PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

Zhou, Xi‐Lang; Wang, Y.; Zhang, C.-J.; Lu, Yu; Cao, Jun‐Li; Yan, Min

doi:10.1016/j.neuroscience.2014.10.025

Cited by 23 publications

(13 citation statements)

References 51 publications

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“…After all experiments, the brains were dissected from paraformaldehyde-perfused rats, dehydrated in sucrose, and sectioned into slices. The immunohistochemistry procedure was performed using a detection kit as described previously [ 9 ]. The dopaminergic or GABAergic VTA neurons were identified using the anti-Tyrosine Hydroxylase (TH) or anti-glutamic acid decarboxylase (GAD 65/67) primary antibody, respectively.…”

Section: Methodsmentioning

confidence: 99%

The Role of Dopaminergic VTA Neurons in General Anesthesia

et al. 2015

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Recent studies have demonstrated that the central dopaminergic system is implicated in the mechanism underlying general anesthesia. Here, we investigated whether dopaminergic ventral tegmental area (VTA) neurons participate in general anesthesia. Dopaminergic VTA neurons were selectively ablated from male Sprague Dawley rats via the bilateral infusion of 6-hydroxydopamine (6-OHDA) into the VTA. Two weeks after infusion, the number of dopaminergic neurons in the bilateral VTA was markedly reduced in the 6-OHDA-treated rats compared with the vehicle-treated rats. These bilateral VTA lesions significantly prolonged the recovery time for propofol but did not significantly alter its onset time or 50% effective dose (ED50) value. In addition, the anesthetic responses to isoflurane and ketamine were unaffected by the VTA lesions. Our findings suggested that dopaminergic VTA neurons might be involved in the emergence from propofol anesthesia.

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Section: Methodsmentioning

confidence: 99%

The Role of Dopaminergic VTA Neurons in General Anesthesia

et al. 2015

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“…Given the important roles of eph-rinB-EphB signaling in the generation and maintenance of chronic pain, researchers have always focused on exploring the upstream and downstream signal pathway (11,12) have demonstrated that some MAPKs such as ERK1/2, p38, and JNK, are involved in the ephrinB-EphB signaling-induced hyperalgesia. Our previous studies have consecutively proved that phosphatidy linositol 3-kinase (PI3K), protein kinase A (PKA), and protein kinase Cγ (PKCγ) act as the downstream factors of ephrinB-EphB signaling in modulating the spinal nociceptive information (7,(43)(44)(45). In the present study, we hypothesized that ERK5/CREB pathway may act as the downstream signal pathway of ephrinB-EphB signaling in modulating pain transduction.…”

Section: Discussionmentioning

confidence: 80%

EphrinB-EphB Signaling Induces Hyperalgesia through ERK5/CREB Pathway in Rats

Sun

Wang

et al. 2017

Pain Phys

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Background: There are numerous studies implicating that EphB receptors and ephrinB ligands play important roles in modulating the transduction of spinal nociceptive information. EphrinB-EphB signaling may contribute to hyperalgesia via various kinds of downstream molecules, the mechanisms of which have not been completely understood. Objective: The aim of the present study was to identify whether ephrinB-EphB signaling could contribute to hyperalgesia through ERK5/CREB pathway. Study Design: Controlled animal study. Setting: University laboratory. Methods: This study attempted to detect the changes of pain behaviors and the protein level of p-ERK5 and p-CREB by activating EphB receptors in the spinal cord of rats. To further confirm our hypothesis, we designed LV-siRNA for knockdown of spinal ERK5. When ERK5 was inhibited, we recorded the changes of spinal p-CREB expression and the pain behaviors of rats after activating EphB receptors. We also confirmed this conclusion in rat CCI model. Statistical analyses were performed using GraphPad Prism 5. Results: Intrathecal injection of ephrinB2-Fc in rats evoked thermal hyperalgesia and mechanical allodynia, along with activation of ERK5 and CREB in the spinal cord. Knockdown of ERK5 inhibited ephrinB2-Fc-induced CREB activation and hyperalgesia. Blocking EphB receptors prevented CCI-induced neuropathic pain and spinal ERK5/CREB activation. Limitations: More underlying mechanisms that underlie the relationship between ephrinBEphB signaling and ERK5/CREB pathway will need to be explored in future studies. Conclusions: Our study suggests that ERK5/CREB pathway plays important roles in the transduction of nociceptive information associated with ephrinB-EphB signaling. This study provides further understanding of the downstream mechanisms of ephrinB-EphB signaling and helps to explore new targets for treating pathological pain. Key words: EphrinB-EphB signaling, MAPK, ERK5, CREB, hyperalgesia, pain, CCI, NMDA

