34 research outputs found

    Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

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    The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species. © 2012 Neely et al

    The Effects of Percutaneous Coronary Intervention on the Flow in Acute Coronary Syndrome Patients—Geometry in Focus

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    Evaluation of the effect of three dimensional (3D) coronary plaque characteristics derived from two dimensional (2D) invasive angiography images (ICA) on coronary flow determined by TIMI frame count (TFC) in acute coronary syndrome (ACS) has not been thoroughly investigated. A total of 71 patients with STEMI, and 73 with NSTEMI were enrolled after primary angioplasty. Pre- and post-PCI TFCs were obtained. From 2D images, 3D reconstruction was performed of the culprit vessel, and multiple plaque parameters were measured. In STEMI, the average post-PCI frame count decreased significantly, resulting in better flow. With regards to 2/3D parameters, no differences were found between the STEMI and NSTEMI groups. The 3D parameters in the subgroup with an increase with at least three frames resulting in worsening post-PCI flow were compared to parameters of the patients with improved or significantly not change flow (delta frame count < 3), and greater minimal luminal diameter and area was found in the worsening (increased) frame group. In STEMI 2/3D, parameters showed no correlation with worsening flow, whereas in NSTEMI, greater minimal luminal diameter and area correlated with decreased flow. We can conclude that certain 2/3D parameters can predict slower flow in ACS, resulting in the use of GP IIb/IIIa receptor blocker

    The inheritance of corneal endothelial cell density

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    BACKGROUND: Although it is known that some corneal diseases and degenerations have a significant heritable background, heritability on corneal endothelial cell density (ECD) has never been clearly determined. Our aim was to determine the heritability of corneal ECD. MATERIAL AND METHODS: Corneal ECD of 114 eyes (66 eyes of 33 monozygotic and 48 eyes of 24 dizygotic pairs; mean age 49.0 +/- 15.5 years) was investigated by Konan Noncon Robo NSP-9900 specular microscopy. Structural equation modeling (ACE model) was applied. RESULTS: Endothelial corneal cell density was highly heritable (82.0%, 95%CI, 70.0-92.0%), whereas the unique environmental contribution was 18.0% (95%CI, 8.0-29.0%). Shared environmental factors had no influence on the endothelial corneal cell density. DISCUSSION: In this twin study, we established first that the density of the corneal endothelial cells is strongly heritable, which should stimulate future genetic studies to identify genes and pathways that are involved in determining ECD which might in turn lead to future treatments to prevent EC loss

    Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain

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    Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB(2) receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-deficient mice showed neuronal and astrocytic IFN-gamma immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-gamma in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.This work was supported by grants from the National Institute on Drug Abuse (1R01-DA016768-0111) (R.M.,A.Z.), European Commission [Framework VI, GENADDICT OJ 2004/C164, 005166 (R.M., A.Z.); PHECOM, LSHM-CT-2007-037669 (R.M.)], Ministerio de Educación y Ciencia (BFU2004-00920/BFI; SAF2007-64062) (R.M.), Generalitat de Catalunya (R.M.), Deutsche Forschungsgemeinschaft (SFB645; FOR926) (A.Z.), and Bundesministerium für Bildung und Forschung (NGFN2) (A.Z.