ expression populations of monocytes, helper T cells, natural killer T cells and basophils in peripheral blood of eczema patients were markedly elevated. It was observed that not only absolute number of mast cells but also SP+ and NK1R+ mast cells are enhanced in the lesion skin of eczema. SP showed a potent chemoattractant action on mast cells as assessed by a mouse peritoneal model and a trans-endothelium cell migration assay. SP-induced mast cell accumulation appears a CD18/CD11a complex, L-selectin and ICAM-1-dependent event which can be blocked by a NK-1R antagonist RP67580. In conclusion, elevated expression of SP in patients with eczema and the ability of SP in induction of mast cell accumulation indicate strongly that SP is a potent proinflammatory mediator, which contributes to the pathogenesis of eczema. Inhibitors of SP and blockers of NK1R are likely useful agents for treatment of eczema.

Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use.

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme-linked immunosorbent assay. Independent samples t-test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7-19years old. Mean±standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4±11·6 vs. 22·9±7·6, P=0·0009). SP in SCD pain was higher than baseline (78·1±43·4 vs. 32·4±11·6, P=0·004). Haemolysis correlated with increased SP: Hb (r=-0·7, P=0·0002), reticulocyte count (r=0·61, P=0·0016), bilirubin (r=0·68, P=0·0216), lactate dehydrogenase (r=0·62, P=0·0332), aspartate aminotransferase (r=0·68, P=0·003). Patients taking hydroxycarbamide had increased SP (β=29·2, P=0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment.

Upregulated expression of substance P in basophils of the patients with chronic spontaneous urticaria: induction of histamine release and basophil accumulation by substance P.

Human basophils have been implicated in the pathogenesis of chronic spontaneous urticaria (CSU), and substance P (SP) is a possible candidate as histamine-releasing factor in some patients with CSU. However, little is known of relationship between basophils and SP in CSU. In the present study, we investigated expression of SP and NK1R on basophils from patients with CSU, and influence of SP on basophil functions by using flow cytometry analysis, basophil challenge, and mouse sensitization model techniques. The results showed that plasma SP level and basophil numbers in CSU patients were higher than that in HC subject. The percentages of SP+ and NK1R+ basophils were markedly elevated in CSU blood in comparison with HC blood. Once added, SP induced up to 41.2% net histamine release from basophils of CSU patients, which was comparable with that provoked by anti-IgE, and fMLP. It appeared that SP induced dramatic increase in blood basophil numbers of mice following peritoneal injection. Ovalbumin (OVA)-sensitized mice had much more SP+ and NK1R+ basophils in blood than non-sensitized mice. In conclusion, the elevated plasma concentration of SP, upregulated expression of SP and NK1R on basophils, and the ability of SP in induction of basophil degranulation and accumulation indicate strongly that SP is most likely a potent proinflammatory mediator, which contributes greatly to the pathogenesis of CSU through basophils. Inhibitors of SP and blockers of NK1R are likely useful agents for treatment of CSU.

