A comparative study on basophil activation test, histamine release assay, and passive sensitization histamine release assay in the diagnosis of peanut allergy.
Larsen L F,Juel-Berg N,Hansen K S,Clare Mills E N,van Ree R,Poulsen L K,Jensen B M
Allergy
BACKGROUND:Allergy can be diagnosed using basophil tests. Several methods measuring basophil activation are available. This study aimed at comparing basophil activation test (BAT), histamine release assay (HR), and passive sensitization histamine release assay (passive HR) in the diagnosis of peanut allergy. METHODS:BAT, HR, and passive HR were performed on 11 peanut-allergic and 14 nonallergic subjects. Blood was incubated with peanut extract or anti-IgE and tests were performed as follows: BAT-CD63 upregulation was assessed by flow cytometry; HR-released histamine was quantified by a glass fiber-based fluorometric method; passive HR-IgE-stripped donor basophils were incubated with participants' serum and histamine release was quantified as HR. RESULTS:CDsens, a measure of basophil allergen sensitivity, was significantly higher for BAT (80.1±17.4) compared to HR (23.4±10.31) and passive HR (11.1±2.0). BAT, HR, and passive HR had a clinical sensitivity of 100%, 100%, and 82% and specificity of 100%, 100%, and 100%, respectively, when excluding inconclusive results. BAT identified 11 of 11 allergic patients, HR 10, and passive HR 9. Likewise, BAT recognized 12 of 14 nonallergic subjects, HR 10, and passive HR 13. However, the tests' diagnostic performances were not statistically different. Interestingly, nonreleasers in HR but not in BAT had lower basophil count compared to releasers (249 vs 630 counts/min). CONCLUSION:BAT displayed a significantly higher CDsens compared to HR and passive HR. The basophil tests' diagnostic performances were not significantly different. Still, BAT could diagnose subjects with low basophil number in contrast to HR.
10.1111/all.13243
The antihistamine olopatadine regulates T cell activation in palladium allergy.
Iguchi Naohiko,Takeda Yuri,Sato Naoki,Ukichi Kenichirou,Katakura Akira,Ueda Kyosuke,Narushima Takayuki,Higuchi Shigehito,Ogasawara Kouetsu
International immunopharmacology
Because of its corrosion resistance palladium (Pd) has been widely used in many consumer products ranging from fashion accessories to dental materials. Recently, however, an increase in Pd allergy cases has been reported. Metal allergy is categorized as a Type IV allergy, which is characterized as a delayed-type hypersensitivity reaction in which T cells are known to play an important role; however, the precise mechanism of their action remains unclear. Here we defined the relationship between histamine and the Pd allergic reaction specifically with respect to T cell responses. To verify the effects of histamine on T cells, we examined whether there is a change in IFN-γ production following stimulation of histamine or the antihistamine, olopatadine hydrochloride (OLP), in vitro. In addition, we assessed whether OLP administration affected the degree of footpad swelling or IFN-γ production during the Pd allergy response in mice. We found that histamine stimulation increased IFN-γ production in T cells, specifically enhancing IFN-γ production in CD8(+) T cells compared with CD4(+) T cells. Interestingly, OLP suppressed the production of IFN-γ in CD8(+) T cells, and this compound inhibited footpad swelling and IFN-γ production in mice with Pd allergy. These results suggest that histamine promotes the Type IV allergic reaction and thus, the histamine 1 receptor (H1R) might be useful therapeutic target for treatment of metal allergy.
10.1016/j.intimp.2016.03.021
Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.
Rocha Sandra M,Saraiva Tatiana,Cristóvão Ana C,Ferreira Raquel,Santos Tiago,Esteves Marta,Saraiva Cláudia,Je Goun,Cortes Luísa,Valero Jorge,Alves Gilberto,Klibanov Alexander,Kim Yoon-Seong,Bernardino Liliana
Journal of neuroinflammation
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.
10.1186/s12974-016-0600-0
Tumor formation and antitumor immunity; the overlooked significance of histamine.
Falus Andras,Gilicze Anna
Journal of leukocyte biology
HA is a biogenic amine, widely distributed throughout the body. Given the observations that HA, the decarboxylated amino acid histidine, can be induced and made available in an unstored, diffusible form in tissues undergoing rapid growth (such as tumors and regenerating tissues), it could have a role in antitumor response beyond the well-studied inflammatory and allergic responses.
10.1189/jlb.3RI0413-217RR
Evidence of a broad histamine footprint on the human exercise transcriptome.
Romero Steven A,Hocker Austin D,Mangum Joshua E,Luttrell Meredith J,Turnbull Douglas W,Struck Adam J,Ely Matthew R,Sieck Dylan C,Dreyer Hans C,Halliwill John R
The Journal of physiology
KEY POINTS:Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity. Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise. We show that the human response to exercise includes an altered expression of thousands of protein-coding genes, and much of this response appears to be driven by histamine. Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training. ABSTRACT:Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors. In humans, aerobic exercise is followed by a post-exercise activation of histamine H1 and H2 receptors localized to the previously exercised muscle. This could trigger a broad range of cellular adaptations in response to exercise. Thus, we exploited RNA sequencing to explore the effects of H1 and H2 receptor blockade on the exercise transcriptome in human skeletal muscle tissue harvested from the vastus lateralis. We found that exercise exerts a profound influence on the human transcriptome, causing the differential expression of more than 3000 protein-coding genes. The influence of histamine blockade post-exercise was notable for 795 genes that were differentially expressed between the control and blockade condition, which represents >25% of the number responding to exercise. The broad histamine footprint on the human exercise transcriptome crosses many cellular functions, including inflammation, vascular function, metabolism, and cellular maintenance.
