The Journal of Practical Medicine >
Research progress on region⁃specific synaptic plasticity in the central nervous system involved in morphine tolerance
Received date: 2025-04-28
Online published: 2025-07-18
The repeated administration of morphine frequently gives rise to tolerance， manifested by a reduction in analgesic efficacy and an elevation in adverse effects. These consequences significantly impinge upon its clinical utility. Synaptic functional plasticity governs long-term alterations in synaptic transmission efficiency through calcium signaling pathways， protein kinase cascade reactions， and glia-neuron interactions， thereby facilitating the development of morphine tolerance. Structural plasticity encompasses the dynamic remodeling of dendritic spine density and morphology， the establishment or elimination of synaptic connections， and the reconstitution of synaptic active zones. Morphine-induced synaptic plasticity within the central nervous system demonstrates region-specific alterations， which jointly drive the process of tolerance. This review comprehensively synthesizes the research advancements regarding the mechanisms of synaptic plasticity in morphine tolerance， with the aim of furnishing a theoretical foundation for the development of innovative analgesic medications and the optimization of clinical treatment strategies.
Yajie HAN , Jian WANG , Zongbin SONG . Research progress on region⁃specific synaptic plasticity in the central nervous system involved in morphine tolerance[J]. The Journal of Practical Medicine, 2025 , 41(13) : 2100 -2104 . DOI: 10.3969/j.issn.1006-5725.2025.13.023
| [1] | MAGEE J C， GRIENBERGER C. Synaptic Plasticity Forms and Functions［J］. Annu Rev Neurosci， 2020， 43：95-117. doi:10.1146/annurev-neuro-090919-022842 |
| [2] | ROTH R H， DING J B. Cortico-basal ganglia plasticity in motor learning［J］. Neuron， 2024， 112（15）：2486-2502. doi:10.1016/j.neuron.2024.06.014 |
| [3] | 郄晓娟，李清开，刘颖，等. 基于补体C3及TGFβ1/Smad信号通路探究七氟烷麻醉对老龄小鼠突触可塑性及工作记忆力损伤的机制［J］. 实用医学杂志，2023，39（2）：204-208. |
| [4] | 王兆涛，徐如祥，马全红，等. 过表达精神分裂断裂基因1对APP/PS1转基因阿尔茨海默病小鼠突触可塑性及学习记忆能力的改善［J］. 实用医学杂志，2021，37（9）：1117-1126. |
| [5] | BRENNAN F H， SWARTS E A， KIGERL K A， et al. Microglia promote maladaptive plasticity in autonomic circuitry after spinal cord injury in mice［J］. Sci Transl Med， 2024， 16（751）：eadi3259. doi:10.1126/scitranslmed.adi3259 |
| [6] | DEJANOVIC B， SHENG M， HANSON J E. Targeting synapse function and loss for treatment of neurodegenerative diseases［J］. Nat Rev Drug Discov， 2024， 23（1）：23-42. doi:10.1038/s41573-023-00823-1 |
| [7] | CHU W G， WANG F D， SUN Z C， et al. TRPC1/4/5 channels contribute to morphine-induced analgesic tolerance and hyperalgesia by enhancing spinal synaptic potentiation and structural plasticity［J］. FASEB J， 2020， 34（6）：8526-8543. doi:10.1096/fj.202000154rr |
| [8] | CHEN S R， CHEN H， JIN D， et al. Brief Opioid Exposure Paradoxically Augments Primary Afferent Input to Spinal Excitatory Neurons via alpha2delta-1-Dependent Presynaptic NMDA Receptors［J］. J Neurosci， 2022， 42（50）：9315-9329. doi:10.1523/jneurosci.1704-22.2022 |
| [9] | BISCHOFF F P， VAN BRANDT S， VIELLEVOYE M， et al. Design， Synthesis， and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration［J］. J Med Chem， 2025， 68（4）：4672-4693. doi:10.1021/acs.jmedchem.4c02751 |
| [10] | ABED A S AL， SELLAMI A， POTIER M， et al. Age-related impairment of declarative memory： Linking memorization of temporal associations to GluN2B redistribution in dorsal CA1［J］. Aging Cell， 2020， 19（10）：e13243. doi:10.1111/acel.13243 |
| [11] | HANSON J E， YUAN H， PERSZYK R E， et al. Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry［J］. Neuropsychopharmacology， 2024， 49（1）：51-66. doi:10.1038/s41386-023-01614-3 |
