Cynandione A attenuates neuropathic pain through p38β MAPK-mediated spinal microglial expression of β-endorphin

Huang, Qian; Mao, Xiao-Fang; Wu, Haiyun; Líu, Hao; Sun, Mingli; Wang, Xiao; Wang, Yongxiang

doi:10.1016/j.bbi.2017.02.005

Cited by 43 publications

(29 citation statements)

References 64 publications

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“…These results solidify our postulation that exenatide specifically induces spinal p38b phosphorylation, which subsequently mediates b-endorphin overexpression and antinociception. The broad impact of spinal p38b activation on endogenous opioid secretion and subsequent antinociception is supported by recent observations in which intrathecal siRNA/p38b blocked cynandione A-or bulleyaconitine A-induced spinal microglial total p38 activation and b-endorphin or dynorphin A expression, and spinal antinociception (Huang et al, 2017;Li et al, 2017).…”

Section: Discussionmentioning

confidence: 61%

p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

Mao

Fan

et al. 2017

Mol Pharmacol

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Recent discoveries established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) mediates neuroprotection and antinociception through microglial -endorphin expression. This study aimed to explore the underlying signaling mechanisms of microglial-endorphin. GLP-1Rs and -endorphin were coexpressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the-endorphin precursor gene proopiomelanocortin (POMC) and peptides, with EC values of 4.1 and 7.5 nM, respectively. Exenatide also significantly increased intracellular cAMP levels and expression of -protein kinase A (PKA),-p38, and -cAMP response element binding protein (CREB) in cultured primary microglia. Furthermore, exenatide-induced microglial expression of POMC was completely blocked by reagents that specifically inhibit adenylyl cyclase and activation of PKA, p38, and CREB. In addition, knockdown of p38 (but not p38) using short interfering RNA (siRNA) eliminated exenatide-induced microglial p38 phosphorylation and POMC expression. In contrast, lipopolysaccharide increased microglial activation of p38, and knockdown of p38 (but not p38) partially suppressed expression of proinflammatory factors (including tumor necrosis factor-, interleukin-1, and interleukin-6). Exenatide-induced phosphorylation of p38 and CREB was also totally blocked by the PKA inhibitor and siRNA/p38, but not by siRNA/p38 Seven-day intrathecal injections of siRNA/p38 (but not siRNA/p38) completely blocked exenatide-induced spinal p38 activation, -endorphin expression, and mechanical antiallodynia in rats with established neuropathy, although siRNA/p38 and siRNA/p38 were not antiallodynic. To our knowledge, our results are the first to show a causal relationship between the PKA-dependent p38 mitogen-activated protein kinase/CREB signal cascade and GLP-1R agonism-mediated microglial -endorphin expression. The differential role of p38 and p38 activation in inflammation and nociception was also highlighted.

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Section: Discussionmentioning

confidence: 61%

p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

Mao

Fan

et al. 2017

Mol Pharmacol

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“…GO enrichment analysis revealed that thousands of target genes were involved in the GO term: biological processes, cellular component, and molecular function, which indicates that these differential circRNAs may influence genes of varied biological function. KEGG analysis showed that there were 112 pathways related to the 100 circRNAs, the top three were reported to be related to neuropathic pain: the Hippo signaling pathway,40 MAPK signaling pathway,41–43 and endocytosis 44,45…”

Section: Discussionmentioning

confidence: 99%

Chronic constriction injury of sciatic nerve changes circular RNA expression in rat spinal dorsal horn