10.1113/JP272177
Histamine Regulates Actin Cytoskeleton in Human Toll-like Receptor 4-activated Monocyte-derived Dendritic Cells Tuning CD4+ T Lymphocyte Response.
Aldinucci Alessandra,Bonechi Elena,Manuelli Cinzia,Nosi Daniele,Masini Emanuela,Passani Maria Beatrice,Ballerini Clara
The Journal of biological chemistry
Histamine, a major mediator in allergic diseases, differentially regulates the polarizing ability of dendritic cells after Toll-like receptor (TLR) stimulation, by not completely explained mechanisms. In this study we investigated the effects of histamine on innate immune reaction during the response of human monocyte-derived DCs (mDCs) to different TLR stimuli: LPS, specific for TLR4, and Pam3Cys, specific for heterodimer molecule TLR1/TLR2. We investigated actin remodeling induced by histamine together with mDCs phenotype, cytokine production, and the stimulatory and polarizing ability of Th0. By confocal microscopy and RT-PCR expression of Rac1/CdC42 Rho GTPases, responsible for actin remodeling, we show that histamine selectively modifies actin cytoskeleton organization induced by TLR4, but not TLR2 and this correlates with increased IL4 production and decreased IFNγ by primed T cells. We also demonstrate that histamine-induced cytoskeleton organization is at least in part mediated by down-regulation of small Rho GTPase CdC42 and the protein target PAK1, but not by down-regulation of Rac1. The presence and relative expression of histamine receptors HR1-4 and TLRs were determined as well. Independently of actin remodeling, histamine down-regulates IL12p70 and CXCL10 production in mDCs after TLR2 and TLR4 stimulation. We also observed a trend of IL10 up-regulation that, despite previous reports, did not reach statistical significance.
10.1074/jbc.M116.720680
Suppression of IFN-γ Production in Murine Splenocytes by Histamine Receptor Antagonists.
Kamei Miho,Otani Yukie,Hayashi Hidenori,Nakamura Tadaho,Yanai Kazuhiko,Furuta Kazuyuki,Tanaka Satoshi
International journal of molecular sciences
Accumulating evidence suggests that histamine synthesis induced in several types of tumor tissues modulates tumor immunity. We found that a transient histamine synthesis was induced in CD11b⁺Gr-1⁺ splenocytes derived from BALB/c mice transplanted with a syngeneic colon carcinoma, CT-26, when they were co-cultured with CT-26 cells. Significant levels of IFN-γ were produced under this co-culture condition. We explored the modulatory roles of histamine on IFN-γ production and found that several histamine receptor antagonists, such as pyrilamine, diphenhydramine, JNJ7777120, and thioperamide, could significantly suppress IFN-γ production. However, suppression of IFN-γ production by these antagonists was also found when splenocytes were derived from the BALB/c mice. Suppressive effects of these antagonists were found on IFN-γ production induced by concanavalin A or the combination of an anti-CD3 antibody and an anti-CD28 antibody in a histamine-independent manner. Murine splenocytes were found to express H₁ and H₂ receptors, but not H₃ and H₄ receptors. IFN-γ production in the splenocytes induced by the combination of an anti-CD3 antibody and an anti-CD28 antibody was significantly suppressed by these antagonists. These findings suggest that pyrilamine, diphenhydramine, JNJ7777120, and thioperamide can suppress IFN-γ production in activated splenocytes in a histamine-independent manner.
10.3390/ijms19124083
Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls.
Pinzer T C,Tietz E,Waldmann E,Schink M,Neurath M F,Zopf Y
Allergy
BACKGROUND:Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting histamine-rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of histamine intolerance, to therefore establish day profiles of histamine levels and DAO activities, and to compare the results between patients with suspected histamine intolerance, food allergy and healthy controls. METHODS:We determined day profiles of histamine plasma levels and DAO serum activities in 33 patients with suspected histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory chemical parameters were evaluated. RESULTS:Twenty-four percent (8 of 33) suspected histamine-intolerant patients showed elevated histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food-allergic and control patients. The remaining 25 patients presented normal histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected histamine-intolerants. There was no correlation between subjective complaints and serological histamine parameters in patients with suspected histamine intolerance. CONCLUSIONS:We determined by daily profiling that decreased DAO activities correlated with elevated histamine levels in a subgroup of suspected histamine-intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms and strongly suggests the presence of histamine intolerance.
10.1111/all.13361
Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells.