The Neuropeptide Substance P Is Elevated in Patients with Sickle Cell Disease

Patients with sickle cell disease (SCD) experience increased pain to thermal (cold, heat) stimuli compared to healthy controls suggesting peripheral and/or central sensitization. However, the underlying etiology of this thermal hypersensitivity is unknown. Substance P (SP), a primary pain neurotransmitter, is a potent mediator of neurogenic inflammation where inflammatory cell activation, vasodilation, and edema occur after the stimulation of sensory nerve fibers. Chronic elevation of SP can sensitize peripheral nociceptors resulting in thermal hypersensitivity and chronic neuropathic pain as shown in mice and humans without SCD and in SCD mice. Little is known about SP levels in patients with SCD in baseline health compared to healthy African American controls. Furthermore, little is known about changes in SP levels during acute SCD pain. The objective of this study was to evaluate plasma SP levels in SCD patients and controls in baseline health and in SCD patients during acute pain. We hypothesized that SCD patients, in baseline health, will have significantly higher SP levels compared to controls suggesting chronic pain sensitization and that SP levels will significantly increase during acute pain.Patients with SCD in baseline health and during admission for acute pain and healthy African American controls were recruited. Our primary outcome was plasma SP level measured in 3 independent cohorts: healthy African American controls, SCD patients in baseline heath, and SCD patients during acute pain. Plasma samples were assayed in duplicate for SP levels using competitive enzyme-linked immunosorbent assay (Cayman Chemical). Independent samples student's t-test was used to compare SP levels between: 1) SCD patients in baseline health and controls and 2) SCD patients in baseline health and those in acute pain. Multivariable linear regression analysis was used to determine the impact of age and gender on SP levels in the 3 independent groups.Thirty-five African American controls, 25 SCD patients in baseline health, and 12 SCD patients during acute pain completed the study. Controls were older than SCD patients in baseline health (mean (SD) age 21.5 (12.5) vs. 11.8 (3.8) yrs, p=0.0004) and there was no difference in the mean age of SCD patients in baseline health compared to those in acute pain (11.8 (3.8) vs. 12.1 (3.5) yrs, p=0.81). Gender did not differ between the same comparison groups. Genotypes of SCD groups were: 1) baseline: 68% SS, 24% SC, 8% Sβ+thal and 2) acute pain: 67% SS, 25% SC, 8% SOArab. The mean (SD) SP level of SCD patients in baseline health was significantly higher than controls (32.4 (11.6) vs. 22.9 (7.6) pg/mL, p=0.0009) (Figure 1). When controls were restricted to patients less than 19 years of age (n=21) to better match SCD patients in baseline health, the significant elevation of SP levels in SCD patients persisted (32.4 (11.5) vs. 21 (7.1) pg/mL, p<0.0001). Mean SP levels were even higher during acute SCD pain compared to SP levels of SCD patients at baseline (78.1 (43.4) vs. 32.4 (11.6) pg/mL, p=0.004) (Figure 1). Age and gender were not associated with differences in SP levels in controls or in SCD patients at baseline or during acute pain.The elevated SP levels in SCD patients during baseline health compared to controls suggests that SP may be a mediator of or marker for chronic pain sensitization. SP levels further increase during acute pain suggesting that SP may also play a role in mediating or marking an acute pain event. The downstream effects of chronically increased levels of SP on the development and propagation of pain in patients with SCD warrant further investigation. Ultimately, SP could differentiate those at risk for development of chronic pain and could be used as a novel biomarker for acute pain and resolution of a painful event. Eventually, compounds aimed at decreasing SP levels or blocking the SP receptor could be a target for novel treatments for SCD pain. [Display omitted] DisclosuresBrandow:NIH, ASH: Research Funding. Hillery:NIH: Research Funding. Panepinto:NKT Therapeutics, Inc: Consultancy; HRSA, NIH: Research Funding.

Niveles plasmáticos de sustancia P en cirugía artroscópica del hombro. ¿Son útiles en la prevención de la capsulitis posquirúrgica?

ObjectivesTo determine the plasma levels of neuropeptide substance P (SP) in patients with chronic subacromial pain due to rotator cuff pathology. To evaluate the correlation between pre and postoperative plasma levels of SP, chronic postoperative pain and postoperative stiffness. MethodsProspective, controlled, observational study of 60 consecutive patients with rotator cuff pathology undergoing shoulder arthroscopy with interscalene nerve block. An additional 15 patients with instability without cuff pathology were included as control group. Plasma samples were obtained preoperatively, at 2hours postoperatively, the day after surgery, and 6 weeks later. Visual analog pain scores and range of motion were registered at 6 weeks. ResultsPreoperative plasma SP levels in patients with rotator cuff pathology were significantly greater than those in the instability control group. Plasma SP levels were sharply decreased soon after surgery in both groups. A statistical correlation was obtained between the sharp fall of circulating plasma SP levels, immediately after surgery, and pain with or without stiffness 6 weeks later. ConclusionPatients with pain, with or without stiffness, 6 weeks after arthroscopic surgery for rotator cuff pathology, could have altered peripheral and central pain processing pathways, as suggested by the differences in circulating plasma SP levels observed. Level of evidence2A. Non-randomized prospective study. Clinical relevanceMeasurement of neuropeptide SP in the clinical setting has the potential of being used as a prognostic aid to guide individual patient treatment or even to be used as a surrogate outcome measure in trials.