| [12] | BUONARATI O R， HAMMES E A， WATSON J F， et al. Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation［J］. Sci Signal， 2019， 12（562）：eaar6889. doi:10.1126/scisignal.aar6889 |
| [13] | RAHBAN M， DANYALI S， ZARINGHALAM J，et al. Pharmacological blockade of neurokinin1 receptor restricts morphine-induced tolerance and hyperalgesia in the rat［J］. Scand J Pain， 2022， 22（1）：193-203. doi:10.1515/sjpain-2021-0052 |
| [14] | RODRíGUEZ-MU?OZ M， SáNCHEZ-BLáZQUEZ P， VICENTE-SáNCHEZ A， et al. The mu-opioid receptor and the NMDA receptor associate in PAG neurons： Implications in pain control［J］. Neuropsychopharmacology， 2012， 37（2）：338-349. doi:10.1038/npp.2011.155 |
| [15] | ZHOU Z， LIU A， XIA S， et al. The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning［J］. Nat Neurosci， 2018， 21（1）：50-62. doi:10.1038/s41593-017-0030-z |
| [16] | HU X， TIAN X， GUO X， et al. AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence［J］. Neuropharmacology， 2018， 137：50-58. doi:10.1016/j.neuropharm.2018.04.020 |
| [17] | YAO C， FANG X， RU Q， et al. Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia［J］. Brain， 2024， 147（7）：2507-2521. doi:10.1093/brain/awae106 |
| [18] | XIAO L， HAN X， WANG X E， et al. Spinal Serum- and Glucocorticoid-Regulated Kinase 1 （SGK1） Signaling Contributes to Morphine-Induced Analgesic Tolerance in Rats［J］. Neuroscience， 2019， 413：206-218. doi:10.1016/j.neuroscience.2019.06.007 |
| [19] | NAZARI S， SADAT-SHIRAZI M S， SHAHBAZI A， et al. The effect of morphine administration on GluN3B NMDA receptor subunit mRNA expression in rat brain［J］. Acta Neurobiol Exp （Wars）， 2024， 84（1）：89-97. doi:10.55782/ane-2024-2545 |
| [20] | NEJAD G G， MOTTARLINI F， TAVASSOLI Z， et al. Conditioned morphine tolerance promotes neurogenesis， dendritic remodeling and pro-plasticity molecules in the adult rat hippocampus［J］. Addict Biol， 2024， 29（3）：e13377. doi:10.1111/adb.13377 |
| [21] | DARVISHMOLLA M， SAEEDI N， TAVASSOLI Z， et al. Maladaptive plasticity induced by morphine is mediated by hippocampal astrocytic Connexin-43［J］. Life Sci， 2023， 330：121969. doi:10.1016/j.lfs.2023.121969 |
| [22] | ANVARI S， JAVAN M， MIRNAJAFI-ZADEH J， et al. Repeated Morphine Exposure Alters Temporoamonic-CA1 Synaptic Plasticity in Male Rat Hippocampus［J］. Neuroscience， 2024， 545：148-157. doi:10.1016/j.neuroscience.2024.03.015 |
| [23] | GHAMKHARINEJAD G， MOTTARLINI F， TAVASSOLI Z， et al. Habituation to novel stimuli alters hippocampal plasticity associated with morphine tolerance in male Wistar rats［J］. Brain Res， 2025， 1853：149508. doi:10.1016/j.brainres.2025.149508 |
| [24] | CAO S， XIAO Z， SUN M， et al. D-serine in the midbrain periaqueductal gray contributes to morphine tolerance in rats［J］. Mol Pain， 2016， 12：1744806916646786. doi:10.1177/1744806916646786 |
| [25] | DENG M， CHEN S R， CHEN H， et al. Mitogen-activated protein kinase signaling mediates opioid-induced presynaptic NMDA receptor activation and analgesic tolerance［J］. J Neurochem， 2019， 148（2）：275-290. doi:10.1111/jnc.14628 |
| [26] | JIN D， CHEN H， ZHOU M H， et al. mGluR5 from Primary Sensory Neurons Promotes Opioid-Induced Hyperalgesia and Tolerance by Interacting with and Potentiating Synaptic NMDA Receptors［J］. J Neurosci， 2023， 43（31）：5593-5607. doi:10.1523/jneurosci.0601-23.2023 |
| [27] | OHASHI Y， SAKHRI F Z， IKEMOTO H， et al. Yokukansan Inhibits the Development of Morphine Tolerance by Regulating Presynaptic Proteins in DRG Neurons［J］. Front Pharmacol， 2022， 13：862539. doi:10.3389/fphar.2022.862539 |