Gamperl Susanne,Stefanzl Gabriele,Peter Barbara,Smiljkovic Dubravka,Bauer Karin,Willmann Michael,Valent Peter,Hadzijusufovic Emir
Veterinary and comparative oncology
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in the treatment of human chronic lymphocytic leukaemia and mantle cell lymphoma. Recent data have shown that ibrutinib also blocks IgE-dependent activation and histamine release in human basophils (BAs) and mast cells (MCs). The aim of this study was to investigate whether BTK serves as a novel therapeutic target in canine mast cell tumours (MCTs). We evaluated the effects of ibrutinib on two canine MC lines, C2 and NI-1 and on primary MCs obtained from canine MCTs (n = 3). Using flow cytometry, we found that ibrutinib suppresses phosphorylation of BTK and of downstream STAT5 in both MC lines. In addition, ibrutinib decreased proliferation of neoplastic MCs, with IC values ranging between 0.1 and 1 μM in primary MCT cells and between 1 and 3 μM in C2 and NI-1 cells. In C2 cells, the combination "ibrutinib + midostaurin" produced synergistic growth-inhibitory effects. At higher concentrations, ibrutinib also induced apoptosis in both MC lines. Finally, ibrutinib was found to suppress IgE-dependent histamine release in primary MCT cells, with IC values ranging from 0.05 to 0.1 μM in NI-1 cells, and from 0.05 to 1 μM in primary MCT cells. In summary, ibrutinib exerts anti-proliferative effects in canine neoplastic MCs and counteracts IgE-dependent histamine release in these cells. Based on our data, ibrutinib may be considered as a novel therapeutic agent for the treatment of canine MCT. The value of BTK inhibition in canine MCT patients remains to be elucidated in clinical trials.
10.1111/vco.12520
Mast Cell-Derived Histamine Regulates Liver Ketogenesis via Oleoylethanolamide Signaling.
Misto Alessandra,Provensi Gustavo,Vozella Valentina,Passani Maria Beatrice,Piomelli Daniele
Cell metabolism
The conversion of lipolysis-derived fatty acids into ketone bodies (ketogenesis) is a crucial metabolic adaptation to prolonged periods of food scarcity. The process occurs primarily in liver mitochondria and is initiated by fatty-acid-mediated stimulation of the ligand-operated transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α). Here, we present evidence that mast cells contribute to the control of fasting-induced ketogenesis via a paracrine mechanism that involves secretion of histamine into the hepatic portal circulation, stimulation of liver H receptors, and local biosynthesis of the high-affinity PPAR-α agonist, oleoylethanolamide (OEA). Genetic or pharmacological interventions that disable any one of these events, including mast cell elimination, deletion of histamine- or OEA-synthesizing enzymes, and H blockade, blunt ketogenesis without affecting lipolysis. The results reveal an unexpected role for mast cells in the regulation of systemic fatty-acid homeostasis, and suggest that OEA may act in concert with lipolysis-derived fatty acids to activate liver PPAR-α and promote ketogenesis.
10.1016/j.cmet.2018.09.014
Histamine: neural circuits and new medications.
Scammell Thomas E,Jackson Alexander C,Franks Nicholas P,Wisden William,Dauvilliers Yves
Sleep
Histamine was first identified in the brain about 50 years ago, but only in the last few years have researchers gained an understanding of how it regulates sleep/wake behavior. We provide a translational overview of the histamine system, from basic research to new clinical trials demonstrating the usefulness of drugs that enhance histamine signaling. The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and like many of the arousal systems, histamine neurons diffusely innervate the cortex, thalamus, and other wake-promoting brain regions. Histamine has generally excitatory effects on target neurons, but paradoxically, histamine neurons may also release the inhibitory neurotransmitter GABA. New research demonstrates that activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation. The number of histamine neurons is increased in narcolepsy, but whether this affects brain levels of histamine is controversial. Of clinical importance, new compounds are becoming available that enhance histamine signaling, and clinical trials show that these medications reduce sleepiness and cataplexy in narcolepsy.
10.1093/sleep/zsy183
Different perception levels of histamine-induced itch sensation in young adult mice.
Ji Yeounjung,Jang Yongwoo,Lee Wook Joo,Yang Young Duk,Shim Won-Sik
Physiology & behavior
Itch is an unpleasant sensation that evokes behavioral responses such as scratching the skin. Interestingly, it is conceived that the perception of itch sensation is influenced by age. Indeed, accumulating evidence supports the idea that even children or younger adults show distinctive itch sensation depending on age. This evidence implies the presence of a mechanism that regulates the perception of itch sensation in an age-dependent fashion. Therefore, the purpose of the present study was to investigate a putative mechanism for the age-dependent perception of itch sensation by comparing histamine-induced scratching behaviors in 45-day old (D45) and 75-day old male "young adult" mice. The results indicated that, following histamine administration, the D75 mice spent a longer time scratching than D45 mice. However, the intensity of the calcium influx induced by histamine in primary culture of dorsal root ganglia (DRG) neurons was not different between D45 and D75 mice. Moreover, no apparent difference was observed in mRNA levels of a characteristic His-related receptor and ion channel. In contrast, the mRNA levels of Toll-Like Receptor 4 (TLR4) were increased approximately by two-fold in D75 DRG compared with D45 DRG. Additionally, D75-derived DRG neurons exhibited enhanced intracellular calcium increase by lipopolysaccharide (LPS, a TLR4 agonist) than those of D45 mice. Furthermore, intensities of calcium influx induced by histamine were significantly potentiated when co-treated with LPS in D75 DRG neurons, but not in those of D45 mice. Thus, it appears that D75 mice showed enhanced histamine-induced scratching behaviors not by increased expression levels of histamine-related genes, but probably due to augmented TLR4 expression in DRG neurons. Consequently, the current study found that different perception levels of histamine-induced itch sensation are present in different age groups of young adult mice.