A Study of the acupuncture point embedding therapy on slow transit constipation along with colon transmission function,plasma SP and VIP

Objective To explore the clinical efficacy of acupuncture point embedding therapy in the treatment of slow transit constipation （STC）and the influence on the colon transmission function,plasma substance P（SP）, vasoactive intestinal peptide（VIP）. Methods A total of 128 slow transit constipation patients were involved in the study and divided randomly into two groups by using stochastic indicator： a treatment group （treated with acupuncture point embedding therapy） and a control group （treated with lactulose oral liquid）. The clinical effects, colon transmission function, the influence of SP, and VIP were observed for STC patients. Results In the treatment group, CCS score was （13.52±3.93） before treatment and（8.15±3.77） after the treatment. In the control group CCS score was （14.11±4.24） and （9.01±2.93） respectively before and after the treatment, CCS score in both groups showed significantly improvement after the treatment （P〈0.01）, and there was no significant difference between groups （P〉0.05）. The plasma SP and VIP level of the two groups after the treatment [treatment group （46.73±1.50） ng/L,（206.10±12.14） ng/L, the control group（40.92±6.25）ng/L,（214.73± 7.62）ng/L] were also improved than before [treatment group was（26.66±0.88）ng/L, （332.68±17.84）ng/L, the control group was （23.32±1.75）ng/L,（306.22±20.01）ng/L], with statistically significant（P〈0.05）, and the difference between the two groups were also significant（P〈0.05）.Conclusion The acupuncture point embedding therapy is effective for STC, and it can regulate the level of SP and VIP. Key words: Acupuncture point embedding therapy; Slow transit constipation; Colon transmission function; SP; VIP

Significant Increase in Salivary Substance P Level after a Single Oral Dose of Cevimeline in Humans

Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30–240 min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline.

The effects of OB-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus

A bi-directional relationship between depression and migraine has been widely reported in epidemiological and clinical studies, but the mechanisms of interaction between these disorders have not been fully examined using animal models. The aim of the present study was to investigate the effects of depression elicited by olfactory bulbectomy (OB) on trigeminovascular nociception in conscious rats. The nociception was induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (SSS); this procedure causes nociception similar to that experienced during vascular headaches such as migraine. We showed that nociceptive behaviors (grooming and head flicks) were significantly enhanced in OB rats as compared to sham-operation (Sham) rats and that these nociceptive behaviors were correlated with depressive-like behaviors. Systemic administration of the antidepressant amitriptyline (AMI) significantly alleviated nociceptive behaviors in both the OB rats and Sham rats. Plasma levels of substance P (SP), but not plasma calcitonin gene-related protein (CGRP), significantly increased in OB rats and plasma SP levels decreased to normal following AMI treatment. Furthermore, changes in plasma SP levels were associated with both depressive-like behaviors and nociceptive behaviors. In conclusion, our results indicate that OB-induced depression can exacerbate trigeminovascular nociception, which may be mediated by SP. Moreover, we demonstrate that inhibition of SP release may contribute to the antinociceptive effect of AMI.

Hydrogen Sulfide and Neurogenic Inflammation in Polymicrobial Sepsis: Involvement of Substance P and ERK-NF-κB Signaling

Hydrogen sulfide (H2S) has been shown to induce transient receptor potential vanilloid 1 (TRPV1)-mediated neurogenic inflammation in polymicrobial sepsis. However, endogenous neural factors that modulate this event and the molecular mechanism by which this occurs remain unclear. Therefore, this study tested the hypothesis that whether substance P (SP) is one important neural element that implicates in H2S-induced neurogenic inflammation in sepsis in a TRPV1-dependent manner, and if so, whether H2S regulates this response through activation of the extracellular signal-regulated kinase-nuclear factor-κB (ERK-NF-κB) pathway. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with TRPV1 antagonist capsazepine 30 minutes before CLP. DL-propargylglycine (PAG), an inhibitor of H2S formation, was administrated 1 hour before or 1 hour after sepsis, whereas sodium hydrosulfide (NaHS), an H2S donor, was given at the same time as CLP. Capsazepine significantly attenuated H2S-induced SP production, inflammatory cytokines, chemokines, and adhesion molecules levels, and protected against lung and liver dysfunction in sepsis. In the absence of H2S, capsazepine caused no significant changes to the PAG-mediated attenuation of lung and plasma SP levels, sepsis-associated systemic inflammatory response and multiple organ dysfunction. In addition, capsazepine greatly inhibited phosphorylation of ERK1/2 and inhibitory κBα, concurrent with suppression of NF-κB activation even in the presence of NaHS. Furthermore, capsazepine had no effect on PAG-mediated abrogation of these levels in sepsis. Taken together, the present findings show that H2S regulates TRPV1-mediated neurogenic inflammation in polymicrobial sepsis through enhancement of SP production and activation of the ERK-NF-κB pathway.

