受损感觉神经元来源的Galectin-3通过重编程脊髓背角小胶质细胞介导神经病理性疼痛

研究背景和目的：神经病理性疼痛对患者生活质量的负面影响极大，由于其发病机制复杂，尚无令人满意的治疗方法，因此对其相关分子机制的研究尤为重要。已有研究表明，脊髓背角（SDH）中的小胶质细胞在神经病理性疼痛的发病机制中扮演着关键角色，然而关于其激活的潜在机制仍未完全明确。本实验研究并发现了Galectin-3（Gal3），一种属于糖配体凝集素家族的多功能蛋白，在神经病理性疼痛中可以作为小胶质细胞的内源性激活剂激活小胶质细胞，本实验通过探究Gal3与小胶质细胞的互作来进一步阐明神经病理性疼痛的新机制及发现新的治疗靶点。

实验方法：通过免疫荧光实验（Immunofluorescence，IF）确定Gal3的表达分布。构建坐骨神经部分结扎（partial sciatic nerve ligation, pSNL）小鼠神经病理性疼痛模型，通过qPCR及蛋白免疫印记（Western blot，WB）确定Gal3在pSNL后表达上调。进一步通过Gal3敲除鼠（Gal3 KO）与野生型（WT）小鼠的机械痛阈值变化曲线及急性鞘内给予Gal3抑制剂之后小鼠机械痛阈值确定Gal3在神经痛中的作用。通过IF检测Gal3 KO与WT鼠脊髓小胶质细胞的激活情况来确定Gal3对小胶质细胞的影响。为了探究Gal3是否会诱导机械痛觉异常及小胶质细胞的激活，本实验检测了鞘内直接注射Gal3之后小鼠的机械疼痛阈值及小胶质细胞激活情况。除此之外，本实验还在原代培养小胶质细胞水平上检测Gal3对小胶质细胞的激活作用。本实验利用单细胞核RNA测序（snRNA-seq）及电生理实验分别验证Gal3对小胶质细胞的重编程机制及对下游神经元兴奋性的影响。

实验结果：本实验发现来自受损伤的感觉神经元的Gal3激活并重编程脊髓背角（SDH）的小胶质细胞，并有助于神经病理性疼痛的形成和维持。首先，在pSNL诱导的神经病理性疼痛模型中，Gal3主要表达于植物凝集素 B4（IB4）标记的非肽能感觉神经元中，并在SDH的背根神经节（DRG）神经元和初级传入末梢中显著上调。在pSNL模型中，Gal3 KO小鼠的机械痛敏显著减少，鞘内注射Gal3抑制剂TD-139产生镇痛作用。同时，pSNL诱导的小胶质增生在Gal3 KO小鼠中显著减少。此外，鞘内注射Gal3通过TLR4直接激活小胶质细胞产生显著的机械痛敏，炎症因子TNF-α和IL-1β也会上调。利用snRNA-seq，本实验发现Gal3靶向小胶质细胞并诱导小胶质细胞重编程，这可能有助于神经病理性疼痛的建立。最后，电生理实验表明Gal3通过激活小胶质细胞增强SDH兴奋性神经元的兴奋性突触传递。

结论：本实验揭示了在神经病理性疼痛的模型中，特定感觉神经元产生的Gal3对小胶质细胞的作用，以及其在疼痛发展中的重要性。关键发现包括：

1. Gal3选择性地表达在IB4标记的非肽能感觉神经元中，且在周围神经损伤引起的神经病理性疼痛模型中显著上调；

2. Gal3通过直接激活小胶质细胞，促使小胶质细胞从稳态状态转变为促炎状态，是神经痛发生过程中神经免疫互作的关键调控因子；

3. Gal3通过激活小胶质细胞参与神经痛中脊髓背角的神经元的可塑性。

[1] RAJA S N, CARR D B, COHEN M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises [J]. Pain, 2020, 161(9): 1976 -82.
