Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

2012 ◽  
Vol 92 (4) ◽  
pp. 1699-1775 ◽  
Author(s):  
Gábor Pethő ◽  
Peter W. Reeh
Keyword(s):  
Nitric Oxide ◽  
Sensory Neurons ◽  
Intracellular Signaling ◽  
Platelet Activating Factor ◽  
Nerve Endings ◽  
Behavioral Models ◽  
Cellular Models ◽  
Signaling Mechanisms ◽  
The Central Nervous System

Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs.

scholarly journals Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling?

2017 ◽  
Vol 312 (4) ◽  
pp. H854-H866 ◽  
Author(s):  
Jaimit Parikh ◽  
Adam Kapela ◽  
Nikolaos M. Tsoukias
Keyword(s):  
Mathematical Modeling ◽  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cellular Models ◽  
No Signaling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We used mathematical modeling to investigate nitric oxide (NO)-dependent vasodilatory signaling in the arteriolar wall. Detailed continuum cellular models of calcium (Ca2+) dynamics and membrane electrophysiology in smooth muscle and endothelial cells (EC) were coupled with models of NO signaling and biotransport in an arteriole. We used this theoretical approach to examine the role of endothelial hemoglobin-α (Hbα) as a modulator of NO-mediated myoendothelial feedback, as previously suggested in Straub et al. ( Nature 491: 473–477, 2012). The model considers enriched expression of inositol 1,4,5-triphosphate receptors (IP3Rs), endothelial nitric oxide synthase (eNOS) enzyme, Ca2+-activated potassium (KCa) channels and Hbα in myoendothelial projections (MPs) between the two cell layers. The model suggests that NO-mediated myoendothelial feedback is plausible if a significant percentage of eNOS is localized within or near the myoendothelial projection. Model results show that the ability of Hbα to regulate the myoendothelial feedback is conditional to its colocalization with eNOS near MPs at concentrations in the high nanomolar range (>0.2 μM or 24,000 molecules). Simulations also show that the effect of Hbα observed in in vitro experimental studies may overestimate its contribution in vivo, in the presence of blood perfusion. Thus, additional experimentation is required to quantify the presence and spatial distribution of Hbα in the EC, as well as to test that the strong effect of Hbα on NO signaling seen in vitro, translates also into a physiologically relevant response in vivo. NEW & NOTEWORTHY Mathematical modeling shows that although regulation of nitric oxide signaling by hemoglobin-α (Hbα) is plausible, it is conditional to its presence in significant concentrations colocalized with endothelial nitric oxide synthase in myoendothelial projections. Additional experimentation is required to test that the strong effect of Hbα seen in vitro translates into a physiologically relevant response in vivo

scholarly journals LysoPC and PAF Trigger Arachidonic Acid Release by Divergent Signaling Mechanisms in Monocytes

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Janne Oestvang ◽  
Marit W. Anthonsen ◽  
Berit Johansen
Keyword(s):  
Intracellular Signaling ◽  
Platelet Activating Factor ◽  
Low Density Lipoproteins ◽  
Intracellular Signaling Pathway ◽  
Signaling Mechanisms ◽  
Paf Receptor ◽  
Sequential Activation ◽  
Acid Release ◽  
Atherosclerosis Prevention ◽  
Macrophage Accumulation

Oxidized low-density lipoproteins (LDLs) play an important role during the development of atherosclerosis characterized by intimal inflammation and macrophage accumulation. A key component of LDL is lysophosphatidylcholine (lysoPC). LysoPC is a strong proinflammatory mediator, and its mechanism is uncertain, but it has been suggested to be mediated via the platelet activating factor (PAF) receptor. Here, we report that PAF triggers a pertussis toxin- (PTX-) sensitive intracellular signaling pathway leading to sequential activation of sPLA2, PLD, cPLA2, and AA release in human-derived monocytes. In contrast, lysoPC initiates two signaling pathways, one sequentially activating PLD and cPLA2, and a second parallel PTX-sensitive pathway activating cPLA2with concomitant activation of sPLA2, all leading to AA release. In conclusion, lysoPC and PAF stimulate AA release by divergent pathways suggesting involvement of independent receptors. Elucidation of monocyte lysoPC-specific signaling mechanisms will aid in the development of novel strategies for atherosclerosis prevention, diagnosis, and therapy.

scholarly journals S-nitrosylation regulates VE-cadherin phosphorylation and internalization in microvascular permeability

