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Research ArticleArticle

κ-Opioid Receptor Inhibition of Calcium Oscillations in Spinal Cord Neurons

Lakshmi Kelamangalath, Shashank M. Dravid, Joju George, Jane V. Aldrich and Thomas F. Murray
Molecular Pharmacology June 2011, 79 (6) 1061-1071; DOI: https://doi.org/10.1124/mol.111.071456
Lakshmi Kelamangalath
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Shashank M. Dravid
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Joju George
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Jane V. Aldrich
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Thomas F. Murray
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Abstract

Mouse embryonic spinal cord neurons in culture exhibit spontaneous calcium oscillations from day in vitro (DIV) 6 through DIV 10. Such spontaneous activity in developing spinal cord contributes to maturation of synapses and development of pattern-generating circuits. Here we demonstrate that these calcium oscillations are regulated by κ opioid receptors (KORs). The κ opioid agonist dynorphin (Dyn)-A (1–13) suppressed calcium oscillations in a concentration-dependent manner, and both the nonselective opioid antagonist naloxone and the κ-selective blocker norbinaltorphimine eliminated this effect. The KOR-selective agonist (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69593) mimicked the effect of Dyn-A (1–13) on calcium oscillations. A κ-specific peptide antagonist, zyklophin, was also able to prevent the suppression of calcium oscillations caused by Dyn-A (1–13). These spontaneous calcium oscillations were blocked by 1 μM tetrodotoxin, indicating that they are action potential-dependent. Although the L-type voltage-gated calcium channel blocker nifedipine did not suppress calcium oscillations, the N-type calcium channel blocker ω-conotoxin inhibited this spontaneous response. Blockers of ionotropic glutamate receptors, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline and dizocilpine maleate (MK-801), also suppressed calcium oscillations, revealing a dependence on glutamate-mediated signaling. Finally, we have demonstrated expression of KORs in glutamatergic spinal neurons and localization in a presynaptic compartment, consistent with previous reports of KOR-mediated inhibition of glutamate release. The KOR-mediated inhibition of spontaneous calcium oscillations may therefore be a consequence of presynaptic inhibition of glutamate release.

Footnotes

  • This work was supported by National Institutes of Health National Institute on Drug Abuse [Grant R01-DA023924].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071456.

  • ABBREVIATIONS:

    CNS
    central nervous system
    KOR
    κ opioid receptors
    DIV
    day(s) in vitro
    nor-BNI
    norbinaltorphimine
    DAMGO
    [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    NMDA
    N-methyl d-aspartate
    AM
    acetoxymethyl ester
    PSD
    postsynaptic density
    NBQX
    2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione
    MK-801
    (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d] cyclohepten-5,10-imine hydrogen (dizocilpine) maleate
    Dyn
    dynorphin
    U69593
    (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide
    TBST
    Tris-buffered saline-Tween 20
    PBS
    phosphate-buffered saline
    Cy-3
    cyanine 3
    TTX
    tetrodotoxin
    CI
    confidence interval.

  • Received January 26, 2011.
  • Accepted March 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

κ-Opioid Receptor Inhibition of Calcium Oscillations in Spinal Cord Neurons

Lakshmi Kelamangalath, Shashank M. Dravid, Joju George, Jane V. Aldrich and Thomas F. Murray
Molecular Pharmacology June 1, 2011, 79 (6) 1061-1071; DOI: https://doi.org/10.1124/mol.111.071456

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Research ArticleArticle

κ-Opioid Receptor Inhibition of Calcium Oscillations in Spinal Cord Neurons

Lakshmi Kelamangalath, Shashank M. Dravid, Joju George, Jane V. Aldrich and Thomas F. Murray
Molecular Pharmacology June 1, 2011, 79 (6) 1061-1071; DOI: https://doi.org/10.1124/mol.111.071456
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