[2] BASBAUM A I, BAUTISTA D M, SCHERRER G, et al. Cellular and molecular mechanisms of pain [J]. Cell, 2009, 139(2): 267 -84.
[3] DJOUHRI L, LAWSON S N. Abeta -fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent A -fiber neurons in mammals [J]. Brain research Brain research reviews, 2004, 46(2): 131-45.
[4] KUNER R, FLOR H. Structural plasticity and reorganisation in chronic pain [J]. Nature reviews Neuroscience, 2016, 18(1): 20 -30.
[5] CAMPBELL J N, MEYER R A. Mechanisms of neuropathic pain [J]. Neuron, 2006, 52(1): 77-92.
[6] FINNERUP N B, KUNER R, JENSEN T S. Neuropathic Pain: From Mechanisms to Treatment [J]. Physiological reviews, 2021, 101(1): 259-301.
[7] COULL J A, BEGGS S, BOUDREAU D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain [J]. Nature, 2005, 438(7070): 1017-21.
[8] GOLD M S, GEBHART G F. Nociceptor sensitization in pain pathogenesis [J]. Nature medicine, 2010, 16(11): 1248 -57.
[9] ZHENG Q, DONG X, GREEN D P, et al. Peripheral mechanisms of chronic pain [J]. Medical review (2021), 2022, 2(3): 251 -70.
[10] LEO M, SCHULTE M, SCHMITT L I, et al. Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF -Induced Pain-Related Behavior [J]. Mediators of inflammation, 2017, 2017: 2786427.
[11] NASSAR M A, LEVATO A, STIRLING L C, et al. Neuropathic pain develops normally in mice lacking both Na(v)1.7 and Na(v)1.8 [J]. Molecular pain, 2005, 1: 24.
[12] YU X, LIU H, HAMEL K A, et al. Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain [J]. Nature communications, 2020, 11(1): 264.
[13] JI R R, CHAMESSIAN A, ZHANG Y Q. Pain regulation by non -neuronal cells and inflammation [J]. Science (New York, NY), 2016, 354(6312): 572 -7.
[14] COSTIGAN M, SCHOLZ J, WOOLF C J. Neuropathic pain: a maladaptive response of the nervous system to damage [J]. Annual review of neuroscience, 2009, 32: 1-32.
[15] BERTA T, PARK C K, XU Z Z, et al. Extracellular caspase -6 drives murine inflammatory pain via microglial TNF-α secretion [J]. The Journal of clinical investigation, 2014, 124(3): 1173 -86.
[16] TSUDA M, SHIGEMOTO-MOGAMI Y, KOIZUMI S, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury [J]. Nature, 2003, 424(6950): 778-83.
[17] VERGE G M, MILLIGAN E D, MAIER S F, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions [J]. The European journal of neuroscience, 2004, 20(5): 1 150-60.
[18] CHEN G, ZHANG Y Q, QADRI Y J, et al. Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain [J]. Neuron, 2018, 100(6): 1292-311.
[19] LEDEBOER A, SLOANE E M, MILLIGAN E D, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation [J]. Pain, 2005, 115(1 -2): 71-83.
[20] JI R R, BERTA T, NEDERGAARD M. Glia and pain: is chronic pain a gliopathy? [J]. Pain, 2013, 154 Suppl 1(0 1): S10 -s28.
[21] CHEN G, PARK C K, XIE R G, et al. Connexin -43 induces chemokine release from spinal cord astrocytes to maintain late -phase neuropathic pain in mice [J]. Brain : a journal of neurology, 2014, 137(Pt 8): 2193 -209.
[22] CHEN O, DONNELLY C R, JI R R. Regulation of pain by neuro -immune interactions between macrophages and nociceptor sensory neurons [J]. Current opinion in neurobiology, 2020, 62: 17 -25.
