Neuropathic pain is a debilitating form of pain arising from injury or disease of the nervous system that affects millions of people worldwide. Despite its prevalence, the underlying mechanisms of neuropathic pain are still not fully understood. Dendritic spines are small protrusions on the surface of neurons that play an important role in synaptic transmission. Recent studies have shown that dendritic spines reorganize in the superficial and deeper laminae of the spinal cord dorsal horn with the development of neuropathic pain in multiple models of disease or injury. Given the importance of dendritic spines in synaptic transmission, it is possible that studying dendritic spines could lead to new therapeutic approaches for managing intractable pain. In this review article, we highlight the emergent role of dendritic spines in neuropathic pain, as well as discuss the potential for studying dendritic spines for the development of new therapeutics.
AckermannMMatusA. 2003. Activity-induced targeting of profilin and stabilization of dendritic spine morphology. Nat Neurosci6(11):1194–200.
2.
AkbarHCancelasJWilliamsDAZhengJZhengY. 2006. Rational design and applications of a Rac GTPase-specific small molecule inhibitor. Methods Enzymol406:554–65.
3.
Al-KhaterKMKerrRToddAJ. 2008. A quantitative study of spinothalamic neurons in laminae I, III, and IV in lumbar and cervical segments of the rat spinal cord. J Comp Neurol511(1):1–18.
4.
AllenJDJafferZMParkSJBurginSHofmannCSellsMA, and others. 2009. p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood113(12):2695–705.
5.
AlonsoMMedinaJHPozzo-MillerL. 2004. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem11(2):172–8.
6.
ArayaREisenthalKBYusteR. 2006. Dendritic spines linearize the summation of excitatory potentials. Proc Natl Acad Sci U S A103(49):18799–804.
7.
ArellanoJIBenavides-PiccioneRDefelipeJYusteR. 2007. Ultrastructure of dendritic spines: correlation between synaptic and spine morphologies. Front Neurosci1(1):131–43.
8.
AscanoMJrMukherjeeNBandaruPMillerJBNusbaumJDCorcoranDL, and others. 2012. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature492(7429):382–6.
9.
AsrarSMengYZhouZTodorovskiZHuangWWJiaZ. 2009. Regulation of hippocampal long-term potentiation by p21-activated protein kinase 1 (PAK1). Neuropharmacology56(1):73–80.
10.
Baker-HermanTLFullerDDBavisRWZabkaAGGolderFJDoperalskiNJ, and others. 2004. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci7(1):48–55.
11.
BaliMS. 2011. Diagnosis and surgical management of a fractured atlas in a cat. J Feline Med Surg13(4):280–2.
12.
BaronR. 2000. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain16(2, Suppl):S12–20.
13.
BeisswengerPJ. 1976. Neuropathic and vascular complications occurring in diabetes. Postgrad Med59(1):169–74.
14.
BensonCAFenrichKKOlsonKLPatwaSBangaloreLWaxmanSG, and others. 2020. Dendritic spine dynamics after peripheral nerve injury: an intravital structural study. J Neurosci40(22):4297–308.
15.
BergSLAleksicAMcGuffeyLDauserRNuchternJBernackyB, and others. 2004. Plasma and cerebrospinal fluid pharmacokinetics of rebeccamycin (NSC 655649) in nonhuman primates. Cancer Chemother Pharmacol54(2): 127–30.
16.
BertaTParkCKXuZZXieRGLiuTLuN, and others. 2014. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion. J Clin Invest124(3):1173–86.
17.
BessonJM. 1999. The neurobiology of pain. Lancet353(9164): 1610–5.
18.
BlackJALiuSTanakaMCumminsTRWaxmanSG. 2004. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain108(3):237–47.
19.
BodaBJourdainLMullerD. 2008. Distinct, but compensatory roles of PAK1 and PAK3 in spine morphogenesis. Hippocampus18(9):857–61.
20.
BolayHMoskowitzMA. 2002. Mechanisms of pain modulation in chronic syndromes. Neurology59(5, Suppl 2):S2–7.
21.
BongmbaOYMartinezLAElhardtMEButlerKTejada-SimonMV. 2011. Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology. Brain Res1399:79–95.
22.
BonhoefferTYusteR. 2002. Spine motility. Phenomenology, mechanisms, and function. Neuron35(6):1019–27.
23.
BorinMSaracenoCCataniaMLorenzettoEPontelliVPaterliniA, and others. 2018. Rac1 activation links tau hyperphosphorylation and Abeta dysmetabolism in Alzheimer’s disease. Acta Neuropathol Commun6(1):61.
24.
BoscoEEMulloyJCZhengY. 2009. Rac1 GTPase: a “Rac” of all trades. Cell Mol Life Sci66(3):370–4.
25.
BoultonA. 1992. What causes neuropathic pain?J Diabetes Complications6(1):58–63.