10.1016/j.physbeh.2018.02.015
Visualization of the activation of the histamine H3 receptor (H3R) using novel fluorescence resonance energy transfer biosensors and their potential application to the study of H3R pharmacology.
Liu Ying,Zeng Hong,Pediani John D,Ward Richard J,Chen Lu-Yao,Wu Nan,Ma Li,Tang Mei,Yang Yang,An Su,Guo Xiao-Xi,Hao Qian,Xu Tian-Rui
The FEBS journal
Activation of the histamine-3 receptor (H3R) is involved in memory processes and cognitive action, while blocking H3R activation can slow the progression of neurological disorders, such as Alzheimer's disease, schizophrenia and narcolepsy. To date, however, no direct way to examine the activation of H3R has been utilized. Here, we describe a novel biosensor that can visualize the activation of H3R through an intramolecular fluorescence resonance energy transfer (FRET) signal. To achieve this, we constructed an intramolecular H3R FRET sensor with cyan fluorescent protein (CFP) attached at the C terminus and yellow fluorescent protein (YFP) inserted into the third intracellular loop. The sensor was found to internalize normally on agonist treatment. We measured FRET signals between the donor CFP and the acceptor YFP in living cells in real time, the results of which indicated that H3R agonist treatment (imetit or histamine) increases the FRET signal in a time- and concentration-dependent manner with Kon and Koff values consistent with published data and which maybe correlated with decreasing cAMP levels and the promotion of ERK1/2 phosphorylation. The FRET signal was inhibited by H3R antagonists, and the introduction of mutations at F419A, F423A, L426A and L427A, once again, the promotion of ERK1/2 phosphorylation, was diminished. Thus, we have built a H3R biosensor which can visualize the activation of receptor through real-time structure changes and which can obtain pharmacological kinetic data at the same time. The FRET signals may allow the sensor to become a useful tool for screening compounds and optimizing useful ligands.
10.1111/febs.14484
Histamine elicits glutamate release from cultured astrocytes.
Kárpáti Anikó,Yoshikawa Takeo,Nakamura Tadaho,Iida Tomomitsu,Matsuzawa Takuro,Kitano Haruna,Harada Ryuichi,Yanai Kazuhiko
Journal of pharmacological sciences
Astrocytes play key roles in regulating brain homeostasis and neuronal activity. This is, in part, accomplished by the ability of neurotransmitters in the synaptic cleft to bind astrocyte membrane receptors, activating signalling cascades that regulate concentration of intracellular Ca ([Ca]) and gliotransmitter release, including ATP and glutamate. Gliotransmitters contribute to dendrite formation and synaptic plasticity, and in some cases, exacerbate neurodegeneration. The neurotransmitter histamine participates in several physiological processes, such as the sleep-wake cycle and learning and memory. Previous studies have demonstrated the expression of histamine receptors on astrocytes, but until now, only a few studies have examined the effects of histamine on astrocyte intracellular signalling and gliotransmitter release. Here, we used the human astrocytoma cell line 1321N1 to study the role of histamine in astrocyte intracellular signalling and gliotransmitter release. We found that histamine activated astrocyte signalling through histamine H and H receptors, leading to distinct cellular responses. Activation of histamine H receptors caused concentration-dependent release of [Ca] from internal stores and concentration-dependent increase in glutamate release. Histamine H receptor activation increased cyclic adenosine monophosphate (cAMP) levels and phosphorylation of transcription factor cAMP response-element binding protein. Taken together, these data emphasize a role for histamine in neuron-glia communication.
10.1016/j.jphs.2018.05.002
Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT).
Razali Nurul Atika,Nazarudin Nur Amiza,Lai Kok Song,Abas Faridah,Ahmad Syahida
BMC complementary and alternative medicine
BACKGROUND:Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells. METHODS:Interleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. RESULTS:Histamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC) value of 4.91 ± 2.50 μM and median lethal concentration (LC) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades. CONCLUSION:Taken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.
10.1186/s12906-018-2223-8
Histamine Excites Striatal Dopamine D1 and D2 Receptor-Expressing Neurons via Postsynaptic H1 and H2 Receptors.
