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A non‐convulsant delta‐opioid receptor agonist, KNT‐127, reduces cortical spreading depression and nitroglycerin‐induced allodynia.

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Title: A non‐convulsant delta‐opioid receptor agonist, KNT‐127, reduces cortical spreading depression and nitroglycerin‐induced allodynia.
Authors: Bertels, Zachariah, Witkowski, Wiktor D., Asif, Sarah, Siegersma, Kendra, Rijn, Richard M., Pradhan, Amynah A.
Source: Headache: The Journal of Head & Face Pain. Jan2021, Vol. 61 Issue 1, p170-178. 9p.
Subjects: Migraine prevention, Allodynia, Animal experimentation, Cell receptors, Cerebral cortex, Evoked potentials (Electrophysiology), Mice, Nitroglycerin
Abstract: Objective: The aim of this study was to determine if the non‐convulsant delta‐opioid receptor (DOR) agonist, KNT‐127, could inhibit migraine‐associated endpoints. Background: The DOR has been identified as a therapeutic target for migraine. However, the development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro‐ and non‐convulsant delta agonists can reduce migraine‐associated allodynia, only the proconvulsant agonist, SNC80, has been shown to decrease cortical spreading depression (CSD). It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce proconvulsant effects. Methods: The effects of the non‐convulsant delta agonist, KNT‐127, were examined. Repetitive CSD was induced in female C57BL6/J (n = 6/group) mice by continuous application of KCl and the effect of KNT‐127/vehicle (Veh) on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT‐127 on established chronic migraine‐associated pain, male and female C57BL6/J mice were treated with nitroglycerin (NTG; 10 mg/kg, ip) every other day for 9 days and tested with KNT‐127 (5 mg/kg, sc) or Veh on day 10 (n = 6/group). DOR‐enhanced green fluorescent protein mice (n = 4/group) were used to confirm the internalization properties of KNT‐127 in the trigeminal ganglia, trigeminal nucleus caudalis, and somatosensory cortex. Results: KNT‐127 inhibited CSD events (t(10) = 3.570, p = 0.0051). In addition, this delta agonist also reversed established cephalic allodynia in the NTG model of chronic migraine (F(1, 20) = 12.80, p < 0.01). Furthermore, KNT‐127 caused limited internalization of DOR in key migraine processing regions. Conclusions: This study shows that the antimigraine effects of DOR agonists can be separated from their proconvulsant effects. This data provides valuable information for the continued development of delta agonists for the treatment of migraine. [ABSTRACT FROM AUTHOR]
Copyright of Headache: The Journal of Head & Face Pain is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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Header DbId: pbh
DbLabel: Psychology and Behavioral Sciences Collection
An: 148337290
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PubTypeId: academicJournal
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  Label: Title
  Group: Ti
  Data: A non‐convulsant delta‐opioid receptor agonist, KNT‐127, reduces cortical spreading depression and nitroglycerin‐induced allodynia.
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  Data: &lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Bertels%2C+Zachariah%22&quot;&gt;Bertels, Zachariah&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Witkowski%2C+Wiktor+D%2E%22&quot;&gt;Witkowski, Wiktor D.&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Asif%2C+Sarah%22&quot;&gt;Asif, Sarah&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Siegersma%2C+Kendra%22&quot;&gt;Siegersma, Kendra&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Rijn%2C+Richard+M%2E%22&quot;&gt;Rijn, Richard M.&lt;/searchLink&gt;&lt;br /&gt;&lt;searchLink fieldCode=&quot;AR&quot; term=&quot;%22Pradhan%2C+Amynah+A%2E%22&quot;&gt;Pradhan, Amynah A.&lt;/searchLink&gt;
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22Headache%3A+The+Journal+of+Head+%26+Face+Pain%22&quot;&gt;Headache: The Journal of Head &amp; Face Pain&lt;/searchLink&gt;. Jan2021, Vol. 61 Issue 1, p170-178. 9p.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: The aim of this study was to determine if the non‐convulsant delta‐opioid receptor (DOR) agonist, KNT‐127, could inhibit migraine‐associated endpoints. Background: The DOR has been identified as a therapeutic target for migraine. However, the development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro‐ and non‐convulsant delta agonists can reduce migraine‐associated allodynia, only the proconvulsant agonist, SNC80, has been shown to decrease cortical spreading depression (CSD). It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce proconvulsant effects. Methods: The effects of the non‐convulsant delta agonist, KNT‐127, were examined. Repetitive CSD was induced in female C57BL6/J (n = 6/group) mice by continuous application of KCl and the effect of KNT‐127/vehicle (Veh) on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT‐127 on established chronic migraine‐associated pain, male and female C57BL6/J mice were treated with nitroglycerin (NTG; 10 mg/kg, ip) every other day for 9 days and tested with KNT‐127 (5 mg/kg, sc) or Veh on day 10 (n = 6/group). DOR‐enhanced green fluorescent protein mice (n = 4/group) were used to confirm the internalization properties of KNT‐127 in the trigeminal ganglia, trigeminal nucleus caudalis, and somatosensory cortex. Results: KNT‐127 inhibited CSD events (t(10) = 3.570, p = 0.0051). In addition, this delta agonist also reversed established cephalic allodynia in the NTG model of chronic migraine (F(1, 20) = 12.80, p &lt; 0.01). Furthermore, KNT‐127 caused limited internalization of DOR in key migraine processing regions. Conclusions: This study shows that the antimigraine effects of DOR agonists can be separated from their proconvulsant effects. This data provides valuable information for the continued development of delta agonists for the treatment of migraine. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: &lt;i&gt;Copyright of Headache: The Journal of Head &amp; Face Pain is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=148337290
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1111/head.14019
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 9
        StartPage: 170
    Subjects:
      – SubjectFull: Migraine prevention
        Type: general
      – SubjectFull: Allodynia
        Type: general
      – SubjectFull: Animal experimentation
        Type: general
      – SubjectFull: Cell receptors
        Type: general
      – SubjectFull: Cerebral cortex
        Type: general
      – SubjectFull: Evoked potentials (Electrophysiology)
        Type: general
      – SubjectFull: Mice
        Type: general
      – SubjectFull: Nitroglycerin
        Type: general
    Titles:
      – TitleFull: A non‐convulsant delta‐opioid receptor agonist, KNT‐127, reduces cortical spreading depression and nitroglycerin‐induced allodynia.
        Type: main
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            NameFull: Bertels, Zachariah
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            NameFull: Witkowski, Wiktor D.
      – PersonEntity:
          Name:
            NameFull: Asif, Sarah
      – PersonEntity:
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            NameFull: Siegersma, Kendra
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            NameFull: Rijn, Richard M.
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            NameFull: Pradhan, Amynah A.
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              M: 01
              Text: Jan2021
              Type: published
              Y: 2021
          Identifiers:
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              Value: 00178748
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              Value: 61
            – Type: issue
              Value: 1
          Titles:
            – TitleFull: Headache: The Journal of Head & Face Pain
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