Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.

Apigenin attenuates inflammatory response in allergic rhinitis mice by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated immune inflammatory response that mainly affects the nasal mucosa. Currently, there is evidence that apigenin, as a flavonoid, has anti-allergic potential. MATERIAL/METHODS: In vitro, compound 48/80 and lipopolysaccharide (LPS) were used to induce mast cell activation and inflammation in HMC-1 cells. In vivo, ovalbumin (OVA) induced and stimulated AR in BALB/c mice. ELISA was used to detect the contents of ß-hexosaminidase, histamine, eosinophil cationic protein (ECP), OVA-specific IgE, IgG1, and IgG2a, inflammatory factors in cells and mouse serum. Cell viability and apoptosis were measured with MTT and flow cytometry. Toll like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/Nuclear transcription factor-κB (NF-κB) pathway-related proteins in cells and mouse nasal mucosa tissues were analyzed with Western blotting. The levels of Th1 (IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines and Th1 (T-bet) and Th2 (GATA-3) specific transcription factors were also assessed. The ratio of Th1 (CD4+ IFN-γ+ ) / Th2 (CD4+ IL-4+ ) cells in mouse peripheral blood mononuclear cells was evaluated by flow cytometry. RESULTS: Apigenin significantly inhibited compound 48/80-induced secretion of ß-hexosaminidase and histamine. Apigenin blocked LPS-induced decrease in cell viability and increase in cell apoptosis and inflammatory cytokine secretion by suppressing the activity of the TLR4/MyD88/NF-κB pathway. Apigenin treatment reduced the levels of OVA-specific IgE, IgG1 and IgG2a as well as ß-hexosaminidase, histamine and ECP levels in mouse serum. Moreover, administration with apigenin decreased Th2 cytokine and transcription factor levels and increased Th1 cytokine and transcription factor levels, and promoted the ratio of Th1/Th2 cells in AR mice. Additionally, apigenin significantly alleviated nasal symptoms and nasal eosinophil infiltration in AR mice. CONCLUSIONS: Apigenin alleviates the inflammatory response of allergic rhinitis by inhibiting the activity of the TLR4/MyD88/NF-κB signaling pathway.

FcεRI deficiency alleviates silica-induced pulmonary inflammation and fibrosis.

Silicosis is one of the most important occupational diseases worldwide, caused by inhalation of silica particles or free crystalline silicon dioxide. As a disease with high mortality, it has no effective treatment and new therapeutic targets are urgently needed. Recent studies have identified FCER1A, encoding α-subunit of the immunoglobulin E (IgE) receptor FcεRI, as a candidate gene involved in the biological pathways leading to respiratory symptoms. FcεRI is known to be important in allergic asthma, but its role in silicosis remains unclear. In this study, serum IgE concentrations and FcεRI expression were assessed in pneumoconiosis patients and silica-exposed mice. The role of FcεRI was explored in a silica-induced mouse model using wild-type and FcεRI-deficient mice. The results showed that serum IgE concentrations were significantly elevated in both pneumoconiosis patients and mice exposed to silica compared with controls. The mRNA and protein expression of FcεRI were also significantly increased in the lung tissue of patients and silica-exposed mice. FcεRI deficiency significantly attenuated the changes in lung function caused by silica exposure. Silica-induced elevations of IL-1ß, IL-6, and TNF-α were significantly attenuated in the lung tissue and bronchoalveolar lavage fluid (BALF) of FcεRI-deficient mice compared with wild-type controls. Additionally, FcεRI-deficient mice showed a significantly lower score of pulmonary fibrosis than wild-type mice following exposure to silica, with significantly lower hydroxyproline content and expression of fibrotic genes Col1a1 and Fn1. Immunofluorescent staining suggested FcεRI mainly on mast cells. Mast cell degranulation took place after silica exposure, as shown by increased serum histamine levels and ß-hexosaminidase activity, which were significantly reduced in FcεRI-deficient mice compared with wild-type controls. Together, these data showed that FcεRI deficiency had a significant protective effect against silica-induced pulmonary inflammation and fibrosis. Our findings provide new insights into the pathophysiological mechanisms of silica-induced pulmonary fibrosis and a potential target for the treatment of silicosis.

Effect of dietary histamine on intestinal morphology, inflammatory status, and gut microbiota in yellow catfish (Pelteobagrus fulvidraco).

