Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia.

Autor:	Yao C; Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35025, USA., Fang X; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Ru Q; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Health and Kinesiology, School of Physical Education, Jianghan University, Wuhan 430056, China., Li W; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35025, USA., Li J; Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35025, USA., Mehsein Z; Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35025, USA., Tolias KF; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Li L; Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35025, USA.; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Jul 05; Vol. 147 (7), pp. 2507-2521.
DOI:	10.1093/brain/awae106
Abstrakt:	Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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