Blog
About

10
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Human genetic studies have implicated the voltage-gated sodium channel Na V1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits Na V1.7 (IC 50 0.9 nM) with at least 40–1000-fold selectivity over all other Na V subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na V1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective Na V1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na V1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na V1.7 inhibitors can only produce analgesia when administered in combination with an opioid.

          Related collections

          Most cited references 71

          • Record: found
          • Abstract: found
          • Article: not found

          Crystallography & NMR system: A new software suite for macromolecular structure determination.

          A new software suite, called Crystallography & NMR System (CNS), has been developed for macromolecular structure determination by X-ray crystallography or solution nuclear magnetic resonance (NMR) spectroscopy. In contrast to existing structure-determination programs, the architecture of CNS is highly flexible, allowing for extension to other structure-determination methods, such as electron microscopy and solid-state NMR spectroscopy. CNS has a hierarchical structure: a high-level hypertext markup language (HTML) user interface, task-oriented user input files, module files, a symbolic structure-determination language (CNS language), and low-level source code. Each layer is accessible to the user. The novice user may just use the HTML interface, while the more advanced user may use any of the other layers. The source code will be distributed, thus source-code modification is possible. The CNS language is sufficiently powerful and flexible that many new algorithms can be easily implemented in the CNS language without changes to the source code. The CNS language allows the user to perform operations on data structures, such as structure factors, electron-density maps, and atomic properties. The power of the CNS language has been demonstrated by the implementation of a comprehensive set of crystallographic procedures for phasing, density modification and refinement. User-friendly task-oriented input files are available for nearly all aspects of macromolecular structure determination by X-ray crystallography and solution NMR.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            MolProbity: all-atom contacts and structure validation for proteins and nucleic acids

            MolProbity is a general-purpose web server offering quality validation for 3D structures of proteins, nucleic acids and complexes. It provides detailed all-atom contact analysis of any steric problems within the molecules as well as updated dihedral-angle diagnostics, and it can calculate and display the H-bond and van der Waals contacts in the interfaces between components. An integral step in the process is the addition and full optimization of all hydrogen atoms, both polar and nonpolar. New analysis functions have been added for RNA, for interfaces, and for NMR ensembles. Additionally, both the web site and major component programs have been rewritten to improve speed, convenience, clarity and integration with other resources. MolProbity results are reported in multiple forms: as overall numeric scores, as lists or charts of local problems, as downloadable PDB and graphics files, and most notably as informative, manipulable 3D kinemage graphics shown online in the KiNG viewer. This service is available free to all users at http://molprobity.biochem.duke.edu.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Quantitative assessment of tactile allodynia in the rat paw.

               J Pogrel,  F. Bach,  T L Yaksh (1994)
              We applied and validated a quantitative allodynia assessment technique, using a recently developed rat surgical neuropathy model wherein nocifensive behaviors are evoked by light touch to the paw. Employing von Frey hairs from 0.41 to 15.1 g, we first characterized the percent response at each stimulus intensity. A smooth log-linear relationship was observed, with a median 50% threshold at 1.97 g (95% confidence limits, 1.12-3.57 g). Subsequently, we applied a paradigm using stimulus oscillation around the response threshold, which allowed more rapid, efficient measurements. Median 50% threshold by this up-down method was 2.4 g (1.81-2.76). Correlation coefficient between the two methods was 0.91. In neuropathic rats, good intra- and inter-observer reproducibility was found for the up-down paradigm; some variability was seen in normal rats, attributable to extensive testing. Thresholds in a sizable group of neuropathic rats showed insignificant variability over 20 days. After 50 days, 61% still met strict neuropathy criteria, using survival analysis. Threshold measurement using the up-down paradigm, in combination with the neuropathic pain model, represents a powerful tool for analyzing the effects of manipulations of the neuropathic pain state.
                Bookmark

                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                20 January 2017
                2017
                : 7
                Affiliations
                [1 ]IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia , Queensland, 4072, Australia
                [2 ]Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney , New South Wales, 2006, Australia
                [3 ]School of Biomedical Sciences, The University of Queensland, St Lucia , Queensland, 4072, Australia
                [4 ]Department of Physiology & Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine , Baltimore, MD 21205, USA
                [5 ]Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System , West Haven, Connecticut 06516, USA
                [6 ]Venomtech, Sophie-Antipolis , 06560, Valbonne, France
                [7 ]Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London , London WC1E 6BT, UK
                [8 ]School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba , Queensland, 4102, Australia
                srep40883
                10.1038/srep40883
                5247677
                28106092
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                Categories
                Article

                Uncategorized

                Comments

                Comment on this article