The toxic effect of dietary histamine on the intestine of aquatic animals has been demonstrated, but reports on the morphological observation of the intestine are limited. Thus, a feeding trial was conducted to determine the effect of dietary histamine on intestinal histology, inflammatory status and gut microbiota of yellow catfish (Pelteobagrus fulvidraco). Here, we showed that histamine-rich diets caused severe abnormality and damage to the intestine, including a decreased villi length and reduced villi number. In addition, the quantitative real-time PCR (qRT-PCR) demonstrates that histamine-rich diets increased the expression of pro-inflammatory genes (Tnfα, Il1ß, and Il8) and decreased the expression of an anti-inflammatory gene (Il10). Furthermore, the alpha-diversity (observed OTUs, Chao1, Shannon and Simpson) and beta-diversity (non-metric multidimensional scaling, with the stress value of 0.17) demonstrated that histamine-rich diets caused alterations in gut microbiota composition and diversity. Co-occurrence networks analysis of the gut microbiota community showed that the histamine influenced the number and the relationship between bacteria species in the phyla of Acidobacteria, Proteobacteria, and Bacteroidetes, which caused the instability of the intestinal microbiota community. Additionally, random forest selected six bacterial species as the biomarkers to separate the three groups, which are Lachnospiraceae Blautia (V520), Bacteroidales S24.7 (V235), Chloroplast Streptophyta (V368), Actinomycetales Streptomycetaceae (V152), Clostridia Clostridiales (V491) and Paraprevotellaceae Prevotella (V245). Finally, Pearson correlation analysis demonstrated that V520, V235, and V491 were negatively correlated with pro-inflammatory factors (Tnfα, Il1ß, and Il8) and positively correlated with an anti-inflammatory factor (Il10), which indicated that V520, V235, and V491 might be anti-inflammatory. These findings improved our understanding of the toxic effect of dietary histamine to intestinal histological damage, the induction of mucosa inflammatory status, and the alteration of gut microbiota.

Evaluation of the Relationship among Biogenic Amines, Nitrite and Microbial Diversity in Fermented Mustard.

Biogenic amines (BAs) and nitrites are both considered harmful compounds for customer health, and are closely correlated with the microorganisms in fermented mustard (FM). In this study, BAs and nitrite contents in fifteen FM samples from different brands were analyzed. The concentrations of cadaverine in one sample and of histamine in one sample were above the toxic level. Moreover, five FM samples contained a high level of nitrite, exceeding the maximum residue limit (20 mg/kg) suggested by the National Food Safety Standard. Then, this study investigated bacterial and fungal communities by high-throughput sequencing analysis. Firmicutes and Basidiomycota were identified as the major bacteria and fungi phylum, respectively. The correlations among microorganisms, BAs and nitrite were analyzed. Typtamine showed a positive correlation with Lactobacillus and Pseudomonas. Cadaverine and nitrite is positively correlated with Leuconostoc. Furthermore, thirteen strains were selected from the samples to evaluate the accumulation and degradation properties of their BAs and nitrite. The results indicated that the Lactobacillus isolates, including L. plantarum GZ-2 and L. brevis SC-2, can significantly reduce BAs and nitrite in FM model experiments. This study not only assessed the contents of BAs and nitrite in FM samples, but also provided potential starter cultures for BAs and nitrite control in the FM products industry.

Perampanel attenuates scratching behavior induced by acute or chronic pruritus in mice.

An itch is defined as an unpleasant sensation that evokes a desire to scratch. Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and has a crucial role in pruriceptive processing in the spinal dorsal horn. It is well known that glutamate exerts its effects by binding to various glutamate receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and that AMPA/kainate receptors play a crucial role in pruriceptive processing; however, the precise role of AMPA receptors remains uncertain. Perampanel, an antiepileptic drug, is an antagonist of AMPA receptors. Pretreatment with perampanel dose-dependently attenuated the induction of scratching, a behavior typically associated with pruritus, by intradermal administration of the pruritogen chloroquine. In addition, the induction of scratching in mice painted with diphenylcyclopropenone and NC/Nga mice treated with Biostir AD, animal models of contact dermatitis and atopic dermatitis, respectively, was dose-dependently alleviated by administration of perampanel. These findings indicate that AMPA receptors play a crucial role in pruriceptive processing in mice with acute or chronic pruritus.

