TY - JOUR T1 - Increased Spinal Dynorphin Levels, and pERK1/2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.059790 SP - mol.109.059790 AU - Ana Campillo AU - Ana Gonzalez-Cuello AU - David Cabanero AU - Paula Garcia-Nogales AU - Asuncion Romero AU - Maria Victoria Milanes AU - Maria Luisa Laorden AU - Margarita M Puig Y1 - 2009/01/01 UR - http://molpharm.aspetjournals.org/content/early/2009/11/16/mol.109.059790.abstract N2 - In humans, remifentanil anesthesia enhances nociceptive sensitization in the postoperative period. We hypothesized that activation of 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 PCR), 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 for 10-14 days, when compared to non-injured 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.The American Society for Pharmacology and Experimental Therapeutics ER -