2016 ◽  
Vol 310 (8) ◽  
pp. H1039-H1044 ◽  
Author(s):  
Anita Guequén ◽  
Rodrigo Carrasco ◽  
Patricia Zamorano ◽  
Lorena Rebolledo ◽  
Pia Burboa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Activating Factor ◽  
Adherens Junction ◽  
Endothelial Barrier ◽  
Main Element ◽  
Nitric Oxide Production ◽  
Vascular Endothelial ◽  
Junctional Proteins

The adherens junction complex, composed mainly of vascular endothelial (VE)-cadherin, β-catenin, p120, and γ-catenin, is the main element of the endothelial barrier in postcapillary venules. S-nitrosylation of β-catenin and p120 is an important step in proinflammatory agents-induced hyperpermeability. We investigated in vitro and in vivo whether or not VE-cadherin is S-nitrosylated using platelet-activating factor (PAF) as agonist. We report that PAF-stimulates S-nitrosylation of VE-cadherin, which disrupts its association with β-catenin. In addition, based on inhibition of nitric oxide production, our results strongly suggest that S-nitrosylation is required for VE-cadherin phosphorylation on tyrosine and for its internalization. Our results unveil an important mechanism to regulate phosphorylation of junctional proteins in association with S-nitrosylation.

scholarly journals The H2S Donor GYY4137 Stimulates Reactive Oxygen Species Generation in BV2 Cells While Suppressing the Secretion of TNF and Nitric Oxide

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2966 ◽  
Author(s):  
Milica Lazarević ◽  
Emanuela Mazzon ◽  
Miljana Momčilović ◽  
Maria Basile ◽  
Giuseppe Colletti ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Microglial Cells ◽  
Oxygen Species ◽  
Bv2 Cells ◽  
The Central Nervous System

GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti-inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 μM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H2S donor, Na2S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted.

Excess nitric oxide does not cause cellular, vascular, or mucosal dysfunction in the cat small intestine

1995 ◽  
Vol 269 (1) ◽  
pp. G34-G41 ◽  
Author(s):  
P. Kubes ◽  
P. H. Reinhardt ◽  
D. Payne ◽  
R. C. Woodman
Keyword(s):  
Nitric Oxide ◽  
Cell Injury ◽  
Venous Pressure ◽  
Platelet Activating Factor ◽  
Cell Permeability ◽  
Mucosal Barrier ◽  
Barrier Dysfunction ◽  
Mucosal Permeability

The overproduction of nitric oxide in the small bowel has been invoked as a cytotoxic event in the vascular, mucosal, and whole organ dysfunction associated with inflammation. We assessed whether exogenous administration of nitric oxide in the form of nitric oxide donors (CAS 754, SIN-1) could cause microvascular and mucosal barrier dysfunction in vivo or epithelial and endothelial cell permeability alterations and cell injury in vitro. Increasing concentrations of CAS 754 or SIN-1 were infused locally into autoperfused segments of cat ileum at 30-min intervals. Baseline epithelial permeability (blood-to-lumen clearance of 51Cr-EDTA) was not affected by CAS 754, whereas vascular protein clearance was reduced. The latter effect could almost entirely be explained by a decrease in intestinal capillary hydrostatic pressure. Therefore, in some experiments venous pressure was elevated and the microvascular reflection coefficient for total proteins was estimated at filtration-independent rates. This direct measurement of microvascular permeability was unaffected by exogenous nitric oxide. CAS 754 did not increase permeability across monolayers of endothelial or epithelial cells and did not cause cell injury. Next, we assessed the possibility that excess nitric oxide may be detrimental, but only in inflamed intestine, by infusing CAS 754 with platelet-activating factor; the latter directly increases microvascular and mucosal permeability. CAS 754 did not exacerbate but rather reduced platelet-activating factor-induced rise in microvascular and mucosal permeability. These results suggest that high concentrations of nitric oxide do not cause breakdown of mucosal or microvascular barrier integrity under normal or inflammatory conditions.

