Protein Kinases Mediate Increment of the Phosphorylation of Cyclic AMP -Responsive Element Binding Protein in Spinal Cord of Rats following Capsaicin Injection

Abstract

Background: Strong noxious stimuli cause plastic changes in spinal nociceptive neurons. Intracellular signal transduction pathways from cellular membrane to nucleus, which may further regulate gene expression by critical transcription factors, convey peripheral stimulation. Cyclic AMP-responsive element binding protein (CREB) is a well-characterized stimulus-induced transcription factor whose activation requires phosphorylation of the Serine-133 residue. Phospho-CREB can further induce gene transcription and strengthen synaptic transmission by the activation of the protein kinase cascades. However, little is known about the mechanisms by which CREB phosphorylation is regulated by protein kinases during nociception. This study was designed to use Western blot analysis to investigate the role of mitogen-activated protein (MAP)/ extracellular signal-regulated kinase (ERK) kinase (MEK 1/2), PKA and PKC in regulating the phosphorylation of CREB in the spinal cord of rats following intraplantar capsaicin injection.

Nuclear expression of PG-21, SRC-1, and pCREB in regions of the lumbosacral spinal cord involved in pelvic innervation in young adult and aged rats

“…Many factors influence pCREB expression and the increase in levels of expression following orchidectomy, which is most marked in the DH and DGC, could be a general effect of surgery as noxious stimulation of peripheral tissues has been shown to have this effect on spinal neurons, including presumptive nociceptive interneurons in the superficial laminae of the DH [108, 109]. The increase might also be related to the up-regulation of SRC-1 following orchidectomy.…”

JNK1 regulates histone acetylation in trigeminal neurons following chemical stimulation

“…CBP is a transcriptional coactivator important for the action of several transcription factors, including CREB, suggesting that histone acetylation is an important regulatory step of gene transcription mediated by CREB [30]. Furthermore, Increased phosphorylation of CREB through the activation of glutamate receptors and the PKA, PKC, CaM kinase, and JNK cascades in peripheral and central sensory neurons was intensively reported in several animal models of painful stimulation [7, 31, 32]. The results identified that a novel neuroepigenetic mechanism was involved in the peripheral neurons in response to environmental chemical stimulation.…”

“…The expression of β-actin served as an internal control. The density of the blotted bands was acquired by using a Doc-It Gel system and analyzed by suing an AlphaEase software [6, 7]. The densitometric units of bands of detected proteins were expressed relative to the values for β-actin.…”

Signal Transduction in Chronic Pain

“…The CaMK II signaling pathway is very important in triggering the activation of critical transcription factors such as c-fos and cyclic AMP-responsive element binding protein (CREB) in spinal nociceptive neurons. 18,[28][29][30] By investigating the role of CaMK II in the regulation of phosphorylation of CREB after capsaicin injection in rats, we found that capsaicin injection produced a significant increase in CREB phosphorylation in the spinal cord, 30,31 which was significantly reduced by intrathecal application of KN-93. 32 This stimulus-induced transcription factor activation, which requires the involvement of CaMK II activity, was also observed in a rat chronic pain model by Miletic et al 28 It was found that sciatic nerve injury-elicited phospho-CREB expression in the spinal dorsal horn was dramatically attenuated by the CaMK II inhibitor AIP.…”