[23] XU Z, ZHU Y, SHEN J, et al. Pain Relief Dependent on IL -17-CD4(+) T Cellβ-Endorphin Axis in Rat Model of Brachial Plexus Root Avulsion After Electroacupuncture Therapy [J]. Frontiers in neuroscience, 2020, 14: 596780.
[24] PINHO-RIBEIRO F A, VERRI W A, JR., CHIU I M. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation [J]. Trends in immunology, 2017, 38(1): 5-19.
[25] KETTENMANN H, HANISCH U K, NODA M, et al. Physiology of microglia [J]. Physiol Rev, 2011, 91(2): 461 -553.
[26] GU N, PENG J, MURUGAN M, et al. Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity after Peripheral Nerve Injury [J]. Cell reports, 2016, 16(3): 605 -14.
[27] KAWASAKI Y, XU Z Z, WANG X, et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain [J]. Nature medicine, 2008, 14(3): 331 -6.
[28] THION M S, GINHOUX F, GAREL S. Microglia and early brain development: An intimate journey [J]. Science (New York, NY), 2018, 362(6411): 185 -9.
[29] GARCíA-REVILLA J, BOZA-SERRANO A, ESPINOSA-OLIVA A M, et al. Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration [J]. Cell death & disease, 2022, 13(7): 628.
[30] GE M M, CHEN N, ZHOU Y Q, et al. Galectin -3 in Microglia -Mediated Neuroinflammation: Implications for Central Nervous System Diseases [J]. Current neuropharmacology, 2022, 20(11): 2066 -80.
[31] TAN Y, ZHENG Y, XU D, et al. Galectin -3: a key player in microglia -mediated neuroinflammation and Alzheimer's disease [J]. Cell & bioscience, 2021, 11(1): 78.
[32] BOZA-SERRANO A, RUIZ R, SANCHEZ-VARO R, et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease [J]. Acta neuropathologica, 2019, 138(2): 251 -73.
[33] INOUE K, TSUDA M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential [J]. Nature reviews Neuroscience, 2018, 19(3): 138-52.
[34] SALTER M W, STEVENS B. Microglia emerge as central players in brain disease [J]. Nature medicine, 2017, 23(9): 1018 -27.
[35] GU N, EYO U B, MURUGAN M, et al. Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain [J]. Brain, behavior, and immunity, 2016, 55: 82 -92.
[36] BATTI L, SUNDUKOVA M, MURANA E, et al. TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States [J]. Cell reports, 2016, 15(12): 2608-15.
[37] ZHANG J, SHI X Q, ECHEVERRY S, et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain [J]. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007, 27(45): 12396-406.
[38] GUAN Z, KUHN J A, WANG X, et al. Injured sensory neuron -derived CSF1 induces microglial proliferation and DAP12 -dependent pain [J]. Nature neuroscience, 2016, 19(1): 94 -101.
[39] OKUBO M, YAMANAKA H, KOBAYASHI K, et al. Macrophage -Colony Stimulating Factor Derived from Injured Primary Afferent Induces Proliferation of Spinal Microglia and Neuropathic Pain in Rats [J]. PloS one, 2016, 11(4): e0153375.
[40] SORGE R E, MAPPLEBECK J C, ROSEN S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice [J]. Nature neuroscience, 2015, 18(8): 1081 -3.
[41] ZHAO J, SEEREERAM A, NASSAR M A, et al. Nociceptor-derived brainderived neurotrophic factor regulates acute and inflammatory but not neuropathic pain [J]. Molecular and cellular neurosciences, 2006, 31(3): 539 -48.
[42] CLARK A K, YIP P K, GRIST J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain [J]. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(25): 10655 -60.
[43] CLARK A K, GRUBER-SCHOFFNEGGER D, DRDLA-SCHUTTING R, et al. Selective activation of microglia facilitates synaptic strength [J]. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015, 35(11): 4552-70.
[44] KANDA H, KOBAYASHI K, YAMANAKA H, et al. COX -1-dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons [J]. Glia, 2013, 61(6): 943 -56.