Cao

Deng

Liu

et al. 2017

JPR

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BackgroundMechanisms of neuropathic pain are still largely unknown. Molecular changes in spinal dorsal horn may contribute to the initiation and development of neuropathic pain. Circular RNAs (circRNAs) have been identified as microRNA sponges and involved in various biological processes, but whether their expression profile changes in neuropathic pain condition is not reported.MethodsTo test whether neuropathic pain influences circRNA expression, we developed a sciatic chronic constriction injury (CCI) model in rats. The CCI ipsilateral spinal dorsal horns of lumbar enlargement segments (L3–L5) were collected, and the total RNA was extracted and subjected to Arraystar Rat circRNA Microarray. Quantitative real-time polymerase chain reaction (qPCR) was used to confirm the circRNA expression profile. To estimate functions of differential circRNAs, bioinformatics analyses including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes Pathway analyses were performed for the top 100 circRNAs and circRNA–microRNA networks were constructed for the top 10 circRNAs.ResultscircRNA microarrays showed that 469 circRNAs were differentially expressed between CCI and sham-operated rats (fold change ≥2). In all, 363 of them were significantly upregulated, and the other 106 were downregulated in the CCI group. Three of them (circRNA_013779, circRNA_008008, and circRNA_003724) overexpressed >10 times after CCI insult. Expression levels of eight circRNAs were verified using qPCR. GO analysis revealed that thousands of predicted target genes were involved in the biological processes, cellular component, and molecular function; in addition, dozens of these genes were enriched in the Hippo signaling pathway, MAPK signaling pathway, and so on. Competing endogenous RNAs analysis showed that circRNA_008008 and circRNA_013779 are the two largest nodes in the circRNA–microRNA interaction network of the top 10 circRNAs.ConclusionCCI resulted in a comprehensive expression profile of circRNAs in the spinal dorsal horn in rats. CircRNAs in the dorsal horn could be helpful to reveal molecular mechanisms of neuropathic pain.

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“…As β-endorphin is an endogenous ligand of μ-opioid receptors [32,44], its involvement in cinobufagin-induced mechanical antiallodynia was investigated. Two groups of female bone cancer pain rats received intrathecal injection of normal saline (10 μL) or the selective μ-opioid receptor antagonist CTAP (10 μg) followed by cinobufagin (30 μg) 30 min later.…”

Section: Cinobufagin Exhibited Mechanical Antiallodynia Through Spinamentioning

confidence: 99%

“…Thus, the possible involvement of the CRF receptor in cinobufagin-induced mechanical antiallodynia was finally tested. Two groups of female bone cancer pain rats received intrathecal injection of normal saline (10 μL) and the specific CRF receptor antagonist α-helical CRF (9-41) (20 μg) [32,59] respectively followed by cinobufagin (30 μg) 30 min later, and withdrawal thresholds were measured in both the contralateral and ipsilateral hindpaws prior to or post the last injection. In contrast to methyllycaconitine, pretreatment with intrathecal injection of α-helical CRF (9-41) failed to block the antiallodynic effect of cinobufagin in the ipsilateral hindpaws (Fig.…”

Section: Activation Of the α7-nachr Mediated Cinobufagininduced Spinamentioning

confidence: 99%

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

Apryani

Ali

Wang

et al. 2020

J Neuroinflammation

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Background: Cinobufagin is the major bufadienolide of Bufonis venenum (Chansu), which has been traditionally used for the treatment of chronic pain especially cancer pain. The current study aimed to evaluate its antinociceptive effects in bone cancer pain and explore the underlying mechanisms. Methods: Rat bone cancer model was used in this study. The withdrawal threshold evoked by stimulation of the hindpaw was determined using a 2290 CE electrical von Frey hair. The β-endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Results: Cinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected E max of 90% MPE and ED 50 of 6.4 μg. Intrathecal cinobufagin also stimulated the gene and protein expression of IL-10 and β-endorphin (but not dynorphin A) in the spinal cords of bone cancer pain rats. In addition, treatment with cinobufagin in cultured primary spinal microglia but not astrocytes or neurons stimulated the mRNA and protein expression of IL-10 and β-endorphin, which was prevented by the pretreatment with the IL-10 antibody but not β-endorphin antiserum. Furthermore, spinal cinobufagin-induced mechanical antiallodynia was inhibited by the pretreatment with intrathecal injection of the microglial inhibitor minocycline, IL-10 antibody, βendorphin antiserum and specific μ-opioid receptor antagonist CTAP. Lastly, cinobufagin-and the specific α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist PHA-543613-induced microglial gene expression of IL-10/βendorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine. Conclusions: Our results illustrate that cinobufagin produces mechanical antiallodynia in bone cancer pain through spinal microglial expression of IL-10 and subsequent β-endorphin following activation of α7-nAChRs. Our results also highlight the broad significance of the recently uncovered spinal microglial IL-10/β-endorphin pathway in antinociception.

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Cynandione A attenuates neuropathic pain through p38β MAPK-mediated spinal microglial expression of β-endorphin

Cited by 43 publications

References 64 publications

p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

Chronic constriction injury of sciatic nerve changes circular RNA expression in rat spinal dorsal horn

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

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