Zhuang Qian-Xing,Xu Han-Ting,Lu Xu-Juan,Li Bin,Yung Wing-Ho,Wang Jian-Jun,Zhu Jing-Ning
Molecular neurobiology
The central histaminergic nervous system, originating from the tuberomammillary nucleus (TMN) of the hypothalamus, widely innervates almost the whole brain, including the basal ganglia. Intriguingly, the histaminergic system is altered in parkinsonian patients. Yet, little is known about the effect and mechanisms of histamine on different types of neurons in the basal ganglia circuitry. Here, by using anterograde tracing, immunostaining, patch clamp recording, and single-cell qPCR techniques, we investigate the histaminergic afferents in the striatum, the major input structure of the basal ganglia, as well as the effect of histamine on the striatal GABAergic medium spiny projection neurons (MSNs). We report a direct histaminergic projection from the hypothalamic TMN to the striatum in rats. Furthermore, histamine exerts a strong postsynaptic excitatory effect on both dopamine D1 and D2 receptor-expressing MSNs. The concentration-response curves and the EC values for histamine on these two types of MSNs are similar. In addition, dopamine D1 and D2 receptor-expressing MSNs co-express histamine H1 and H2 receptor mRNAs. Both histamine H1 and H2 receptors are co-localized on dopamine D1 and D2 receptor-expressing MSNs and co-mediate the histamine-induced excitation on the two types of neurons. These results suggest that the histaminergic afferent inputs in the striatum may modulate both dopamine D1 and D2 receptor-expressing MSNs by activation of postsynaptic histamine H1 and H2 receptors and thus serve as an important extrastriatal modulator for biasing the direct and indirect pathways to actively regulate functions of the basal ganglia and participate in the pathogenesis and pathophysiology of basal ganglia diseases.
10.1007/s12035-018-0976-1
[Drug hypersensitivity in patients with presumed histamine intolerance and mast cell activation disease].
Schmid-Grendelmeier Peter,Schnyder Benno
Therapeutische Umschau. Revue therapeutique
Drug hypersensitivity in patients with presumed histamine intolerance and mast cell activation disease There is no evidence to suggest that sensitization against drugs occurs more frequently among patients with presumed histamine intolerance compared to patients with normal tolerance to histamine. However, preclinical data suggest interactions between some drugs and histamine catabolism. Nevertheless, the clinical relevance of these findings remains unclear as histamine in humans can be catabolized by different pathways. There are no drugs for which induction or worsening of histamine intolerance has been established clinically. In patients with mastocytosis an increased rate of sensitization and specific allergies to drugs is unlikely. However, pathophysiologic understanding suggests that mast cell activation disease might enhance drug reactions, which are induced by mast cell degranulation. Additionally a possible lower threshold for unspecific mast cell degranulation in patients with mastocytosis could lead to pseudoallergic drug reactions. However an increase in the number of drug substances triggering such reactions is not expected. Nevertheless, there are lists of drug substances which are assumed to cause anaphylactic / anaphylactoid reactions especially in patients with mastocytosis. Conversely, these lists are rarely based on clinical evidence. A recently published prospective trial did not find any relevant increase of acetyl salicylic acid hypersensitivity in patients with mastocytosis. Patients with mastocytosis and a history of drug hypersensitivity should be thoroughly assessed by an allergological workup and advised to avoid triggering and / or cross reactive drug substances. We recommend that these patients avoid drugs which may interfere with the treatment of anaphylaxis like beta blockers, certain antidepressants or Catechol-O-methyltransferase inhibitors because of the increased risk for enhanced hypersensitivity reactions.
10.1024/0040-5930/a001058
Intracerebroventricular injection of histamine induces the hypothalamic-pituitary-gonadal axis activation in male rats.
Niaz Nasir,Guvenc Gokcen,Altinbas Burcin,Berk Toker Mehmed,Aydin Begum,Udum-Kucuksen Duygu,Alcay Selim,Gokce Elif,Ustuner Burcu,Yalcin Murat
Brain research
Brain histamine holds a key position in the regulation of behavioral states, biological rhythms, body weight, energy metabolism, thermoregulation, fluid balance, stress and reproduction in female animals. However, it is not clear whether central histamine exerts any effect on hypothalamic-pituitary-testicular in male rats and if so, the involvement of type of central histamine receptors. The current study was designed to determine the effect of centrally administrated histamine on plasma gonadotropin hormone-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone level, and sperm parameters, and to show the mediation of the central histaminergic H1, H2 and H3/H4 receptors on histamine-evoked hormonal and sperm parameters' effects. Studies were performed in male Sprague-Dawley rats. A total of 50 or 100 nmol doses of histamine were injected intracerebroventricularly (icv). 100 nmol dose of histamine significantly caused increases in plasma GnRH, LH, FSH and testosterone levels of animals, but not 50 nmol dose of histamine. Moreover, central pretreatment with chlorpheniramine, histaminergic H1 receptor antagonist (100 nmol), ranitidine and histaminergic H2 receptor antagonist (100 nmol) completely prevented histamine evoked increase in plasma GnRH, LH, FSH and testosterone levels, while thioperamide, histaminergic H3/H4 receptor antagonist (100 nmol) pretreatment failed to reverse sex hormones responses to histamine. Both central histamine treatment alone and central histamine treatment after central histaminergic receptors antagonists' pretreatments did not alter any sperm parameters in rats. In conclusion, our findings show that centrally administered histamine increases plasma GnRH, LH, FSH and testosterone levels of conscious male rats without change any sperm parameters. Moreover, according to our findings, central histaminergic H1, and H2 receptors mediate these histamine-induced effects.