[45] OKUBO M, YAMANAKA H, KOBAYASHI K, et al. Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain [J]. Glia, 2010, 58(5): 599 -610.
[46] TANSLEY S, GU N, GUZMáN A U, et al. Microglia -mediated degradation of perineuronal nets promotes pain [J]. Science (New York, NY), 2022, 377(6601): 80-6.
[47] XU Y, MOULDING D, JIN W, et al. Microglial phagocytosis mediates long -term restructuring of spinal GABAergic circuits following early life injury [J]. Brain, behavior, and immunity, 2023, 111: 127 -37.
[48] YOUSEFPOUR N, LOCKE S, DEAMOND H, et al. Time -dependent and selective microglia -mediated removal of spinal synapses in neuropathic pain [J]. Cell reports, 2023, 42(1): 112010.
[49] KOHNO K, SHIRASAKA R, YOSHIHARA K, et al. A spinal microglia population involved in remitting and relapsing neuropathic pain [J]. Science (New York, NY), 2022, 376(6588): 86 -90.
[50] TRIPPEL T D, MENDE M, DüNGEN H D, et al. The diagnostic and prognostic value of galectin-3 in patients at risk for heart failure with preserved ejection fraction: results from the DIAST-CHF study [J]. ESC heart failure, 2021, 8(2): 829-41.
[51] MANSOUR A A, KRAUTTER F, ZHI Z, et al. The interplay of galectins-1, -3, and -9 in the immune -inflammatory response underlying cardiovascular and metabolic disease [J]. Cardiovascular diabetology, 2022, 21(1): 253.
[52] ZHOU Z, FENG Z, SUN X, et al. The Role of Galectin -3 in Retinal Degeneration and Other Ocular Diseases: A Potential Novel Biomarker and Therapeutic Target [J]. International journal of molecular sciences, 2023, 24(21).
[53] HARA A, NIWA M, NOGUCHI K, et al. Galectin -3 as a Next-Generation Biomarker for Detecting Early Stage of Various Diseases [J]. Biomolecules, 2020, 10(3).
[54] CHIP S, FERNáNDEZ-LóPEZ D, LI F, et al. Genetic deletion of galectin -3 enhances neuroinflammation, affects microglial activation and contributes to sub-chronic injury in experimental neonatal focal stroke [J]. Brain, behavior, and immunity, 2017, 60: 270-81.
[55] YOUNG C C, AL-DALAHMAH O, LEWIS N J, et al. Blocked angiogenesis in Galectin-3 null mice does not alter cellular and behavioral recovery after middle cerebral artery occlusion stroke [J]. Neurobiology of disease, 2014, 63: 155-64.
[56] DE JONG C, GABIUS H J, BARON W. The emerging role of galectins in (re)myelination and its potential for developing new approaches to treat multiple sclerosis [J]. Cellular and molecular life sciences : CMLS, 2020, 77(7): 1289-317.
[57] BOZA-SERRANO A, REYES J F, REY N L, et al. The role of Galectin -3 in αsynuclein-inducedmicroglial activation [J]. Acta neuropathologica communications, 2014, 2: 156.
[58] SIEW J J, CHEN H M, CHEN H Y, et al. Galectin -3 is required for the microglia-mediated brain inflammation in a model of Huntington's disease [J]. Nature communications, 2019, 10(1): 3473.
[59] VENKATESAN C, CHRZASZCZ M, CHOI N, et al. Chronic upregulation of activated microglia immunoreactive for galectin -3/Mac-2 and nerve growth factor following diffuse axonal injury [J]. Journal of neuroinflammation, 2010, 7: 32.
[60] YIP P K, CARRILLO-JIMENEZ A, KING P, et al. Galectin -3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration [J]. Scientific reports, 2017, 7: 41689.
