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Molecular Pharmacology

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Research ArticleArticle

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Ana Campillo, Ana González-Cuello, David Cabañero, Paula Garcia-Nogales, Asunción Romero, M. Victoria Milanés, M. Luisa Laorden and Margarita M. Puig
Molecular Pharmacology February 2010, 77 (2) 185-194; DOI: https://doi.org/10.1124/mol.109.059790
Ana Campillo
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Ana González-Cuello
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David Cabañero
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Paula Garcia-Nogales
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Asunción Romero
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M. Victoria Milanés
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M. Luisa Laorden
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Margarita M. Puig
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Abstract

In humans, remifentanil anesthesia enhances nociceptive sensitization in the postoperative period. We hypothesized that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the expression of c-Fos, prodynorphin (mRNA), and dynorphin in the spinal cord could participate in the molecular mechanisms underlying postoperative opioid-induced sensitization. In a mouse model of incisional pain, we evaluated thermal (Hargreaves test) and mechanical (von Frey) hyperalgesia during the first 21 postoperative days. Moreover, prodynorphin (mRNA, real-time polymerase chain reaction), dynorphin (enzymatic immunoassay), c-Fos expression, and ERK1/2 phosphorylation (both by immunohistochemistry) in the lumbar spinal cord were assessed. Surgery performed under remifentanil anesthesia induced a maximal decrease in nociceptive thresholds between 4 h and 2 days postoperatively (p < 0.001) that lasted 10 to 14 days compared with noninjured animals. In the same experimental conditions, a significant increase in prodynorphin mRNA expression (at 2 and 4 days) followed by a sustained increase of dynorphin (days 2 to 10) in the spinal cord was observed. We also identified an early expression of c-Fos immunoreactivity in the superficial laminae of the dorsal horn of the spinal cord (peak at 4 h; p < 0.001), together with a partial activation of ERK1/2 (4 h; p < 0.001). These findings suggest that activated ERK1/2 could induce c-Fos expression and trigger the transcription of prodynorphin in the spinal cord. This in turn would result in long-lasting increased levels of dynorphin that, in our model, could participate in the persistence of pain but not in the manifestation of first pain.

Footnotes

  • This work was supported by grants from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Madrid, Spain [Grants PI030245 and PI060669]; Marató de Televisió de Catalunya, TV3 [Grant 071110], the Endowed Chair in Pain Management Universitat Autònoma de Barcelona-Institut Municipal d'Assitència Sanitària-MENARINI; and a Predoctoral Fellowship from the Spanish Ministry of Education [Grant AP2006-4718].

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

    doi:10.1124/mol.109.059790.

  • ABBREVIATIONS:

    NMDA
    N-methyl-d-aspartate
    AAC
    area above the curve
    CREB
    cAMP-responsive element binding protein
    ERK1/2
    extracellular signal-regulated kinases 1 and 2
    L4–L6
    lumbar spinal cord segments 4 and 6
    MAPK
    mitogen-activated protein kinase
    PBS
    phosphate-buffered saline
    RT-PCR
    reverse transcription-polymerase chain reaction.

  • Received July 24, 2009.
  • Accepted November 16, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Ana Campillo, Ana González-Cuello, David Cabañero, Paula Garcia-Nogales, Asunción Romero, M. Victoria Milanés, M. Luisa Laorden and Margarita M. Puig
Molecular Pharmacology February 1, 2010, 77 (2) 185-194; DOI: https://doi.org/10.1124/mol.109.059790

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Research ArticleArticle

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Ana Campillo, Ana González-Cuello, David Cabañero, Paula Garcia-Nogales, Asunción Romero, M. Victoria Milanés, M. Luisa Laorden and Margarita M. Puig
Molecular Pharmacology February 1, 2010, 77 (2) 185-194; DOI: https://doi.org/10.1124/mol.109.059790
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