10.1016/j.brainres.2018.08.020
Binding of histamine to the H1 receptor-a molecular dynamics study.
Söldner Christian A,Horn Anselm H C,Sticht Heinrich
Journal of molecular modeling
Binding of histamine to the G-protein coupled histamine H receptor plays an important role in the context of allergic reactions; however, no crystal structure of the resulting complex is available yet. To deduce the histamine binding site, we performed unbiased molecular dynamics (MD) simulations on a microsecond time scale, which allowed to monitor one binding event, in which particularly the residues of the extracellular loop 2 were involved in the initial recognition process. The final histamine binding pose in the orthosteric pocket is characterized by interactions with Asp107, Tyr108, Thr194, Asn198, Trp428, Tyr431, Phe432, and Phe435, which is in agreement with existing mutational data. The conformational stability of the obtained complex structure was subsequently confirmed in 2 μs equilibrium MD simulations, and a metadynamics simulation proved that the detected binding site represents an energy minimum. A complementary investigation of a D107A mutant, which has experimentally been shown to abolish ligand binding, revealed that this exchange results in a significantly weaker interaction and enhanced ligand dynamics. This finding underlines the importance of the electrostatic interaction between the histamine ammonium group and the side chain of Asp107 for histamine binding.
10.1007/s00894-018-3873-7
Histamine Excites Rat GABAergic Ventral Pallidum Neurons via Co-activation of H1 and H2 Receptors.
Ji Miao-Jin,Zhang Xiao-Yang,Peng Xiao-Chun,Zhang Yang-Xun,Chen Zi,Yu Lei,Wang Jian-Jun,Zhu Jing-Ning
Neuroscience bulletin
The ventral pallidum (VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion. Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamic-derived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.
10.1007/s12264-018-0277-8
Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.
Hawro T,Lehmann S,Deuring E,Weller K,Altrichter S,Church M K,Maurer M,Metz M
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES:This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS:Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS:Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION:This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.
10.1111/jdv.15743
Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade.
Grauers Wiktorin Hanna,Nilsson Malin S,Kiffin Roberta,Sander Frida Ewald,Lenox Brianna,Rydström Anna,Hellstrand Kristoffer,Martner Anna
Cancer immunology, immunotherapy : CII
Myeloid-derived suppressor cells (MDSCs) are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive reactive oxygen species (ROS) via the myeloid cell NADPH oxidase (NOX2). Histamine dihydrochloride (HDC), a NOX2 inhibitor, exerts anti-cancer efficacy in experimental tumor models but the detailed mechanisms are insufficiently understood. To determine effects of HDC on the MDSC compartment we utilized three murine cancer models known to entail accumulation of MDSC, i.e. EL-4 lymphoma, MC-38 colorectal carcinoma, and 4T1 mammary carcinoma. In vivo treatment with HDC delayed EL-4 and 4T1 tumor growth and reduced the ROS formation by intratumoral MDSCs. HDC treatment of EL-4 bearing mice also reduced the accumulation of intratumoral MDSCs and reduced MDSC-induced suppression of T cells ex vivo. Experiments using GR1-depleted and Nox2 knock out mice supported that the anti-tumor efficacy of HDC required presence of NOX2 GR1 cells in vivo. In addition, treatment with HDC enhanced the anti-tumor efficacy of programmed cell death receptor 1 (PD-1) and PD-1 ligand checkpoint blockade in EL-4- and MC-38-bearing mice. Immunomodulatory effects of a HDC-containing regimen on MDSCs were further analyzed in a phase IV trial (Re:Mission Trial, ClinicalTrials.gov; NCT01347996) where patients with acute myeloid leukemia received HDC in conjunction with low-dose IL-2 (HDC/IL-2) for relapse prevention. Peripheral CD14HLA-DR MDSCs (M-MDSCs) were reduced during cycles of HDC/IL-2 therapy and a pronounced reduction of M-MDSCs during HDC/IL-2 treatment heralded favorable clinical outcome. We propose that anti-tumor properties of HDC may comprise the targeting of MDSCs.
10.1007/s00262-018-2253-6
Histamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions.
Pfanzagl Beatrix,Zevallos Victor F,Schuppan Detlef,Pfragner Roswitha,Jensen-Jarolim Erika
American journal of physiology. Gastrointestinal and liver physiology
The P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellular calcium concentration ([Ca]) via histamine 1 receptors involving T-type voltage-gated calcium channels (VGCCs). Sensitivity to histamine was enhanced by pretreatment with the inflammatory cytokine tumor necrosis factor-α (TNF-α). In accordance with the relief it offers some inflammatory bowel disease patients, otilonium bromide, a gut-impermeable inhibitor of T-type (and L-type) VGCCs and muscarinic ACh receptors, efficiently inhibited the [Ca] responses induced by histamine plus ACh or by histamine alone in P-STS cells. It will take clinical studies to show whether otilonium bromide has promise for the treatment of adverse food reactions. The cells did not react to the nutrient constituents glutamate, capsaicin, cinnamaldehyde, or amylase-trypsin inhibitors and the transient receptor potential channel vanilloid 4 agonist GSK-1016790A. The bacterial product butyrate evoked a rise in [Ca] only when added together with ACh. Lipopolysaccharide had no effect on [Ca] despite the presence of Toll-like receptor 4 protein. Our results indicate that inflammatory conditions with elevated levels of TNF-α might enhance histamine-induced serotonin release from intestinal neuroendocrine cells. NEW & NOTEWORTHY We show that histamine synergistically enhances the intracellular calcium response to the physiological agonist acetylcholine in human ileal enterochromaffin tumor cells. This synergistic activation and cell activation by histamine alone largely depend on T-type voltage-gated calcium channels and are inhibited by the antispasmodic otilonium bromide. The cells showed no response to wheat amylase-trypsin inhibitors, suggesting that enterochromaffin cells are not directly involved in nongluten wheat sensitivity.
