thioperamide and Inflammation

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Cell Line; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Inflammation; Isoflavones; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Neuroprotective Agents; Receptors, Histamine H3; Structure-Activity Relationship

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in

Topics: Animals; Biomarkers, Tumor; Cimetidine; Cromolyn Sodium; Dose-Response Relationship, Drug; Hypersensitivity; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Mast Cells; Mice; Phosphoric Diester Hydrolases; Piperidines; Promethazine; Rabbits; Rats; Skin Diseases; Spider Venoms; Tumor Cells, Cultured; Tumor Protein, Translationally-Controlled 1

Opioids provide effective analgesia in adult patients with painful inflammatory diseases. The proposed mechanism of action is the activation of peripheral opioid receptors, which may be up-regulated in such conditions. Here, by using a chronic inflammation model, namely subplantar injection of Complete Freund's adjuvant, we show a peripheral synergistic interaction between the histamine H(3) receptor agonist R-(alpha)-methylhistamine and fentanyl on the inhibition of thermal hyperalgesia and of peripheral substance P accumulation. Firstly, dose-related effects obtained for the subplantar antinociceptive effect of fentanyl (0.05-1 microg) in the presence of a fixed dose of R-(alpha)-methylhistamine (12.5 microg) showed a shift to the left when compared to that obtained with fentanyl alone. In a similar way, the subcutaneous administration of fentanyl (0.005-0.1mg/kg) plus a fixed dose of R-(alpha)-methylhistamine (0.5mg/kg) induced a supra additive effect on the inhibition of substance P accumulation in the hind-paw skin of inflamed mice. Interestingly, when a neurokinin-1 receptor antagonist was co-administered, the antinociceptive effects of the combined treatment were potentiated. The peripheral adjuvant effect of R-(alpha)-methylhistamine on fentanyl antinociception and inhibition of substance P accumulation was also demonstrated by means of opioid and histamine H(3) receptors selective antagonists: first, naloxone blockade of fentanyl-mediated effects were partially reversed by co-administration of R-(alpha)-methylhistamine, and second, thioperamide partially antagonised the combined R-(alpha)-methylhistamine/fentanyl effects. Overall, our results clearly show that R-(alpha)-methylhistamine enhances fentanyl effects at peripheral sites, and that the control of substance P levels might be one of the mechanisms responsible of such interaction.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fentanyl; Freund's Adjuvant; Histamine Agonists; Hyperalgesia; Inflammation; Male; Methylhistamines; Mice; Naloxone; Pain; Piperidines; Receptors, Histamine H3; Skin; Substance P

Pharmacological activation of histamine H3 receptors is known to reduce the release of inflammatory peptides, thereby reducing pain and inflammation, but the site(s) and mechanism(s) of these effects are currently unknown. The present study addressed these questions by examining the effects of the H3 agonist immepip and the H3 antagonist thioperamide on nociceptive behaviors and swelling produced during the rat formalin test. Systemic administration of immepip (5 and 30 mg/kg, s.c.) significantly attenuated formalin-induced flinching but not licking responses during both phases. This attenuation was reversed by either systemic (15 mg/kg, i.p.) or intrathecal (20 or 50 microg) administration of thioperamide. Furthermore, immepip (30 mg/kg, s.c.) significantly inhibited formalin-induced swelling, an action which was completely reversed by systemic (15 mg/kg, i.p.), but not intrathecal (50 microg) thioperamide. Also consistent with this pattern, intrathecal immepip (50 microg) reduced flinching responses, but had no effect on formalin-induced paw swelling. The present findings suggest that activation of H3 receptors located on peripheral and spinal terminals of deep dermal fibers attenuates formalin-induced swelling and flinching, respectively. Pharmacological stimulation of H3 receptors could be an important therapeutic approach for many disorders related to deep dermal or inflammatory pain.

Topics: Animals; Behavior, Animal; Brain; Edema; Formaldehyde; Histamine Agonists; Histamine Antagonists; Imidazoles; Inflammation; Injections, Spinal; Male; Nerve Endings; Nerve Fibers; Neurons, Afferent; Pain Measurement; Peripheral Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Skin; Spinal Cord

1. Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2. Incubation of the minced granulation tissue in the presence of histamine (1 and 10 microM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3. The increase in the content of VEGF protein in the conditioned medium by histamine (10 microM) was suppressed by the H(2) receptor antagonist cimetidine (IC(50) 0.37 microM), but not by the H(1) receptor antagonist pyrilamine maleate, the H(3) receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4. The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC(50) 6.8 microM), and the protein kinase A inhibitor H-89 (IC(50) 12.5 microM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5. Simultaneous injection of cimetidine (400 microg) and indomethacin (100 microg) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6. These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H(2) receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cells, Cultured; Cimetidine; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation; Granulation Tissue; Histamine; Histamine Antagonists; Immunohistochemistry; Indoles; Indomethacin; Inflammation; Isoquinolines; Lymphokines; Macrophages, Peritoneal; Male; Maleimides; Naphthalenes; Neovascularization, Pathologic; Piperidines; Protein Kinase C; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H2; RNA, Messenger; Specific Pathogen-Free Organisms; Sulfonamides; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In this study, we have characterized the phenotype of mast cells in rat dura mater and their topological and functional relationships with C-fibers in normal and inflammatory conditions. Three mast cell populations with different size, morphology and localization were characterized by their content of specific neutral serine proteases. They showed immunoreactivity corresponding to rat mast cell protease I, rat mast cell protease II, or both proteases. Using confocal microscopy, all three mast cell types were observed in close apposition (distance less than 100 nm) to calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in both controls and rats infected with the nematode Nippostrongylus brasiliensis. After nematode infection or neonatal treatment with capsaicin, a large increase in the number of rat mast cell protease II-immunoreactive mast cells was found within dura mater segments (+1478% and +596%, respectively), without concomitant changes of rat mast cell protease I- or rat mast cell protease I/II-immunoreactive mast cells. Under both these conditions, the increase in mast cell number was accompanied by a significant increase in rat mast cell protease II level within tissue extracts (+281% after nematode infection and +36% after capsaicin treatment). The functional interaction of mast cells with sensory nerve fibers in the dura mater was assessed by evaluating [3H]histamine synthesis after administration of L-[3H]histidine, an index of mast cell activity. The H3 receptor agonist (R)-alpha-methylhistamine (15 mg/kg, i.p.) had no effect, but administration of the H3 receptor antagonist, thioperamide (10 mg/kg, i.p.), resulted in a significant increase of [3H]histamine synthesis (+62%). This effect was reduced in neonatal capsaicin-treated rats, but not completely suppressed (+35%), very likely because of partial denervation, as assessed by monitoring calcitonin gene-related peptide immunoreactivity. It is concluded that, in the dura mater, as in peripheral tissues, sensory nerve fibers and mast cells actively synthesizing and releasing histamine form a short inhibitory feedback loop involving prejunctional H3 receptors that could regulate the release of pro-inflammatory mediators, thus limiting the extent of inflammatory reactions.

Topics: Animals; Animals, Newborn; Capsaicin; Cerebral Cortex; Chymases; Denervation; Dura Mater; Enzyme-Linked Immunosorbent Assay; Histamine; Histamine Antagonists; Inflammation; Male; Mast Cells; Methylhistamines; Nerve Fibers; Neurons, Afferent; Nippostrongylus; Piperidines; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Serine Endopeptidases; Strongylida Infections

Dispase-dissociated primary cultures of human conjunctival epithelial (HCE) cells were stimulated with histamine and the generation of inositol phosphates ([3H]IPs) from [3H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca2+]i) were studied using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. Histamine (100 microM) maximally stimulated PI turnover in HCE cells by 210 +/- 10% (n = 21) above basal levels and with a potency (EC50) of 3.3 microM (n = 4). Histamine (EC50 = 5.8 microM, n = 3) rapidly mobilized [Ca2+]i which peaked within 10 sec but which was still significantly elevated 20 min after stimulation. The histamine-induced [Ca2+]i responses did not desensitize upon repeated applications of histamine. The effects of histamine (100 microM) on PI turnover and [Ca2+]i were potently antagonized by the H1-antagonists, emedastine (IC50 = 1.6-2.9 nM), triprolidine (IC50 = 3.1 nM) and levocabastine (IC50 = 8 nM), but weakly by the H2-(ranitidine/cimetidine) and H3-(thioperamide) antagonists (IC50s = 10-100 microM). In conclusion, HCE cells have been shown to possess functional H1-histamine receptors that couple to inositol phosphates generation which then mobilize intracellular calcium. These intracellular signaling mechanisms may be intimately linked with the process of inflammatory cytokine secretion from the HCE cells after stimulation by histamine released from the conjunctival mast cells. The current results strongly suggest that the HCE cells are active participants in mediating, and perhaps amplifying, the pro-inflammatory and allergic effects of histamine which is released from conjunctival mast cells during ocular allergic and inflammatory reactions.

Topics: Benzimidazoles; Calcium; Cells, Cultured; Chromatography, Ion Exchange; Conjunctiva; Cytokines; Epithelium; Eye Diseases; Histamine; Histamine Antagonists; Humans; Hypersensitivity; Inflammation; Phosphatidylinositols; Piperidines; Receptors, Histamine H1; Stimulation, Chemical; Triprolidine

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H1, non-H2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H1 or H2 antagonists, but could be inhibited by the H3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H3 receptors. However, when the known H3 agonists were tested for activity ([R]-alpha-methylhistamine, N alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H3 receptors and this eosinophil histamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anticonvulsants; Asthma; Burimamide; Calcium; Eosinophils; Fura-2; Histamine Agonists; Histamine Antagonists; Humans; Impromidine; Inflammation; Intracellular Fluid; Mast Cells; Methylhistamines; Phosphatidylethanolamines; Piperidines; Platelet Aggregation Inhibitors; Receptors, Histamine