The Neuropeptide Y Y2 Receptor Is Coexpressed with Nppb in Primary Afferent Neurons and Y2 Activation Reduces Histaminergic and IL-31-Induced Itch.

Itch stimuli are detected by specialized primary afferents that convey the signal to the spinal cord, but how itch transmission is regulated is still not completely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y2 receptor system on scratch behavior. The inhibitory Y2 receptor is expressed on mouse primary afferents, and intrathecal administration of the Y2 agonist peptide YY (PYY)3-36 reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal preadministration of the Y2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36 In contrast, scratch behavior induced by α-methyl-5HT, protease-activated receptor-2-activating peptide SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2 Primary afferent neurons expressing the Npy2r gene were found to coexpress itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor, and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT: The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y2 receptor. The Y2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b, and interleukin 31 receptors.

Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model.

BACKGROUND: Histamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine. METHODS: Dogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1-90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented. RESULTS: In the 12 dogs in this study, nasal congestion occurred at 5-10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1-90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30-60 min after administration) in the saline group. Clinical observations included salivation and emesis. CONCLUSION: IN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.

Flare Size but Not Intensity Reflects Histamine-Induced Itch.

INTRODUCTION: Flare reactions arise due to the release of vasodilators from sensory nerves caused by antidromic transmission of action potentials after the induction of itch. OBJECTIVE: We investigated the link between flare and itch using 3 models of itch. METHODS: Skin provocations with histamine, capsaicin, and cowhage were performed in 31 subjects. Itch was quantified using the visual analog scale. Flare was assessed using laser speckle contrast imaging (LSCI) and digital photography. RESULTS: The duration, intensity, and area under the curve of histamine-induced itch correlated with the area of increased blood flow measured with LSCI (r = 0.545, p = 0.002; r = 0.575, p = 0.001; and r = 0.649, p < 0.001, respectively). Itch and skin blood flow in response to capsaicin or cowhage did not correlate. CONCLUSION: In histamine-induced skin inflammation, itch and increased blood flow are linked. Thus, the area of histamine-induced flare may be used as a surrogate marker for histamine-induced itch.

Histamine and migraine revisited: mechanisms and possible drug targets.

OBJECTIVE: To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine. BACKGROUND: Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H3 and H4) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again. METHODS: For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H3 receptor, histamine H4 receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65. FINDINGS: Early studies of H1 and H2 antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H1 mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H3 and H4 receptors are found in primarily in CNS and immune tissues, respectively. H3 is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H3 agent, pitolisant, is a brain penetrant H3 antagonist/inverse agonist which increases central histamine and causes headache. The experimental H3 agonist Nα-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H4 receptor it is questionable whether or not the receptor is involved in migraine. CONCLUSION: There is insufficient support for first generation antihistamines (both H1 and H2) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H1 antihistamines need to be appropriately tested. Central H3 receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.

Histamine food poisonings: A systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to assess the mean of histamine concentration in food poisoning. DESIGN: Systematic review and meta-analysis of reports published between 1959 and 2013. STUDY SELECTION: Main criteria for inclusion of studies were: all report types that present outbreaks of "histamine poisoning' or "scombroid syndrome" from food, including histamine content and type of food. Health status of people involved must be nonpathological. RESULTS: Fifty-five (55) reports were included, these studies reported 103 incidents. All pooled analyses were based on random effect model; histamine mean concentration in poisoning samples was 1107.21 mg/kg with confidence interval for the meta-mean of 422.62-2900.78 mg/kg; heterogeneity index (I2) was 100% (P < 0.0001); prediction interval was 24.12-50822.78 mg/kg. Fish involved in histamine poisoning was mainly tuna or Istiophoridae species. No clues of association between concomitant conditions (female sex, alcohol consumption, previous medication, and consumption of histamine releasing food) and histamine poisoning, were highlighted. CONCLUSIONS: This is the first systematic review and meta-analysis that analyzes all the available data on histamine poisoning outbreaks evaluating the histamine concentration in food involved. Histamine mean concentration in poisoning samples was fairly high. Our study suffers from some limitations, which are intrinsic of the studies included, for instance the lack of a complete anamnesis of each poisoning episode. Protocol registration: Methods were specified in advance and have been published as a protocol in PROSPERO database (18/07/2012 -CRD42012002566).