Atrial natriuretic factor stimulates exocrine pancreatic secretion in the rat through NPR-C receptors

2003 ◽  
Vol 285 (5) ◽  
pp. G929-G937 ◽  
Author(s):  
María E. Sabbatini ◽  
Alberto Villagra ◽  
Carlos A. Davio ◽  
Marcelo S. Vatta ◽  
Belisario E. Fernández ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pancreatic Secretion ◽  
Intracellular Signaling ◽  
Atrial Natriuretic Factor ◽  
Adrenergic Blockade ◽  
Exocrine Pancreatic Secretion ◽  
Pancreatic Acini ◽  
Natriuretic Factor ◽  
Atrial Natriuretic

Increasing evidence supports the role of atrial natriuretic factor (ANF) in the modulation of gastrointestinal physiology. The effect of ANF on exocrine pancreatic secretion and the possible receptors and pathways involved were studied in vivo. Anesthetized rats were prepared with pancreatic duct cannulation, pyloric ligation, and bile diversion into the duodenum. ANF dose-dependently increased pancreatic secretion of fluid and proteins and enhanced secretin and CCK-evoked response. ANF decreased chloride secretion and increased the pH of the pancreatic juice. Neither cholinergic nor adrenergic blockade affected ANF-stimulated pancreatic secretion. Furthermore, ANF response was not mediated by the release of nitric oxide. ANF-evoked protein secretion was not inhibited by truncal vagotomy, atropine, or Nω-nitro-l-arginine methyl ester administration. The selective natriuretic peptide receptor-C (NPR-C) receptor agonist cANP-(4–23) mimicked ANF response in a dose-dependent fashion. When the intracellular signaling coupled to NPR-C receptors was investigated in isolated pancreatic acini, results showed that ANF did not modify basal or forskolin-evoked cAMP formation, but it dose-dependently enhanced phosphoinositide hydrolysis, which was blocked by the selective PLC inhibitor U-73122. ANF stimulated exocrine pancreatic secretion in the rat, and its effect was not mediated by nitric oxide or parasympathetic or sympathetic activity. Furthermore, CCK and secretin appear not to be involved in ANF response. Present findings support that ANF exerts a stimulatory effect on pancreatic exocrine secretion mediated by NPR-C receptors coupled to the phosphoinositide pathway.

scholarly journals Differential Glycosylation of Tractin and LeechCAM, Two Novel Ig Superfamily Members, Regulates Neurite Extension and Fascicle Formation

1997 ◽  
Vol 138 (1) ◽  
pp. 143-157 ◽  
Author(s):  
Yueqiao Huang ◽  
John Jellies ◽  
Kristen M. Johansen ◽  
Jørgen Johansen
Keyword(s):  
Central Nervous System ◽  
Extracellular Matrix ◽  
Nervous System ◽  
Sensory Neurons ◽  
Immunoaffinity Purification ◽  
Repeat Domain ◽  
Ig Superfamily ◽  
The Central Nervous System ◽  
Peripheral Sensory

By immunoaffinity purification with the mAb Lan3-2, we have identified two novel Ig superfamily members, Tractin and LeechCAM. LeechCAM is an NCAM/FasII/ApCAM homologue, whereas Tractin is a cleaved protein with several unique features that include a PG/YG repeat domain that may be part of or interact with the extracellular matrix. Tractin and LeechCAM are widely expressed neural proteins that are differentially glycosylated in sets and subsets of peripheral sensory neurons that form specific fascicles in the central nervous system. In vivo antibody perturbation of the Lan3-2 glycoepitope demonstrates that it can selectively regulate extension of neurites and filopodia. Thus, these experiments provide evidence that differential glycosylation can confer functional diversity and specificity to widely expressed neural proteins.

Neurodegeneration in models of Gram-positive bacterial infections of the central nervous system

2007 ◽  
Vol 35 (5) ◽  
pp. 1166-1167 ◽  
Author(s):  
J.J. Neher ◽  
G.C. Brown
Keyword(s):  
Nitric Oxide ◽  
Central Nervous System ◽  
Nervous System ◽  
Bacterial Infections ◽  
Muramyl Dipeptide ◽  
Nuclear Factor Κb ◽  
Gram Positive ◽  
The Central Nervous System

Gram-positive bacterial infections of the central nervous system, such as meningitis, induce an extensive inflammatory response, which in turn may damage neurons. LTA (lipoteichoic acid) is a component of the Gram-positive bacterial cell wall that induces glial inflammatory activation in vitro and in vivo. It does so by binding to Toll-like receptor-2 on microglia and astrocytes, rapidly activating ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPKs (mitogen-activated protein kinases), causing NF-κB (nuclear factor κB) activation and leading to the production of pro-inflammatory cytokines and expression of inducible nitric oxide synthase (in synergy with muramyl dipeptide). LTA-activated microglia kill co-cultured neurons apparently via nitric oxide, superoxide and peroxynitrite, which may induce apoptosis of neurons that are then phagocytosed by microglia.

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