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Effects of surgery and/or remifentanil administration on the expression of pERK1/2, c-Fos and dynorphin in the dorsal root ganglia in mice

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Abstract

Tissue injury and/or opioids induce plastic changes in the spinal cord resulting in pain hypersensitivity; the contribution of the dorsal root ganglia (DRG) is poorly understood. We evaluated DRG phenotypic changes induced by surgery and/or remifentanil in a mice model of postoperative pain using as neuronal markers ERK1/2 and c-Fos; prodynorphin mRNA and dynorphin levels were also determined. We hypothesized that a correlation between nociception and DRG reactivity would occur. Surgery and/or remifentanil induced mechanical hypersensitivity, correlated with ERK1/2 phosphorylation and c-Fos expression in the DRG; changes were greater in the remifentanil + incision group and still present on day 14 (p < 0.01 vs. control). Intrathecal PD98059 (ERK1/2 inhibitor) partially reversed the mechanical hypersensitivity (44%, p < 0.05) observed in the remifentanil + incision group. In this group, significant increases in prodynorphin mRNA (at 2, 7, and 14 days, p < 0.01) roughly coincided with increases in dynorphin (days 2 and 14, p < 0.001) in the DRG. Remifentanil or incision (alone) also induced an up-regulation in prodynorphin mRNA expression on days 7 and 14 (p < 0.01, p < 0.05, respectively), partially correlating with dynorphin levels. On day 21, all molecular changes returned to control levels in all experimental conditions, concurring with the complete recovery of nociceptive thresholds. Surgery and/or remifentanil induce up-regulation of c-Fos and pERK in the DRG, approximately correlating with nociceptive behavior, also associated with an increased expression of prodynorphin/dynorphin. These changes support the role of the DRG in the development and maintenance of pain hypersensitivity after surgery. The findings could contribute to the development of new therapeutic agents focused on peripheral targets.

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Abbreviations

AACs:

Areas above curve

DRG:

Dorsal root ganglia

ERK:

Extracellular signal-related kinase

MAPK:

Mitogen-activated protein kinase

NMDA-R:

N-Methyl-d-aspartate receptors

JNK:

c-Jun N-terminal kinase

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Acknowledgments

This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Madrid, Spain (PS09/01270), Marató de Televisió de Catalunya TV3, Barcelona, Spain (071110), and the Endowed Chair in Pain Management Universitat Autònoma de Barcelona—Parc de Salut Mar-Menarini (MMP). The authors thank Marta Pulido, MD for editing the manuscript and editorial assistance, and Klaus Langohr, Ph.D. for his assistance in the statistical analysis.

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Romero, A., González-Cuello, A., Laorden, M.L. et al. Effects of surgery and/or remifentanil administration on the expression of pERK1/2, c-Fos and dynorphin in the dorsal root ganglia in mice. Naunyn-Schmiedeberg's Arch Pharmacol 385, 397–409 (2012). https://doi.org/10.1007/s00210-011-0721-z

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