α2 noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with inflammatory pain

Wang, Xintai; Lian, Xia; Xu, Ying-Ming; Suo, Zhan-Wei; Yang, Xian; Hu, Xiaodong

doi:10.1016/j.ejphar.2013.12.026

Cited by 16 publications

(10 citation statements)

References 42 publications

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“…This study examined the CaMKII/CREB pathway because it is important for the modulation of spinal central sensitization in chronic pain. Accumulating evidence suggests that CaMKII/CREB is functionally implicated in animal models of inflammatory pain 42 , neuropathic pain 43 and visceral pain 44 . Therefore, we herein investigated whether CaMKII/CREB was stimulated in the bone cancer state and contributed to pain sensitization.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain

Zhang

et al. 2017

Sci Rep

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We previously demonstrated that the chemokine receptor CXCR4 plays an important role in cancer-induced bone pain by activating spinal neurons and glial cells. However, the specific neuronal mechanism of CXCR4 signaling is not clear. We further report that CXCR4 contributes to the activation of the neuronal CaMKII/CREB pathway in cancer-induced bone pain. We used a tumor cell implantation (TCI) model and observed that CXCR4, p-CaMKII and p-CREB were persistently up-regulated in spinal neurons. CXCR4 also co-expressed with p-CaMKII and p-CREB, and mediated p-CaMKII and p-CREB expression after TCI. Intrathecal delivery of CXCR4 siRNA or CaMKII inhibitor AIP2 abrogated TCI-induced pain hypersensitivity and TCI-induced increase in p-CaMKII and p-CREB expression. Intrathecal injection of the principal ligand for CXCR4, SDF-1, promoted p-CaMKII and p-CREB expression in naive rats, which was prevented by post-administration of CXCR4 inhibitor Plerixafor or PLC inhibitor U73122. Plerixafor, U73122, or AIP2 also alleviated SDF-1-elicited pain behaviors. Intrathecal injection of CXCR4 siRNA significantly suppressed TCI-induced up-regulation of NMDAR1 mRNA and protein, which is a known gene target of CREB. Collectively, these results suggest that the CaMKII/CREB pathway in spinal neurons mediates CXCR4-facilitated pain hypersensitivity in cancer rats.

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Section: Discussionmentioning

confidence: 99%

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain

Zhang

et al. 2017

Sci Rep

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“…Our recent study also found a critical role of CaMKIIa in the laterocapcular division of the central amygdala (CeLC) in opioid-induced hyperalgesia (Li et al, 2016). Moreover, there is accumulating evidence demonstrating increased expression and activity of CaMKII in the spinal cord and DRG of various chronic pain models (Liang et al, 2004a;Crown et al, 2012;Ferhatovic et al, 2013a;Hung et al, 2014;Wang et al, 2014). Additionally, CaMKII inhibitors could alleviate pain-related behaviors in a dose-dependent manner in these models.…”

Section: Introductionmentioning

confidence: 74%

Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain

Zhou

Liu

Chen

et al. 2017

J Pharmacol Exp Ther

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Chronic pain, often defined as any pain lasting more than 3 months, is poorly managed because of its multifaceted and complex mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays a fundamental role in synaptic plasticity, learning, and memory. Recent emerging evidence demonstrates increased expression and activity of CaMKII in the spinal cord and dorsal root ganglia of various chronic pain models. Moreover, our previous studies also find that inhibiting CaMKII could attenuate inflammatory pain and neuropathic pain. In this review, we provide evidence for the involvement of CaMKII in the initiation and development of chronic pain, including neuropathic pain, bone cancer pain, and inflammatory pain. Novel CaMKII inhibitors with potent inhibitory effect and high specificity may be alternative therapeutic strategies for the management of chronic pain in the future.

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“…Transverse sections (16 μm) were blocked with 10% normal goat serum and 0.3% Triton X‐100 in PBS, followed by incubation with rabbit anti‐FAK(pY397) antibody at 4°C for 72 hr. After several washes, the sections were incubated with goat anti‐rabbit Cy3‐conjugated secondary antibodies for 2 hr before image capture (Wang et al, ).…”

Section: Methodsmentioning

confidence: 99%

Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice

Lian

Wang

et al. 2015

J of Neuroscience Research

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Focal adhesion kinase (FAK) is one of the nonreceptor protein tyrosine kinases critical for the dynamic regulation of cell adhesion structures. Recent studies have demonstrated that FAK is also localized at excitatory glutamatergic synapses and is involved in long-term modification of synaptic strength. However, whether FAK is engaged in nociceptive processing in the spinal dorsal horn remains unresolved. The current study shows that intraplantar injection of complete Freund's adjuvant (CFA) in mice significantly increases FAK autophosphorylation at Tyr397, indicating a close correlation of FAK activation with inflammatory pain. FAK activation depended on the activity of N-methyl-D-aspartate-subtype glutamate receptor (NMDAR) and metabotropic glutamate receptor (mGluR) because pharmacological inhibition of NMDAR or group I mGluR totally abolished FAK phosphorylation induced by CFA. The active FAK operated to stimulate extracellular signal-regulated kinase1/2 (ERK1/2), which boosted the protein expression of GluN2B subunit-containing NMDAR at the synaptosomal membrane fraction. Inhibition of FAK activity by spinal expression of a kinase-dead FAK(Y397F) mutant repressed ERK1/2 hyperactivity and reduced the synaptic concentration of NMDAR in CFA-injected mice. Electrophysiological recording demonstrated that intracellular loading of specific anti-FAK antibody significantly reduced the amplitudes of NMDAR-mediated excitatory postsynaptic currents on lamina II neurons from inflamed mice but not from naive mice. Behavioral tests showed that spinal expression of FAK(Y397F) generated a long-lasting alleviation of CFA-induced mechanical allodynia and thermal hyperalgesia. These data indicate that FAK might exaggerate NMDAR-mediated synaptic transmission in the spinal dorsal horn to sensitize nociceptive behaviors.

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α2 noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with inflammatory pain

Cited by 16 publications

References 42 publications

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain

Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain

Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain

Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice

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