10.1152/ajpgi.00261.2018
VAS2870 Inhibits Histamine-Induced Calcium Signaling and vWF Secretion in Human Umbilical Vein Endothelial Cells.
Avdonin Pavel V,Rybakova Elena Yu,Avdonin Piotr P,Trufanov Sergei K,Mironova Galina Yu,Tsitrina Alexandra A,Goncharov Nikolay V
Cells
In this study, we investigated the effects of NAD(P)H oxidase (NOX) inhibitor VAS2870 (3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo[4,5-d]pyrimidine) on the histamine-induced elevation of free cytoplasmic calcium concentration ([Ca]) and the secretion of von Willebrand factor (vWF) in human umbilical vein endothelial cells (HUVECs) and on relaxation of rat aorta in response to histamine. At 10 μM concentration, VAS2870 suppressed the [Ca] rise induced by histamine. Inhibition was not competitive, with IC50 3.64 and 3.22 μM at 1 and 100 μM concentrations of histamine, respectively. There was no inhibition of [Ca] elevation by VAS2870 in HUVECs in response to the agonist of type 1 protease-activated receptor SFLLRN. VAS2870 attenuated histamine-induced secretion of vWF and did not inhibit basal secretion. VAS2870 did not change the degree of histamine-induced relaxation of rat aortic rings constricted by norepinephrine. We suggest that NOX inhibitors might be used as a tool for preventing thrombosis induced by histamine release from mast cells without affecting vasorelaxation.
10.3390/cells8020196
Histamine and migraine revisited: mechanisms and possible drug targets.
The journal of headache and pain
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 (H and H) 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 H receptor, histamine H 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 H and H 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 H mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H and H receptors are found in primarily in CNS and immune tissues, respectively. H is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H agent, pitolisant, is a brain penetrant H antagonist/inverse agonist which increases central histamine and causes headache. The experimental H agonist N-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H receptor it is questionable whether or not the receptor is involved in migraine. CONCLUSION:There is insufficient support for first generation antihistamines (both H and H) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H antihistamines need to be appropriately tested. Central H receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.
10.1186/s10194-019-0984-1
Association of body mass index and season with histamine skin reactivity in Chinese children with allergic rhinitis.
Yang You,Gu Manli
Pediatrics and neonatology
BACKGROUND:To investigate the association between histamine skin reactivity and body mass index (BMI) and other clinical factors, 526 children (3-6 years old) who underwent a skin-prick test (SPT) to diagnose allergic rhinitis were enrolled. METHODS:The SPT was carried out using 43 common allergens (commercial kit). The wheal size was analyzed. The associations between histamine reactivity and age, gender, BMI, atopy, parental smoking history, and testing season were examined. RESULTS:Mean age was 4.6 ± 1.1 years. Among all 526 children, 202 (38.4%) had intermittent allergic rhinitis (IAR), 164 (32.1%) had IAR + persistent allergic rhinitis (PER), and 160 (30.4%) had PER. The size of the histamine skin wheal and maximum diameter for positive allergens showed significant seasonal differences (P = 0.001 and P = 0.02, respectively). Children with biparental allergy history had a higher BMI (P = 0.006). BMI (P < 0.001), summer testing (P = 0.001), and autumn testing (P < 0.001) were independently associated with the size of the histamine skin wheal. Only winter testing was independently associated with the maximal diameter for positive allergens (P = 0.002). CONCLUSIONS:Higher histamine skin reactivity was associated with higher BMI and summer or autumn testing. Subject BMI and season should be considered for better interpretation of the SPT. The mechanisms underlying these associations require further study.
10.1016/j.pedneo.2018.05.011
Histamine uptake mediated by plasma membrane monoamine transporter and organic cation transporters in rat mast cell lines.
