Cellular mechanisms involved in the induction and maintenance of long-term potentiation (LTP) in the spinal dorsal horn
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AbstractThe cellular processes leading to spinal long-term potentiation (LTP) are regarded as underlying mechanisms of sensitization in the dorsal horn. In this study, spinal LTP was induced by high-frequency stimulation (HFS) conditioning of the sciatic nerve. Electrophysiological extracellular recordings from nociceptive single dorsal horn neurons were used in combination with quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) to examine the mechanisms for induction and maintenance of spinal LTP.
Spinal administration of the N-methyl-D-aspartate-2B (NMDA-2B) receptor antagonist Ro 25-6981 showed an antinociceptive effect on spinal dorsal horn neuronal activity and clearly attenuated the magnitude of spinal LTP. Moreover, induction of LTP after HFS conditioning was not observed following pre-treatment of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. A transient increase in the expression of the gene for the transcription factor Zif268 was observed in the spinal cord 120 minutes after HFS conditioning. Further, the expression of the genes for interleukin-1β (IL-1β), glial cell linederived neurotrophic factor (GDNF) and inducible nitric oxide synthase (iNOS) increased significantly in the ipsilateral dorsal horn 360 minutes after HFS conditioning.
These data demonstrate that activation of the spinal NMDA-2B receptor and the intracellular CaMKII enzyme may be important for the induction of spinal LTP. Moreover our results indicate that increased gene expression of Zif268, IL-1β, GDNF and iNOS following HFS might be associated with the maintenance of spinal LTP.
LIST OF PAPERS
Paper I. Pedersen, L. M. and Gjerstad, J. (2008) Spinal cord long-term potentiation (LTP) is attenuated by the NMDA-2B receptor antagonist Ro 25-6981. Acta Physiologica, 192 (3): 421-427. doi:10.1111/j.1748-1716.2007.01756.x
Paper II. Pedersen, L. M., Lien, G. F., Bollerud, I. and Gjerstad, J. (2005) Induction of long-term potentiation in single nociceptive dorsal horn neurons is blocked by the CaMKII inhibitor AIP. Brain Research, 1041:66-71. doi:10.1016/j.brainres.2005.02.004
Paper III. Gjerstad, J. Lien, G. F., Pedersen, L. M., Valen, E. C. and Mollerup, S. (2005) Changes in gene expression of Zif, c-fos and cyclooxygenase-2 associated with spinal long-term potentiation. Neuroreport, 16 (13): 1477-1481. doi:10.1097/01.wnr.0000177004.19946.12
Paper IV. Pedersen, L. M., Jacobsen, L. M., Mollerup, S. and Gjerstad, J. (2009) Spinal cord long-term potentiation (LTP) is associated with increased spinal gene expression of IL-1Î², GDNF and iNOS. European Journal of Pain, In press. doi:10.1016/j.ejpain.2009.05.016