| [28] | ZHONG W， MA X， XING Y， et al. Blockade of peripheral nociceptive signal input relieves the formation of spinal central sensitization and retains morphine efficacy in a neuropathic pain rat model［J］. Neurosci Lett， 2020， 716：134643. doi:10.1016/j.neulet.2019.134643 |
| [29] | YUAN L， LUO L， MA X， et al. Chronic morphine induces cyclic adenosine monophosphate formation and hyperpolarization-activated cyclic nucleotide-gated channel expression in the spinal cord of mice［J］. Neuropharmacology， 2020， 176：108222. doi:10.1016/j.neuropharm.2020.108222 |
| [30] | WILSON-POE A R， JEONG H J， VAUGHAN C W. Chronic morphine reduces the readily releasable pool of GABA， a presynaptic mechanism of opioid tolerance［J］. J Physiol， 2017， 595（20）：6541-6555. doi:10.1113/jp274157 |
| [31] | ZHU Q M， WU L X， ZHANG B， et al. Donepezil prevents morphine tolerance by regulating N-methyl-d-aspartate receptor， protein kinase C and CaM-dependent kinase II expression in rats［J］. Pharmacol Biochem Behav， 2021， 206：173209. doi:10.1016/j.pbb.2021.173209 |
| [32] | HIROKI T， SUTO T， OHTA J， et al. Spinal gamma-Aminobutyric Acid Interneuron Plasticity Is Involved in the Reduced Analgesic Effects of Morphine on Neuropathic Pain［J］. J Pain， 2022， 23（4）：547-557. doi:10.1016/j.jpain.2021.10.002 |
| [33] | ZHANG J， LIU Z， LIU X， et al. Intravenous Injection of GluR2-3Y Inhibits Repeated Morphine-Primed Reinstatement of Drug Seeking in Rats［J］. Brain Sci， 2023， 13（4）：590. doi:10.3390/brainsci13040590 |
| [34] | RUSSELL S E， PUTTICK D J， SAWYER A M， et al. Nucleus Accumbens AMPA Receptors Are Necessary for Morphine-Withdrawal-Induced Negative-Affective States in Rats［J］. J Neurosci， 2016， 36（21）：5748-5762. doi:10.1523/jneurosci.2875-12.2016 |
| [35] | GEOFFROY H， CANESTRELLI C， MARIE N， et al. Morphine-Induced Dendritic Spine Remodeling in Rat Nucleus Accumbens Is Corticosterone Dependent［J］. Int J Neuropsychopharmacol， 2019， 22（6）：394-401. doi:10.1093/ijnp/pyz014 |
| [36] | MADAYAG A C， GOMEZ D， ANDERSON E M， et al. Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward， reinstatement， and spontaneous withdrawal［J］. Brain Struct Funct， 2019， 224（7）：2311-2324. doi:10.1007/s00429-019-01903-y |
| [37] | LEFEVRE E M， GAUTHIER E A， BYSTROM L L， et al. Differential Patterns of Synaptic Plasticity in the Nucleus Accumbens Caused by Continuous and Interrupted Morphine Exposure［J］. J Neurosci， 2023， 43（2）：308-318. doi:10.1523/jneurosci.0595-22.2022 |
| [38] | JAECKEL E R， ARIAS-HERVERT E R， PEREZ-MEDINA A L， et al. Chronic morphine treatment induces sex- and synapse-specific cellular tolerance on thalamo-cortical mu opioid receptor signaling［J］. J Neurophysiol， 2024， 132（3）：968-978. doi:10.1152/jn.00265.2024 |
| [39] | CHEN G， HAN W， LI A， et al. Phosphorylation of GluN2B subunits of N-methyl-d-aspartate receptors in the frontal association cortex involved in morphine-induced conditioned place preference in mice［J］. Neurosci Lett， 2021， 741：135470. doi:10.1016/j.neulet.2020.135470 |
| [40] | YANG Z Z， LI L， WANG L， et al. siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice： A mechanism for acute morphine tolerance suppression［J］. Sci Rep， 2016， 6：33338. doi:10.1038/srep33338 |
| [41] | SENEY M L， KIM S M， GLAUSIER J R， et al. Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder［J］. Biol Psychiatry， 2021， 90（8）：550-562. doi:10.1016/j.biopsych.2021.06.007 |
| [42] | LASEK A W， CHEN H， CHEN W Y. Releasing Addiction Memories Trapped in Perineuronal Nets［J］. Trends Genet， 2018， 34（3）：197-208. doi:10.1016/j.tig.2017.12.004 |
| [43] | CHEN Y H， HU N Y， WU D Y， et al. PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction［J］. Mol Psychiatry， 2022， 27（2）：896-906. doi:10.1038/s41380-021-01355-z |
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