Melaleuca styphelioides Sm. Polyphenols Modulate Interferon Gamma/Histamine-Induced Inflammation in Human NCTC 2544 Keratinocytes.

Melaleuca styphelioides, known as the prickly-leaf tea tree, contains a variety of bioactive compounds. The purposes of this study were to characterize the polyphenols extracted from Melaleuca styphelioides leaves and assess their potential antioxidant and anti-inflammatory effects. The polyphenol extracts were prepared by maceration with solvents of increasing polarity. The LC/MS-MS technique was used to identify and quantify the phenolic compounds. An assessment of the radical scavenging activity of all extracts was performed using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) (ABTS⁺), and ferric reducing antioxidant power (FRAP) assays. The anti-inflammatory activity was determined on interferon gamma (IFN-γ)/histamine (H)-stimulated human NCTC 2544 keratinocytes by Western blot and RT-PCR. Compared to other solvents, methanolic extract presented the highest level of phenolic contents. The most frequent phenolic compounds were quercetin, followed by gallic acid and ellagic acid. DPPH, ABTS⁺, and FRAP assays showed that methanolic extract exhibits strong concentration-dependent antioxidant activity. IFN-γ/H treatment of human NCTC 2544 keratinocytes induced the secretion of high levels of the pro-inflammatory mediator inter-cellular adhesion molecule-1 (ICAM-1), nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB), which were inhibited by extract. In conclusion, the extract of Melaleuca styphelioides leaves is rich in flavonoids, and presents antioxidant and anti-inflammatory proprieties. It can be proposed as a useful compound to treat inflammatory skin diseases.

[Three cases of scombroid poisoning]. / Trois cas de scombroïdose.

INTRODUCTION: Scombroid poisoning is a poorly known type of food poisoning due to the presence of histamine in spoiled fish of the Scombridae family. We report 3 cases of scombroid poisoning seen at the Fréjus-Saint-Raphaël hospital in the Var region. OBSERVATIONS: Within around thirty minutes of eating a meal containing tuna, three patients presented varied symptoms: malaise, itchy rash, headache, and for two of them, nausea. The diagnosis of scombroid poisoning was based on the circumstances in which the clinical signs appeared and on the signs themselves. The patients were given antihistamines and one injection of intravenous corticosteroids, and symptoms regressed rapidly within a few hours. DISCUSSION: The symptoms of scombroid poisoning appear within a few minutes after eating fish of the Scombridae family and related species. The first symptoms are cutaneous, with flush, pruritus, and erythema of the face and trunk having an urticarial appearance, together with faintness. Gastrointestinal symptoms include nausea, vomiting, abdominal cramps and occasionally diarrhea. Symptoms subside within a few hours. Histamine is present in the flesh of these fish due to decarboxylation of histidine through the action of Gram-negative bacteria whose development is enhanced by heat and sun. Scombroid poisoning is one of the most common types of poisoning caused by eating fish but it is underdiagnosed by dermatologists. The diagnosis is made by measuring histamine levels in the incriminated fish or in the patient's plasma.

Anti-pruritic effect of topical capsaicin against histamine-induced pruritus on canine skin.

Several human studies have reported that capsaicin has anti-pruritic effects. Moreover, sever- al concentrations of topical capsaicin have been used to alleviate itch. The aim of this study was to investigate the anti-pruritic effect of capsaicin against histamine-induced pruritus compared with that of topical steroid or vehicle in 15 healthy beagles. Fifteen dogs were divided into three groups (n = 5 each), and treated topically with one of the following on the left side of the neck: capsaicin, positive control (steroid), or negative control (vehicle). Each treatment was performed twice daily for 8 days. All dogs were injected with histamine intradermally before treatment and on the 2nd, 4th, 6th, and 8th days of the treatment to evoke itch. Pruritus, wheal, and erythema intensity were assessed at each evaluation; cutaneous temperature was also recorded. On the final day, skin biopsy was conducted for histopathological evaluation for all dogs. The severity of pruritus was lesser in the capsaicin-treated group compared with the negative control group on day 8 (p⟨0.05). In the capsaicin and steroid groups, wheal size, erythema index, and cutaneous temperature also decreased compared with pretreatment. Histopathological evaluation showed that the capsaicin-treated group had a higher number of inflammatory cells in the dermis com- pared to the vehicle control group; however, the steroid-treated group showed less severe inflam- matory reactions than the vehicle control group. These results suggest that capsaicin cannot reduce inflammation but may play a helpful role in reducing pruritus in dogs.

Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-ones as potassium-competitive acid blockers.

With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.

Anti-Inflammatory and Analgesic Activities of the Complex of Flavonoids from Lychnis chalcedonica L.

Anti-inflammatory and analgesic activities of the complex of flavonoids from Lychnis chalcedonica L. were studied in the models of acute aseptic inflammation induced by carrageenan, histamine, and serotonin and acetic acid-induced painful chemical stimulation. It is demonstrated that course treatment with flavonoids derived from Lychnis chalcedonica L. produced a stable pharmacological effect comparable with that of the reference anti-inflammatory drug diclofenac.

Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.

BACKGROUND: Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival. METHODS: The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice. RESULTS: We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo. CONCLUSIONS: Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia-induced neuroinflammation. Importantly, our results also open promising new perspectives for the therapeutic use of H1R antagonists to treat or ameliorate neurodegenerative processes.

Photobacterium angustum and Photobacterium kishitanii, Psychrotrophic High-Level Histamine-Producing Bacteria Indigenous to Tuna.

Scombrotoxin fish poisoning (SFP) remains the main contributor of fish poisoning incidents in the United States, despite efforts to control its spread. Psychrotrophic histamine-producing bacteria (HPB) indigenous to scombrotoxin-forming fish may contribute to the incidence of SFP. We examined the gills, skin, and anal vents of yellowfin (n = 3), skipjack (n = 1), and albacore (n = 6) tuna for the presence of indigenous HPB. Thirteen HPB strains were isolated from the anal vent samples from albacore (n = 3) and yellowfin (n = 2) tuna. Four of these isolates were identified as Photobacterium kishitanii and nine isolates as Photobacterium angustum; these isolates produced 560 to 603 and 1,582 to 2,338 ppm histamine in marine broth containing 1% histidine (25°C for 48 h), respectively. The optimum growth temperatures and salt concentrations were 26 to 27°C and 1% salt for P. kishitanii and 30 to 32°C and 2% salt for P. angustum in Luria 70% seawater (LSW-70). The optimum activity of the HDC enzyme was at 15 to 30°C for both species. At 5°C, P. kishitanii and P. angustum had growth rates of 0.1 and 0.2 h(-1), respectively, and the activities of histidine decarboxylase (HDC) enzymes were 71% and 63%, respectively. These results show that indigenous HPB in tuna are capable of growing at elevated and refrigeration temperatures. These findings demonstrate the need to examine the relationships between the rate of histamine production at refrigeration temperatures, seafood shelf life, and regulatory limits.

Assessment of Itch and Pain in Animal Models and Human Subjects.

For the past century, scientists have developed a variety of methods to evaluate itch and pain in both animal models and human subjects to throw light on some of the most important pathways mediating these unpleasant sensations. Discoveries in the mechanisms underlying itch and pain in both physiological and pathological conditions relied greatly upon these studies and may eventually lead to the discovery of new therapeutics. However, it was a much more complicated job to access itch and pain in animal models than in human subjects due to the subjective nature of these sensations. The results could be contradictory or even misleading when applying different methodologies in animal models, especially under pathological conditions with a mixed sensation of itch and pain. This chapter introduces and evaluates some of the classical and newly designed methodologies to access the sensation of itch and pain in animal models as well as human subjects.

Polidocanol inhibits cowhage - but not histamine-induced itch in humans.

Polidocanol is a local anaesthetic and antipruritic compound that is used in the treatment of itching skin conditions such as eczema. Its mechanisms of action are largely ill defined. This study has compared the antipruritic efficacy of topical polidocanol in histamine-induced itch and a histamine-independent, cowhage-induced model of pruritus. Polidocanol (3%) or vehicle was applied topically under occlusion for 1 h to the forearms of 45 healthy volunteers before itch was provoked by rubbing in 40-45 spicules of cowhage or skin prick testing with 10 mg/ml histamine. Itch was recorded at 1-min intervals for 30 min on a 100-mm visual analogue scale. Polidocanol significantly reduced the area under the curve for cowhage-induced itch by 58% (P < 0.05), but had no significant effect on histamine-induced itch. This result underlines the importance of histamine-independent itch models in the development of topical antipruritic agents.