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
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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].
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.059790.
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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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