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Increased Nociceptive Responses in Streptozotocin-Induced Diabetic Rats and the Related Expression of Spinal NR2B Subunit of N-Methyl-D-Aspartate Receptors
Che Aishah Nazariah Ismail, Rapeah Suppian, Che Badariah Abd Aziz, Khalilah Haris, Idris Long
Diabetes Metab J. 2019;43(2):222-235.   Published online November 19, 2018
DOI: https://doi.org/10.4093/dmj.2018.0020
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  • 14 Web of Science
  • 14 Crossref
AbstractAbstract PDFPubReader   
Background

This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli.

Methods

Thirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 µg/day) (I 0.5) or higher dose (1.0 µg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed.

Results

DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B.

Conclusion

We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.

Citations

Citations to this article as recorded by  
  • Painful diabetic neuropathy: The role of ion channels
    Qi Wang, Yifei Ye, Linghui Yang, Lifan Xiao, Jin Liu, Wensheng Zhang, Guizhi Du
    Biomedicine & Pharmacotherapy.2024; 173: 116417.     CrossRef
  • Enantiomerically Pure Indazole Bioisosteres of Ifenprodil and Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors with the GluN2B Subunit
    Judith Lüken, Gunnar Goerges, Julian A. Schreiber, Judith Schmidt, Bastian Frehland, Dirk Schepmann, Guiscard Seebohm, Bernhard Wünsch
    Journal of Medicinal Chemistry.2024; 67(21): 19678.     CrossRef
  • Therapeutic potential of progesterone in spinal cord injury‐induced neuropathic pain: At the crossroads between neuroinflammation and N‐methyl‐D‐aspartate receptor
    Sol Ferreyra, Susana González
    Journal of Neuroendocrinology.2023;[Epub]     CrossRef
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    Biological Chemistry.2023; 404(4): 279.     CrossRef
  • Mechanisms of Transmission and Processing of Pain: A Narrative Review
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    International Journal of Environmental Research and Public Health.2023; 20(4): 3064.     CrossRef
  • Indazole as a Phenol Bioisostere: Structure–Affinity Relationships of GluN2B-Selective NMDA Receptor Antagonists
    Judith Lüken, Gunnar Goerges, Nadine Ritter, Paul Disse, Julian A. Schreiber, Judith Schmidt, Bastian Frehland, Dirk Schepmann, Guiscard Seebohm, Bernhard Wünsch
    Journal of Medicinal Chemistry.2023; 66(16): 11573.     CrossRef
  • Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators
    Alexander Markus, Dirk Schepmann, Bernhard Wünsch
    Archiv der Pharmazie.2022;[Epub]     CrossRef
  • Phenol—Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B‐selective N‐methyl‐d‐aspartate receptor antagonists
    Alexander Markus, Julian A. Schreiber, Gunnar Goerges, Bastian Frehland, Guiscard Seebohm, Dirk Schepmann, Bernhard Wünsch
    Archiv der Pharmazie.2022;[Epub]     CrossRef
  • Ifenprodil Reduced Expression of Activated Microglia, BDNF and DREAM Proteins in the Spinal Cord Following Formalin Injection During the Early Stage of Painful Diabetic Neuropathy in Rats
    Che Aishah Nazariah Ismail, Rapeah Suppian, Che Badariah Ab Aziz, Idris Long
    Journal of Molecular Neuroscience.2021; 71(2): 379.     CrossRef
  • Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity
    Elena Bechthold, Julian A. Schreiber, Kirstin Lehmkuhl, Bastian Frehland, Dirk Schepmann, Freddy A. Bernal, Constantin Daniliuc, Inés Álvarez, Cristina Val Garcia, Thomas J. Schmidt, Guiscard Seebohm, Bernhard Wünsch
    Journal of Medicinal Chemistry.2021; 64(2): 1170.     CrossRef
  • The anti-diabetic effects of betanin in streptozotocin-induced diabetic rats through modulating AMPK/SIRT1/NF-κB signaling pathway
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    Nutrition & Metabolism.2021;[Epub]     CrossRef
  • Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms?
    Nigel A. Calcutt
    Pain.2020; 161(Supplement): S65.     CrossRef
  • N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy
    Serena Notartomaso, Pamela Scarselli, Giada Mascio, Francesca Liberatore, Emanuela Mazzon, Santa Mammana, Agnese Gugliandolo, Giorgio Cruccu, Valeria Bruno, Ferdinando Nicoletti, Giuseppe Battaglia
    Molecular Pain.2020;[Epub]     CrossRef
  • Effect of aerobic exercise on innate immune responses and inflammatory mediators in the spinal cord of diabetic rats
    A. Kaki, M. Nikbakht, A.H. Habibi, H.F. Moghadam
    Comparative Exercise Physiology.2020; 16(4): 293.     CrossRef

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