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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1467305
This article is part of the Research Topic Pharmacological Advances to Treat Pathological Pain View all 4 articles

Microglial Adenosine A2A Receptor in the Paraventricular Thalamic Nucleus Regulates Pain Sensation and Analgesic Effects Independent of Opioid and Cannabinoid Receptors

Provisionally accepted
Yiping Cao Yiping Cao 1,2,3*Zhou Wu Zhou Wu 1,2,3*Moruo Zhang Moruo Zhang 1,2,3Ran Ji Ran Ji 1,2,3*Hongxing Zhang Hongxing Zhang 1,2,3*Lingzhen Song Lingzhen Song 1,2,3*
  • 1 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
  • 2 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
  • 3 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China

The final, formatted version of the article will be published soon.

    The paraventricular thalamic nucleus (PVT) is recognized for its critical role in pain regulation, yet the precise molecular mechanisms involved remain poorly understood. Here, we demonstrated an essential role of the microglial adenosine A2A receptor (A2AR) in the PVT in regulating pain sensation and non-opioid analgesia. Method and Results: Specifically, A2AR was predominantly expressed in ionized calcium binding adapter molecule 1 (Iba1)-positive microglia cells within the PVT, with expression levels remaining unchanged in mice experiencing persistent inflammatory pain induced by complete Freund's adjuvant (CFA). Pharmacological activation of local PVT A2AR with its agonist CGS21680 induced significantly decreased 50% paw withdrawal threshold (50%PWTs) and paw withdrawal latency (PWLs), as measured by the Von Frey test and Hargreaves test in adult mice.Conversely, intra-PVT infusion of A2AR antagonist SCH58261 increased 50%PWTs and PWLs in mice, a robust analgesic effect was also observed in CFA mice with inflammatory pain. Importantly, these analgesic effects of A2AR antagonist SCH58261were not affected by adjunctive intraperitoneal administration of naloxone or rimonabant, inhibitors of opioid receptor and cannabinoid CB1 receptor (CB1R), respectively. Discussion: Overall, these pharmacological experiments underscore an essential role of microglia-expressed A2AR with in PVT in pain sensation while revealing a novel analgesic action independent of opioid and cannabinoids receptors. Thus, these findings highlight PVT microglial adenosine A2A receptor as a promising target for novel approaches to pain modulation and future analgesic development.

    Keywords: A2A receptor, PVT, Microglia, Pain sensation, Opioid Receptor, Cannabinoid receptor, Non-opioid analgesia

    Received: 19 Jul 2024; Accepted: 03 Dec 2024.

    Copyright: © 2024 Cao, Wu, Zhang, Ji, Zhang and Song. 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) or licensor 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.

    * Correspondence:
    Yiping Cao, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
    Zhou Wu, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
    Ran Ji, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
    Hongxing Zhang, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China
    Lingzhen Song, Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.