Platelet-Activating Factor and Pain

Tsuda, Makoto; Tozaki‐Saitoh, Hidetoshi; Inoue, Kazuhide

doi:10.1248/bpb.34.1159

Cited by 25 publications

(19 citation statements)

References 47 publications

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“…Neutrophils are activated by PAF via PAFR, which is a member of the seven‐transmembrane domain receptor family (also termed G‐protein‐coupled receptors), which participate in various second messenger systems, including those involving phospholipase A 2 , C and D activation and the MAPK cascade . By using a PAFR antagonist, we found evidence that the effects on LXRα activation induced by PAF were mediated by this receptor.…”

Section: Discussionmentioning

confidence: 94%

Platelet‐activating factor downregulates the expression of liver X receptor‐α and its target genes in human neutrophils

et al. 2014

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Liver X receptors (LXRs) are ligand-activated members of the nuclear receptor superfamily that regulate the expression of genes involved in lipid metabolism and inflammation, although their role in inflammation and immunity is less well known. It has been reported that oxysterols/LXRs may act as anti-inflammatory molecules, although opposite actions have also been reported. In this study, we investigated the effect of platelet-activating factor (PAF), a proinflammatory molecule, on LXRa signalling in human neutrophils. We found that PAF exerted an inhibitory effect on mRNA expression of TO901317-induced LXRa, ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and sterol response element binding protein 1c. This negative action was mediated by the PAF receptor, and was dependent on the release of reactive oxygen species elicited by PAF, as it was enhanced by pro-oxidant treatment and reversed by antioxidants. Current data also support the idea that PAF induces phosphorylation of the LXRa molecule in an extracellular signal-regulated kinase 1/2-mediated fashion. These results suggest that a possible mechanism by which PAF exerts its proinflammatory effect is through the downregulation of LXRa and its related genes, which supports the notion that LXRa ligands exert a modulatory role in the neutrophil-mediated inflammatory response.

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Section: Discussionmentioning

confidence: 94%

Platelet‐activating factor downregulates the expression of liver X receptor‐α and its target genes in human neutrophils

et al. 2014

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“…For instance, some studies show that local injection of PAF into peripheral tissues, such as skin, enhances pain sensitivity in animals and humans [33], thus suggesting that PAF is an important substrate in the complex biological pathways leading to the pain. In the central nervous system, it has been reported that PAF is implicated in the induction of pain behaviors.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Analysis and Modeling Suggest a Lysophosphocholines-PAF Receptor Interaction in Fibromyalgia

et al. 2014

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Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14∶0/0∶0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16∶0/0∶0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14∶0/0∶0) and PC(16∶0/0∶0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS.

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“…Liquid chromatographyselected reaction monitoring-mass spectrometry was performed with a Nexera Ultra High-Performance Liquid Chromatography (UHPLC) system and a triple quadrupole mass spectrometer (LCMS-8040; Shimadzu, Kyoto, Japan). An Acquity UPLC BEH C8 column (1.7 mm, 2.1 3 100 mm; Waters) was used with the following ternary mobile phase compositions: 5 mM NH 4…”

Section: Measurement Of Pc From Tissuesmentioning

confidence: 99%

“…Several biomolecules have been implicated in neuropathic pain, including ATP, lysophosphatidic acid, and platelet-activating factor (PAF) (1)(2)(3). Nerve injury is known to induce the expression of the P2X4 and P2Y12 receptors, brain-derived neurotrophic factor, and PAF-related genes in the spinal cord dorsal horn in association with neuropathic pain (4)(5)(6)(7)(8). Recently, Masuda et al (9) reported that microglia are also activated by ATP released from dorsal horn neurons via a vesicular nucleotide transporter.…”

mentioning

confidence: 99%

Relief from neuropathic pain by blocking of the platelet‐activating factor‐pain loop

et al. 2017

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Neuropathic pain resulting from peripheral neuronal damage is largely resistant to treatment with currently available analgesic drugs. Recently, ATP, lysophosphatidic acid, and platelet-activating factor (PAF) have been reported to play important inductive roles in neuropathic pain. In the present study, we found that pain-like behaviors resulting from partial sciatic nerve ligation (PSL) were largely attenuated by deficiency of lysophosphatidylcholine acyltransferase (LPCAT)2, which is one of the PAF biosynthetic enzymes. By contrast, deficiency of the other PAF biosynthetic enzyme, LPCAT1, did not ameliorate neuropathic pain. With regard to the mechanism of the observed effects, LPCAT2 was detected in wild-type spinal cord microglia, and the absence of LPCAT2 expression precluded spinal PAF expression in LPCAT2-knockout mice. Furthermore, ATP-stimulated PAF biosynthesis in macrophages was decreased by pretreatment with the PAF receptor antagonist ABT-491, indicating the existence of a positive feedback loop of PAF biosynthesis, which we designated the PAF–pain loop. In conclusion, LPCAT2 is a novel therapeutic target for newly categorized analgesic drugs; in addition, our data call for the re-evaluation of the clinical utility of PAF receptor antagonists.—Shindou, H., Shiraishi, S., Tokuoka, S. M., Takahashi Y., Harayama, T., Abe, T., Bando, K., Miyano, K., Kita, Y., Uezono, Y., Shimizu, T. Relief from neuropathic pain by blocking of the platelet-activating factor–pain loop.

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Platelet-Activating Factor and Pain

Cited by 25 publications

References 47 publications

Platelet‐activating factor downregulates the expression of liver X receptor‐α and its target genes in human neutrophils

Platelet‐activating factor downregulates the expression of liver X receptor‐α and its target genes in human neutrophils

Metabolomics Analysis and Modeling Suggest a Lysophosphocholines-PAF Receptor Interaction in Fibromyalgia

Relief from neuropathic pain by blocking of the platelet‐activating factor‐pain loop

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