Adrenomedullin is an Important Pathological Mediator in Progression of Chronic Neuropathic Pain

Wang, Chunmei; Xue, Yunfei; Lu, Qiuhua; Shi, Yonghui; Tang, Wei; Wang, Dongmei

doi:10.31083/j.fbl2707220

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…CGRP is a 37-amino acid neuropeptide released from nociceptive primary afferents. In addition to causing vasodilation and sensitizing nociceptors [ 64 ], CGRP in the spinal cord induces microglial activation by acting on several microglial CGRP receptors [calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (CRCP)] [ 65 , 66 ]. It has been known that enhanced CGRP signaling in the spinal dorsal horn is a crucial mechanism contributing to the genesis of neuropathic pain [ 67 , 68 , 69 ].…”

Section: Upstream Signaling Molecules Regulating Ezh2 Protein Express...mentioning

confidence: 99%

EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

Weng

Taing

Chen

et al. 2023

Cells

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Recent studies by us and others have shown that enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, in glial cells regulates the genesis of neuropathic pain by modulating the production of proinflammatory cytokines and chemokines. In this review, we summarize recent advances in this research area. EZH2 is a subunit of polycomb repressive complex 2 (PRC2), which primarily serves as a histone methyltransferase to catalyze methylation of histone 3 on lysine 27 (H3K27), ultimately resulting in transcriptional repression. Animals with neuropathic pain exhibit increased EZH2 activity and neuroinflammation of the injured nerve, spinal cord, and anterior cingulate cortex. Inhibition of EZH2 with DZNep or GSK-126 ameliorates neuroinflammation and neuropathic pain. EZH2 protein expression increases upon activation of Toll-like receptor 4 and calcitonin gene-related peptide receptors, downregulation of miR-124-3p and miR-378 microRNAs, or upregulation of Lncenc1 and MALAT1 long noncoding RNAs. Genes suppressed by EZH2 include suppressor of cytokine signaling 3 (SOCS3), nuclear factor (erythroid-derived 2)-like-2 factor (NrF2), miR-29b-3p, miR-146a-5p, and brain-specific angiogenesis inhibitor 1 (BAI1). Pro-inflammatory mediators facilitate neuronal activation along pain-signaling pathways by sensitizing nociceptors in the periphery, as well as enhancing excitatory synaptic activities and suppressing inhibitory synaptic activities in the CNS. These studies collectively reveal that EZH2 is implicated in signaling pathways known to be key players in the process of neuroinflammation and genesis of neuropathic pain. Therefore, targeting the EZH2 signaling pathway may open a new avenue to mitigate neuroinflammation and neuropathic pain.

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Section: Upstream Signaling Molecules Regulating Ezh2 Protein Express...mentioning

confidence: 99%

EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

Weng

Taing

Chen

et al. 2023

Cells

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Most reactions leading to neuropathic pain at dorsal root ganglion of rats with spinal nerve ligation have occurred in the early phase

Wang

Lin²,

Tang³

et al. 2022

Animal Gene

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Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis

et al. 2023

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STUDY QUESTION What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? SUMMARY ANSWER Endometriosis-associated pain subtypes exhibited distinct plasma proteomic profiles. WHAT IS KNOWN ALREADY Endometriosis patients, especially those diagnosed in adolescents and young adults, are often plagued by various pain symptoms. However, it is not clear what biological processes underlie this heterogeneity. STUDY DESIGN, SIZE, DURATION We conducted a cross-sectional analysis using data and plasma samples from 142 adolescent or young adult participants of the Women’s Health Study: From Adolescence to Adulthood cohort with laparoscopically confirmed endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS We measured 1305 plasma protein levels by SomaScan. We classified self-reported endometriosis-associated pain into subtypes of dysmenorrhea, acyclic pelvic pain, life impacting pelvic pain, bladder pain, bowel pain, and widespread pain phenotype. We used logistic regression to calculate the odds ratios and 95% confidence intervals for differentially expressed proteins, adjusting for age, BMI, fasting status, and hormone use at blood draw. Ingenuity Pathway Analysis identified enriched biological pathways. MAIN RESULTS AND THE ROLE OF CHANCE Our study population consisted mainly of adolescents and young adults (mean age at blood draw = 18 years), with nearly all (97%) scored as rASRM stage I/II at laparoscopic diagnosis of endometriosis, which is a common clinical presentation of endometriosis diagnosed at a younger age. Pain subtypes exhibited distinct plasma proteomic profiles. Multiple cell movement pathways were downregulated in cases with severe dysmenorrhea and life impacting pelvic pain compared to those without (P < 7.5×10−15). Endometriosis cases with acyclic pelvic pain had upregulation of immune cell adhesion pathways (P < 9.0×10−9), while those with bladder pain had upregulation of immune cell migration (P < 3.7×10−8) and those with bowel pain had downregulation (P < 6.5×10−7) of the immune cell migration pathways compared to those without. Having a wide-spread pain phenotype involved downregulation of multiple immune pathways (P < 8.0×10−10). LIMITATIONS, REASONS FOR CAUTION Our study was limited by the lack of an independent validation cohort. We were also only able to explore any presence of a pain subtype and could not evaluate multiple combinations by pain subtypes. Further mechanistic studies are warranted to elucidate the differences in pathophysiology by endometriosis-pain subtype. WIDER IMPLICATIONS OF THE FINDINGS The observed variation in plasma protein profiles by pain subtypes suggests different underlying molecular mechanisms, highlighting the need for potential consideration of pain subtypes for effectively treating endometriosis patients presenting with various pain symptoms. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Department of Defense W81XWH1910318 and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., and K.L.T. have received funding from the Marriott Family Foundation. C.B.S. is funded by an R35 MIRA Award from NIGMS (5R35GM142676). S.A.M. and K.L.T. are supported by NICHD R01HD094842. S.A.M. reports serving as an advisory board member for AbbVie and Roche, Field Chief Editor for Frontiers in Reproductive Health, personal fees from Abbott for roundtable participation; none of these are related to this study. Other authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

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Adrenomedullin is an Important Pathological Mediator in Progression of Chronic Neuropathic Pain

Cited by 3 publications

References 48 publications

EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

Most reactions leading to neuropathic pain at dorsal root ganglion of rats with spinal nerve ligation have occurred in the early phase

Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis

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