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“…Intrathecal injection was performed with a 28 G stainless steel needle between the L5 and L6 vertebrae to deliver drugs to the subarachnoid space. 19 siRNAs were mixed with Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) before intrathecal injection.…”

Section: Drugs and Reagentsmentioning

confidence: 99%

“…Paw withdrawal latency (PWL) to thermal stimulus and paw withdrawal threshold (PWT) to mechanical stimulus were performed as described. 19 For PWL, mice were placed on a glass plate in a plastic box and allowed to adapt for 1 h. The plantar surface of the hind paw was exposed to radiant heat through the glass. Baseline values were adjusted to 12e15 s and an automatic 25 s cutoff was used to prevent injury.…”

Section: Behavioural Testingmentioning

confidence: 99%

“…Protein samples, prepared as described, 19 were separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred onto polyvinylidene difluoride membranes. After blocking with non-fat milk, blots were incubated with primary antibodies against ROR2, phosphotyrosine, phosphoserine, GluN1, GluN2A, GluN2B, GluN2BeSer 1303, GluN2BeSer 1323, GluN2B-Tyr1336, GluN2B-Tyr1472, and b-actin overnight at 4 C. Blots were extensively washed and further incubated with HRP-conjugated secondary antibody at room temperature for 2 h, with immune complexes detected by using chemiluminescence (Pierce, Dallas, TX, USA).…”

Section: Western Blot and Immunoprecipitationmentioning

confidence: 99%

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ROR2 modulates neuropathic pain via phosphorylation of NMDA receptor subunit GluN2B in rats

Zhou

Zhang

Peng

et al. 2019

British Journal of Anaesthesia

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Background: Neuropathic pain, a type of chronic pain as a result of direct central or peripheral nerve damage, is associated with significant quality of life and functional impairment. Its underlying mechanisms remain unclear. We investigated whether ROR2, a member of the receptor tyrosine kinase-like orphan receptor (ROR) family, participates in modulation of neuropathic pain. Methods: Thermal hyperalgesia and mechanical allodynia were measured using radiant heat and von Frey filament testing. Immunofluorescence staining was used to detect expression of ROR2 in neuronal nuclei. Fos expression was determined by immunocytochemistry. Phosphorylation status was detected by western blot and immunoprecipitation. Small interfering RNA was used to knock down ROR2 expression. Results: ROR2 was upregulated and activated in spinal neurones after chronic constriction injury (CCI) in mice [1.3 (0.1) to 2.1 (0.1)-fold of sham, P<0.01] from Day 1e21. CCI induced significant demethylation of the CpG island in the ROR2 gene promoter [0.37 (0.06) vs 0.12 (0.03)% CpG methylation, P<0.001]. Knockdown of ROR2 in the spinal cord prevented and reversed CCI-induced pain behaviours and spinal neuronal sensitisation [Fos expression: 130 (12) vs 81 (8) cells, P<0.05; 120 (11) vs 70 (7) cells, P<0.05]. In contrast, activation of spinal ROR2 by intrathecal injection of Wnt5a induced pain behaviours and spinal neuronal sensitisation [Fos expression: 11 (1) vs 100 (12) cells, P<0.001] in wild-type mice. Furthermore, ROR2-mediated pain modulation required phosphorylation of N-methyl-D-aspartate receptor 2B subunit (GluN2B) at Ser 1303 and Tyr1472 by pathways involving protein kinase C (PKC) and Src family kinases. Intrathecal injection of GluN2B, PKC, or Src family kinase-specific inhibitors significantly attenuated Wnt5a-induced pain behaviours. Conclusions: ROR2 in the spinal cord regulates neuropathic pain via phosphorylation of GluN2B, suggesting a potential target for prevention and relief of neuropathic pain.

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PKA is required for the modulation of spinal nociceptive information related to ephrinB–EphB signaling in mice

Cited by 23 publications

References 51 publications

The Role of Dopaminergic VTA Neurons in General Anesthesia

The Role of Dopaminergic VTA Neurons in General Anesthesia

EphrinB-EphB Signaling Induces Hyperalgesia through ERK5/CREB Pathway in Rats

ROR2 modulates neuropathic pain via phosphorylation of NMDA receptor subunit GluN2B in rats

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