Increased spinal dynorphin levels and phospho-extracellular signal-regulated kinases 1 and 2 and c-Fos immunoreactivity after surgery under remifentanil anesthesia in mice.
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.
Campillo
Ana
A
Department of Anesthesiology, Hospital Universitari del Mar, Universitat Autònoma de Barcelona, Passeig Marítim 25-29, E-08003 Barcelona, Spain.
González-Cuello
Ana
A
Cabañero
David
D
Garcia-Nogales
Paula
P
Romero
Asunción
A
Milanés
M Victoria
MV
Laorden
M Luisa
ML
Puig
Margarita M
MM
D018686:Anesthetics, Intravenous / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004399:Dynorphins / Q000096:biosynthesis*; D016762:Genes, fos / Q000502:physiology*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010149:Postoperative Pain / Q000378:metabolism* / Q000517:prevention & control; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D018686:Anesthetics, Intravenous; D010880:Piperidines; D004399:Dynorphins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077208:Remifentanil