中枢神经系统区域特异性突触可塑性参与吗啡耐受的研究进展

doi:10.3969/j.issn.1006-5725.2025.13.023

摘要/Abstract

摘要：

连续使用吗啡易引发耐受，导致镇痛效果下降及不良反应增多，严重影响临床应用。突触功能可塑性通过谷氨酸能受体介导的钙信号通路、PKA/PKC/MAPK级联及胶质细胞触发的神经炎症信号，调节突触传递效能的持久性变化，促进吗啡耐受的发展。结构可塑性则涉及树突棘密度与形态的动态重塑、突触连接的新增或修剪，以及突触活性区的重构。吗啡处理后，中枢神经系统突触可塑性呈现区域特异性改变，协同推动耐受进程。本文系统综述了突触可塑性在吗啡耐受中的机制研究进展，以期为开发新型镇痛药物和优化临床治疗提供理论依据。

关键词: 吗啡耐受, 突触, 功能可塑性, 结构可塑性, 中枢神经系统

Abstract:

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.

Key words: morphine tolerance, synapse, functional plasticity, structural plasticity, central nervous system

中图分类号:

R749.6

韩雅洁,王健,宋宗斌. 中枢神经系统区域特异性突触可塑性参与吗啡耐受的研究进展[J]. 实用医学杂志, 2025, 41(13): 2100-2104.

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.

参考文献 43

[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 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 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 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 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 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 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 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 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 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 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 doi: 10.1515/sjpain-2021-0052
[14]	RODRÍGUEZ-MUÑOZ 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 doi: 10.1038/s41380-021-01355-z