Plasma Substance P Levels in Patients with Persistent Cough

Background: Substance P (SP) is involved in the pathogenesis of cough in animal models. However, few studies in humans have been reported and the roles of SP in clinical cough remain obscure. Objectives: To clarify the relevance of plasma levels of SP in patients with persistent cough. Methods: We studied 82 patients with cough persisting for at least 3 weeks and 15 healthy controls. Patients were classified as having asthmatic cough (cough-variant asthma and cough-predominant asthma; n = 61) or nonasthmatic cough (n = 21; postinfectious cough, n = 6; gastroesophageal reflux disease, n = 5; idiopathic cough, n = 5, and others, n = 5). Correlations were evaluated between plasma SP levels as measured with ELISA and methacholine airway hyperresponsiveness (airway sensitivity and airway reactivity), capsaicin cough sensitivity, sputum eosinophil and neutrophil counts, and pulmonary function. Results: Plasma SP levels were significantly elevated in patients with both asthmatic and nonasthmatic cough compared with controls [31.1 pg/ml (range 18.0–52.2) and 30.0 pg/ml (range 15.1–50.3) vs. 15.4 pg/ml (range 11.3–23.7); p = 0.003 and p = 0.038, respectively] but did not differ between the two patient groups (p = 0.90). Plasma SP levels correlated with airway sensitivity (threshold dose of methacholine) in the patients with asthmatic cough (r = –0.37, p = 0.005) but not with airway reactivity, cough sensitivity, FEV₁ values, or sputum eosinophil and neutrophil counts in either group. Conclusions: Increased levels of SP in plasma are associated with persistent cough in humans and might be related to airway sensitivity in asthmatic cough.

Plasma and saliva levels of nerve growth factor and neuropeptides in chronic migraine patients

To investigate the level and interrelationship of nerve growth factor (NGF) and sensory neuropeptides [substance P (SP), calcitonin gene-related peptide (CGRP)] in plasma and saliva of chronic migraine patients, and to analyze the association between pain intensity and their concentration. Plasma and resting whole saliva were collected from 33 chronic migraine patients and 36 control subjects. NGF, SP, and CGRP concentrations were measured by enzyme immunoassay and pain intensity of each subject was measured using the Graded Chronic Pain Scale. Chronic migraine patients showed higher NGF and neuropeptide levels in both plasma and saliva compared to the control subjects. Plasma NGF, and plasma and saliva levels of SP and CGRP were highly associated with pain intensity. There was a significant positive correlation between NGF and both neuropeptide levels in plasma, and between the neuropeptide levels in both plasma and saliva. Plasma levels of SP and CGRP were significantly correlated with their saliva level. The increased production of NGF and sensory neuropeptides may play an important role in the maintenance of pain in chronic migraine and analysis results of human saliva could act as an index of disease state and therapeutic outcome.

Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis

Mastocytosis is characterized by abnormal growth and accumulation of mast cells (MCs) in different organs. MCs have been shown to express receptors for neuropeptides. Furthermore, neuropeptides can activate MCs inducing cytokine production and MC mediator release, which further contribute to MC chemotaxis and stimulate the release of vasoactive peptides from sensory nerves. Thus, a contribution of neuropeptides to mastocytosis seems highly conceivable, but has not been investigated sufficiently yet. This study aimed to analyse blood levels of the neuropeptides substance P (SP), somatostatin (SST), vasoactive intestinal peptide (VIP), calcitonine gene--related peptide (CGRP) and expression of the SP receptor NK-1R in the skin of patients with mastocytosis (n = 46) compared to healthy controls (n = 69). Substance P, SST, VIP and CGRP plasma levels were analysed by ELISA, serum tryptase levels with the UniCAP System and NK-1R expression in the skin by immunohistochemistry. Plasma levels of SP (P < 0.0001), SST, (P = 0.007), VIP (P < 0.0001) and CGRP (P = 0.003) were significantly increased in patients with mastocytosis compared to controls. Tryptase serum levels correlated significantly with neuropeptide levels, implying a link between MC load and neuropeptide blood levels in mastocytosis. NK-1R was expressed on the majority of MCs, and NK-1R-positive cells were increased in lesional mastocytosis skin compared to control skin (P = 0.01). Elevated blood levels of the neuropeptides SP, SST, VIP and CGRP correlate with MC load and together with an increased expression of NK-1R in the skin of patients with mastocytosis indicate a role of neuropeptides in the pathophysiology of mastocytosis.