The impact of CREB and its phosphorylation at Ser142 on inflammatory nociception

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Abstract

Peripheral noxious stimulation leads to phosphorylation and thereby activation of the transcription factor CREB in the spinal cord. CREB phosphorylation occurs mainly at serine 133, but the phosphorylation site at serine 142 may also be important. We investigated the impact of spinal CREB protein levels and phosphorylation at Ser142 on the nociceptive behaviour in rat and mouse models of inflammatory nociception. Downregulation of total CREB protein in the rat spinal cord by antisense-oligonucleotides resulted in antinociceptive effects. After peripheral noxious stimulation CREB was phosphorylated in the spinal cord at serine 133 and 142 indicating a potential role of both residues in nociceptive processing. However, Ser142 mutant mice developed equal behavioural correlates of hyperalgesia as wild-type mice in different inflammatory models.

Thus, our data confirm that CREB is essential for spinal nociceptive processing. However, prevention of phosphorylation only at serine 142 is not sufficient to modulate the nociceptive response.

Section snippets

Materials and methods

Animals. Experimentally naive male Sprague–Dawley rats (Charles River, Sulzfeld, Germany) weighing 150–200 g at the time of surgery were used for antisense knock down of CREB. Mice with a mutation in the CREB serine 142 phosphorylation site where serine is exchanged for alanine (CREB S142A mice) and wild-type control mice were kindly provided by Prof. Günther Schütz, DKFZ Heidelberg. These mice are viable and fertile and show no obvious abnormalities in size or morphology in comparison to

Nociceptive behaviour after CREB antisense knock down in the rat spinal cord

The role of CREB in nociceptive transmission has been evaluated by investigation of the CFA-induced thermal hyperalgesia in rats treated either with CREB-sense or -antisense-oligonucleotides. Spinal perfusion with the CREB-antisense-oligonucleotide caused a significant reduction of CREB protein in the lumbar spinal cord as compared to treatment with sense-oligonucleotides (Fig. 1A). At baseline the two groups showed no differences in the paw withdrawal latency (PWL) in response to a thermal

Discussion

Several studies have shown that the activation of CREB in spinal cord dorsal horn neurons plays a central role in the transmission of nociceptive stimuli and long term adaptive responses in the central nervous system [3], [5], [22]. CREB is a constitutive transcription factor which is activated by phosphorylation through various kinases including PKA, PKC, Erk, p38 MAPK, and PKG that all contribute to the immediate adaptation to nociceptive input. Supporting this view we show here, that

Acknowledgments

The authors thank Christine Manderscheid for excellent technical assistance as well as Prof. Günther Schütz, DKFZ Heidelberg, Germany, for kindly providing CREB S142A mice and antibody against phospho-CREB (Serine 142). The study was supported by the Deutsche Forschungsgemeinschaft DFG (GE 695/2-2).

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