[61] WANG Z, JIANG C, YAO H, et al. Central opioid receptors mediate morphine -induced itch and chronic itch via disinhibition [J]. Brain : a journal of neurology, 2021, 144(2): 665-81.
[62] KIM K J, YOON Y W, CHUNG J M. Comparison of three rodent neuropathic pain models [J]. Experimental brain research, 1997, 113(2): 200 -6.
[63] JAMES N D, ANGéRIA M, BRADBURY E J, et al. Structural and Functional Substitution of Deleted Primary Sensory Neurons by New Growth from Intrinsic Spinal Cord Nerve Cells: An Alternative Concept in Reconstruction of Spinal Cord Circuits [J]. Frontiers in neurology, 2017, 8: 358.
[64] TSUJIKAWA S, DEMEULENAERE K E, CENTENO M V, et al. Regulation of neuropathic pain by microglial Orai1 channels [J]. Science advances, 2023, 9(4): eade7002.
[65] WU W, LI Y, WEI Y, et al. Microglial depletion aggravates the severity of acute and chronic seizures in mice [J]. Brain, behavior, and immunity, 2020, 89: 245-55.
[66] WANG Z, JIANG C, HE Q, et al. Anti-PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates [J]. Science translational medicine, 2020, 12(531).
[67] SATIJA R, FARRELL J A, GENNERT D, et al. Spatial reconstruction of single-cell gene expression data [J]. Nature biotechnology, 2015, 33(5): 495 -502.
[68] MCGINNIS C S, MURROW L M, GARTNER Z J. DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors [J]. Cell systems, 2019, 8(4): 329 -37.e4.
[69] YU G, WANG L G, HAN Y, et al. clusterProfiler: an R package for comparing biological themes among gene clusters [J]. Omics : a journal of integrative biology, 2012, 16(5): 284-7.
[70] USOSKIN D, FURLAN A, ISLAM S, et al. Unbiased classification of sensory neuron types by large -scale single-cell RNA sequencing [J]. Nature neuroscience, 2015, 18(1): 145 -53.
[71] WANG K, WANG S, CHEN Y, et al. Single -cell transcriptomic analysis of somatosensory neurons uncovers temporal development of neuropathic pain [J]. Cell research, 2021, 31(8): 904 -18.
[72] KOYANAGI M, IMAI S, MATSUMOTO M, et al. Pronociceptive Roles of Schwann Cell-Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy [J]. Cancer research, 2021, 81(8): 2207 -19.
[73] TAKASAKI I, TANIGUCHI K, KOMATSU F, et al. Contribution of spinal galectin-3 to acute herpetic allodynia in mice [J]. Pain, 2012, 153(3): 585 -92.
[74] OCHOCKA N, SEGIT P, WALENTYNOWICZ K A, et al. Single -cell RNA sequencing reveals functional heterogeneity of glioma -associated brain macrophages [J]. Nature communications, 2021, 12(1): 1151.
[75] GRUBER-SCHOFFNEGGER D, DRDLA-SCHUTTING R, HöNIGSPERGER C, et al. Induction of thermal hyperalgesia and synaptic long -term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells [J]. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013, 33(15): 6540 -51.
[76] KAWASAKI Y, ZHANG L, CHENG J K, et al. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin -1beta, interleukin6,and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord [J]. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008, 28(20): 5189 -94.
[77] OLMOS G, LLADó J. Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity [J]. Mediators of inflammation, 2014, 2014: 861231.
[78] ZHANG H, NEI H, DOUGHERTY P M. A p38 mitogen -activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-alpha [J]. The Journal of neuroscience : the official journal of the Society fo r Neuroscience, 2010, 30(38): 12844 -55.
[79] LE PICHON C E, CHESLER A T. The functional and anatomical dissection of somatosensory subpopulations using mouse genetics [J]. Frontiers in neuroanatomy, 2014, 8: 21.
[80] LUO X, FITZSIMMONS B, MOHAN A, et al. Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4 -induced pain in male mice [J]. Brain, behavior, and immunity , 2018, 72: 34-44.
