Alpha 2-adrenoceptor participates in anti-hyperalgesia by regulating metabolic demand

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Abstract

The α2-adrenoceptor agonist dexmedetomidine is a commonly used drug for sedatives in clinics and has analgesic effects; however, its mechanism of analgesia in the spine remains unclear. In this study, we systematically used behavioural and transcriptomic sequencing, pharmacological intervention, electrophysiological recording and ultrasound imaging to explore the analgesic effects of the α2-adrenoceptor and its molecular mechanism. Firstly, we found that spinal nerve injury changed the spinal transcriptome expression, and the differential genes were mainly related to calcium signalling and tissue metabolic pathways. In addition, α2-adrenoceptor mRNA expression was significantly upregulated, and α2-adrenoceptor was significantly colocalised with markers, particularly neuronal markers. Intrathecal dexmedetomidine suppressed neuropathic pain and acute inflammatory pain in a dose-dependent manner. The transcriptome results demonstrated that the analgesic effect of dexmedetomidine may be related to the modulation of neuronal metabolism. Weighted gene correlation network analysis indicated that turquoise, brown, yellow and grey modules were the most correlated with dexmedetomidine-induced analgesic effects. Bioinformatics also annotated the involvement of metabolic processes and neural plasticity. A cardiovascular–mitochondrial interaction was found, and ultrasound imaging revealed that injection of dexmedetomidine significantly enhanced spinal cord perfusion in rats with neuropathic pain, which might be regulated by pyruvate dehydrogenase kinase 4 (pdk4), cholesterol 25-hydroxylase (ch25 h) and GTP cyclohydrolase 1 (gch1). Increasing the perfusion doses of dexmedetomidine significantly suppressed the frequency and amplitude of spinal nerve ligation-induced miniature excitatory postsynaptic currents. Overall, dexmedetomidine exerts analgesic effects by restoring neuronal metabolic processes through agonism of the α2-adrenoceptor and subsequently inhibiting changes in synaptic plasticity.

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Methods Used to Evaluate Pain Behaviors in Rodents

Jennifer R Deuis, Lucie S. Dvorakova, Irina Vetter (2017)

Rodents are commonly used to study the pathophysiological mechanisms of pain as studies in humans may be difficult to perform and ethically limited. As pain cannot be directly measured in rodents, many methods that quantify “pain-like” behaviors or nociception have been developed. These behavioral methods can be divided into stimulus-evoked or non-stimulus evoked (spontaneous) nociception, based on whether or not application of an external stimulus is used to elicit a withdrawal response. Stimulus-evoked methods, which include manual and electronic von Frey, Randall-Selitto and the Hargreaves test, were the first to be developed and continue to be in widespread use. However, concerns over the clinical translatability of stimulus-evoked nociception in recent years has led to the development and increasing implementation of non-stimulus evoked methods, such as grimace scales, burrowing, weight bearing and gait analysis. This review article provides an overview, as well as discussion of the advantages and disadvantages of the most commonly used behavioral methods of stimulus-evoked and non-stimulus-evoked nociception used in rodents.

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Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells.

Elena Smirnova, Lorena Griparic, Dixie-Lee Shurland … (2001)

Mutations in the human dynamin-related protein Drp1 cause mitochondria to form perinuclear clusters. We show here that these mitochondrial clusters consist of highly interconnected mitochondrial tubules. The increased connectivity between mitochondria indicates that the balance between mitochondrial division and fusion is shifted toward fusion. Such a shift is consistent with a block in mitochondrial division. Immunofluorescence and subcellular fractionation show that endogenous Drp1 is localized to mitochondria, which is also consistent with a role in mitochondrial division. A direct role in mitochondrial division is suggested by time-lapse photography of transfected cells, in which green fluorescent protein fused to Drp1 is concentrated in spots that mark actual mitochondrial division events. We find that purified human Drp1 can self-assemble into multimeric ring-like structures with dimensions similar to those of dynamin multimers. The structural and functional similarities between dynamin and Drp1 suggest that Drp1 wraps around the constriction points of dividing mitochondria, analogous to dynamin collars at the necks of budding vesicles. We conclude that Drp1 contributes to mitochondrial division in mammalian cells.

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The CH25H–CYP7B1–RORα axis of cholesterol metabolism regulates osteoarthritis

Wan-Su Choi, Gyuseok Lee, Won-Hyun Song … (2019)

Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

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Author and article information

Contributors

Ke Zhang: URI : https://loop.frontiersin.org/people/2575562/overviewRole: Role: Role: Role:

Yu-Qing Ren: Role: Role: Role:

Yan Xue: Role: Role: Role: Role:

Dongxia Duan: URI : https://loop.frontiersin.org/people/533560/overviewRole: Role: Role: Role:

Tong Zhou: Role: Role:

Ying-Zhuo Ding: URI : https://loop.frontiersin.org/people/2621685/overviewRole: Role: Role: Role:

Xiang Li: Role: Role: Role:

Wan-Kun Gong: URI : https://loop.frontiersin.org/people/968810/overviewRole: Role: Role:

Jiao-Qiong Guan: Role: Role: Role:

Le Ma: URI : https://loop.frontiersin.org/people/1238113/overviewRole: Role: Role:

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 21 March 2024

Publication date Collection: 2024

Volume: 15

Electronic Location Identifier: 1359319

Affiliations

[1] ¹ Department of Anesthesiology , Affiliated Shanghai Sixth People’s Hospital , Shanghai Jiao Tong University School of Medicine , Shanghai, China

[2] ² Shanghai Key Laboratory of Psychotic Disorders , Brain Health Institute , National Center for Mental Disorders , Shanghai Mental Health Center , Shanghai Jiao Tong University School of Medicine , Shanghai, China

[3] ³ Department of Anesthesiology , Renji Hospital , Shanghai Jiao Tong University School of Medicine , Shanghai, China

[4] ⁴ Shanghai Eye Disease Prevention and Treatment Center/Shanghai Eye Hospital , Department of Pharmacy , Shanghai, China

[5] ⁵ Department of Orthopedics , The Fifth People’s Hospital of Shanghai , Fudan University , Shanghai, China

Author notes

Edited by: Weijie Xie, Tongji University, China

Reviewed by: Khalil Ali Ahmad, University of Texas MD Anderson Cancer Center, United States

Yang Hong Xu, Chinese Academy of Sciences (CAS), China

Muhammad Usman, Western University, Canada

*Correspondence: Jiao-Qiong Guan, eyjqguan@ 123456scut.edu.can ; Le Ma, male412810253@ 123456sjtu.edu.cn

[ † ]

These authors have contributed equally to this work and share first authorship

Article

Publisher ID: 1359319

DOI: 10.3389/fphar.2024.1359319

PMC ID: 10996398

PubMed ID: 38584597

SO-VID: cce2c3d5-9b52-4121-898b-5eb4497c62d0

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 21 December 2023

Date accepted : 20 February 2024

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study is supported by the Postdoctoral Science Foundation of China (2021M692118, W-JX; 2022M712126, W-KG; 2023M742355, GZC20231656, KZ) and Shanghai Mental Health Center (2021-YJ11 and 2023-YJ02).

Custom metadata

section-at-acceptance Neuropharmacology

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: α2-adrenoceptor,pain,transcriptome,cardiovascular-mitochondrial interaction,metabolic processes

Data availability:

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: α2-adrenoceptor, pain, transcriptome, cardiovascular-mitochondrial interaction, metabolic processes

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