Language
English
Publication Date
7-5-2024
Journal
Brain
DOI
10.1093/brain/awae106
PMID
38577773
PMCID
PMC11224607
PubMedCentral® Posted Date
4-5-2024
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Morphine, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Hyperalgesia, Neuronal Plasticity, Drug Tolerance, Mice, Analgesics, Opioid, Male, Mice, Inbred C57BL, Posterior Horn Cells, rac1 GTP-Binding Protein, opioid tolerance, opioid-induced hyperalgesia, tiam1, synaptic plasticity, chronic pain management
Published Open-Access
yes
Recommended Citation
Yao, Changqun; Fang, Xing; Ru, Qin; et al., "Tiam1-Mediated Maladaptive Plasticity Underlying Morphine Tolerance and Hyperalgesia" (2024). Faculty and Staff Publications. 5307.
https://digitalcommons.library.tmc.edu/baylor_docs/5307