Slamet Soetanto Trivadila,Liu Shuang,Sahid Muhammad Novrizal Abdi,Toyama Kensuke,Maeyama Kazutaka,Mogi Masaki
European journal of pharmacology
The resources of released histamine from activated mast cells, as initial effectors of allergic disease, include not only endogenous prepackaged histamine and newly synthesized histamine, but also histamine that is obtained through the de novo reuptake pathway. To investigate the de novo histamine production pathway, a mast cell line, RBL-2H3 Sc98 in which endogenous histamine production is lacking and only the de novo histamine release pathway via transporters is maintained, was used to dissect histamine reuptake in the present study. Histamine content measurements indicated that RBL-2H3 Sc98 cells took up extracellular histamine for storage in granules and subsequent release after stimulation by an antigen. Profiling and inhibition analysis of possible transporters suggested that the plasma membrane monoamine transporter and organic cation transporter 1 may be candidate transporters for histamine uptake from extracellular spaces, and that vesicular monoamine transporter 2 was responsible for intracellular vesicle uptake. These results may provide the foundation to understand the contribution of exogenous histamine to outward histamine release that is mediated by mechanisms other than conventional exocytosis.
10.1016/j.ejphar.2019.01.050
The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy.
Yamauchi Kohei,Ogasawara Masahito
International journal of molecular sciences
Mast cells play a critical role in the pathogenesis of allergic asthma. Histamine is a central mediator released from mast cells through allergic reactions. Histamine plays a role in airway obstruction via smooth muscle contraction, bronchial secretion, and airway mucosal edema. However, previous clinical trials of H1 receptor antagonists (H1RAs) as a treatment for asthma were not successful. In recent years, type 2 innate immunity has been demonstrated to be involved in allergic airway inflammation. Allergic asthma is defined by IgE antibody-mediated mast cell degranulation, while group 2 innate lymphoid cells (ILC2) induce eosinophilic inflammation in nonallergic asthma without allergen-specific IgE. Anti-IgE therapy has demonstrated prominent efficacy in the treatment of severe allergic asthmatics sensitized with specific perennial allergens. Furthermore, recent trials of specific cytokine antagonists indicated that these antagonists were effective in only some subtypes of asthma. Accordingly, H1RAs may show significant clinical efficacy for some subtypes of allergic asthma in which histamine is deeply associated with the pathophysiology.
10.3390/ijms20071733
Development and validation of a highly sensitive LC-MS/MS method for in vitro measurement of histamine concentration.
Kim Kwang-Youl,Kwon Hyun-Jung,Cho Sang-Heon,Nam Moonsuk,Kim Cheol-Woo
Journal of pharmaceutical and biomedical analysis
The basophil histamine release test (HRT) is an important in vitro diagnostic assay to evaluate immunoglobin E (IgE)-mediated allergic responses. In this study, a bioanalytical LC-MS/MS method was developed and validated to quantify histamine in the leukocyte suspension from human peripheral blood. The method used pre-column derivatization with phenylisothiocyanate (PITC) and the resulting phenylthiocarbamyl (PTC) histamine was analyzed by positive-ion electrospray ionization using the multiple reaction monitoring mode. Chromatographic separation was achieved using an Imtakt-HT C18 column (2.1 mm × 50 mm, 3.0 μm), with a flow rate of 0.35 mL/min, 2 μL injection, and gradient elution with a mixture of acetonitrile-2 mM ammonium acetate buffer (both containing 0.1% formic acid). The total runtime of the method was 3.0 min including equilibration time. The method had a lower limit of detection of 0.1 ng/mL, and the quantifiable range was 0.1-100 ng/mL in the leukocyte suspension. The intra-day and inter-day precision and accuracy results were within the acceptable limits. It was established that histamine quantification should be performed within 2 h of preparing the leukocyte suspension, and freezing and thawing should be avoided. This method was successfully applied to the diagnosis and evaluation of the pathophysiologic mechanism of respiratory or cutaneous allergic diseases.
10.1016/j.jpba.2019.04.025
Microinjection of histamine and its H receptor agonist and antagonist into the agranular insular cortex influence sensory and affective components of neuropathic pain in rats.
Salimi Sara,Tamaddonfard Esmaeal
European journal of pharmacology
Many areas of the brain along with neurotransmitters involve in processing of nociceptive, emotional and cognitive dimensions of neuropathic pain. Brian neuronal histamine through H, H, H and H receptors mediates many physiological functions such as cognition, emotion and pain. In the present study we investigated the effects of intra-agranular insular cortex microinjection of histamine and its H receptor agonist and antagonist on sensory and affective aspects of neuropathic pain. Spared nerve injury model of neuropathic pain was used. Two guide cannulas were surgically implanted in the right and left sides of agranular insular cortex. Sensory component (mechanical hyperalgesia) was recorded by application of von Frey filaments onto the plantar surface of the hind paw. Area under curve of mechanical hyperalgesia was calculated. Affective aspect (place escape avoidance paradigm) was recorded using an inverse white/black chamber. Histamine (0.5, 1 and 2 μg/site) and thioperamide (a histamine H receptor antagonist, 4 μg/site) decreased, whereas immepip (a histamine H receptor agonist, 2 μg/site) increased the percentages of paw withdrawal frequency and time spent in white side of white/black box. Prior administration of thioperamide (4 μg/site) increased the suppressive effects induced by histamine and inhibited immepip (2 μg/site)-induced hyperalgesia and aversion. Based on the present results, it is concluded that histamine and its H receptor at the agranular insular cortex level may involve in modulation of sensory and affective components of neuropathic pain.
10.1016/j.ejphar.2019.172450