[81] MAPPLEBECK J C S, DALGARNO R, TU Y, et al. Microglial P2X4R-evoked pain hypersensitivity is sexually dimorphic in rats [J]. Pain, 2018, 159(9): 1752-63.
[82] SORGE R E, LACROIX-FRALISH M L, TUTTLE A H, et al. Spinal cord Tolllikereceptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice [J]. The Journal of neuroscience : the official journal of the Society for Neuroscie nce, 2011, 31(43): 15450-4.
[83] TAVES S, BERTA T, LIU D L, et al. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex -dependent microglial signaling in the spinal cord [J]. Brain, behavior, and immunity, 2016, 55: 70-81.
[84] YI M H, LIU Y U, LIU K, et al. Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice [J]. Brain, behavior, and immunity, 2021, 92: 78 -89.
[85] PENG J, GU N, ZHOU L, et al. Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury [J]. Nature communications, 2016, 7: 12029.
[86] TANSLEY S, UTTAM S, UREñA GUZMáN A, et al. Single -cell RNA sequencing reveals time - and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain [J]. Nature communications, 2022, 13(1): 843.
[87] AKIYOSHI R, WAKE H, KATO D, et al. Microglia Enhance Synapse Activity to Promote Local Network Synchronization [J]. eNeuro, 2018, 5(5).
[88] ANDOH M, KOYAMA R. Microglia regulate synaptic development and plasticity [J]. Developmental neurobiology, 2021, 81(5): 568 -90.
[89] WAKE H, MOORHOUSE A J, MIYAMOTO A, et al. Microglia: actively surveying and shaping neuronal circuit structure and function [J]. Trends in neurosciences, 2013, 36(4): 209 -17.
[90] WILTON D K, DISSING-OLESEN L, STEVENS B. Neuron -Glia Signaling in Synapse Elimination [J]. Annual review of neuroscience, 2019, 42: 107 -27.
[91] BOAKYE P A, TANG S J, SMITH P A. Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β [J]. Frontiers in pain research (Lausanne, Switzerland), 2021, 2: 698157.
[92] SIDERIS-LAMPRETSAS G, OGGERO S, ZEBOUDJ L, et al. Galectin -3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer's disease [J]. Nature communications, 2023, 14(1): 3579.
[93] MOORE K A, KOHNO T, KARCHEWSKI L A, et al. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord [J]. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002, 22(15): 6724 -31.
[94] SCHOLZ J, BROOM D C, YOUN D H, et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury [J]. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005, 25(32): 7317-23.
[95] MA Z, HAN Q, WANG X, et al. Galectin -3 Inhibition Is Associated with Neuropathic Pain Attenuation after Peripheral Nerve Injury [J]. PloS one, 2016, 11(2): e0148792.
[96] WU Z S, LO J J, WU S H, et al. Early Hyperbaric Oxygen Treatment Attenuates Burn-Induced Neuroinflammation by Inhibiting the Galectin -3-Dependent Toll-Like Receptor-4 Pathway in a Rat Model [J]. International journal of molecular sciences, 2018, 19(8).
[97] WANG T, FEI Y, YAO M, et al. Correlation between Galectin -3 and Early Herpes Zoster Neuralgia and Postherpetic Neuralgia: A Retrospective Clinical Observation [J]. Pain research & management, 2020, 2020: 8730918.
[98] ELSHAMLY M, KINSLECHNER K, GROHS J G, et al. Galectins-1 and -3 in Human Intervertebral Disc Degeneration: Non -Uniform Distribution Profiles and Activation of Disease Markers Involving NF -κB by Galectin-1 [J]. Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2019, 37(10): 2204-16.
[99] CAO M Y, WANG J, GAO X L, et al. Serum galectin -3 concentrations in patients with ankylosing spondylitis [J]. Journal of clinical laboratory analysis, 2019, 33(6): e22914.