26.
BourneJHarrisKM. 2007. Do thin spines learn to be mushroom spines that remember?Curr Opin Neurobiol17(3):381–6.
27.
BourneJNHarrisKM. 2008. Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci31:47–67.
28.
BramhamCR. 2008. Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol18(5):524–31.
29.
CalabreseBSaffinJMHalpainS. 2014. Activity-dependent dendritic spine shrinkage and growth involve downregulation of cofilin via distinct mechanisms. PLoS One9(4): e94787.
30.
CalabreseBWilsonMSHalpainS. 2006. Development and regulation of dendritic spine synapses. Physiology (Bethesda)21:38–47.
31.
CaoXCPappalardoLWWaxmanSGTanAM. 2017. Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury. Mol Pain13:1744806916688016.
32.
ChangYWTanASaabCWaxmanS. 2010. Unilateral focal burn injury is followed by long-lasting bilateral allodynia and neuronal hyperexcitability in spinal cord dorsal horn. J Pain11(2):119–30.
33.
ChangYWWaxmanSG. 2010. Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury. J Pain11(11):1146–54.
34.
ChattopadhyayMMataMFinkDJ. 2008. Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J Neurosci28(26):6652–8.
35.
ChenLYRexCSBabayanAHKramarEALynchGGallCM, and others. 2010. Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. J Neurosci30(33): 10977–84.
36.
ChenXLevyJMHouAWintersCAzzamRSousaAA, and others. 2015. PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density. Proc Natl Acad Sci U S A112(50): E6983–92.
37.
ChenZZhangSNieBHuangJHanZChenX, and others. 2020. Distinct roles of srGAP3-Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel. J Physiol598(12):2415–30.
38.
ChirilaAMBrownTEBishopRABellonoNWPucciFGKauerJA. 2014. Long-term potentiation of glycinergic synapses triggered by interleukin 1beta. Proc Natl Acad Sci U S A111(22):8263–8.
39.
ChisholmKILo ReLPolgarEGutierrez-MecinasMToddAJMcMahonSB. 2021. Encoding of cutaneous stimuli by lamina I projection neurons. Pain162(9):2405–17.
40.
ClarkAKGentryCBradburyEJMcMahonSBMalcangioM. 2007. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain11(2):223–30.
ClarkAKWodarskiRGuidaFSassoOMalcangioM. 2010. Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia58(14):1710–26.
43.
CollinCMiyaguchiKSegalM. 1997. Dendritic spine density and LTP induction in cultured hippocampal slices. J Neurophysiol77(3):1614–23.
44.
CorbettaSGualdoniSCiceriGMonariMZuccaroETybulewiczVL, and others. 2009. Essential role of Rac1 and Rac3 GTPases in neuronal development. FASEB J23(5):1347–57.
45.
CornaraLBiagiMXiaoJBurlandoB. 2017. Therapeutic properties of bioactive compounds from different honeybee products. Front Pharmacol8:412.
46.
CostaJFDinesMLamprechtR. 2020. The role of Rac GTPase in dendritic spine morphogenesis and memory. Front Synaptic Neurosci12:12.
47.
CostiganMScholzJWoolfCJ. 2009. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci32:1–32.
48.
CoullJABeggsSBoudreauDBoivinDTsudaMInoueK, and others. 2005. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature438(7070):1017–21.
49.
CranerMJKleinJPBlackJAWaxmanSG. 2002a. Preferential expression of IGF-I in small DRG neurons and down-regulation following injury. Neuroreport13(13):1649–52.
50.
CranerMJKleinJPRenganathanMBlackJAWaxmanSG. 2002b. Changes of sodium channel expression in experimental painful diabetic neuropathy. Ann Neurol52(6):786–92.
51.
DrdlaRSandkuhlerJ. 2008. Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo. Mol Pain4:18.
52.
Drdla-SchuttingRBenrathJWunderbaldingerGSandkuhlerJ. 2012. Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration. Science335(6065):235–8.
53.
DrewGMSiddallPJDugganAW. 2004. Mechanical allodynia following contusion injury of the rat spinal cord is associated with loss of GABAergic inhibition in the dorsal horn. Pain109(3):379–88.
54.
DubreuilCIWintonMJMcKerracherL. 2003. Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system. J Cell Biol162(2):233–43.
55.
EcheverrySShiXQYangMHuangHWuYLorenzoLE, and others. 2017. Spinal microglia are required for long-term maintenance of neuropathic pain. Pain158(9):1792–801.
56.
El-HusseiniAESchnellEChetkovichDMNicollRABredtDS. 2000. PSD-95 involvement in maturation of excitatory synapses. Science290(5495):1364–8.
57.
EmptageNBlissTVFineA. 1999. Single synaptic events evoke NMDA receptor-mediated release of calcium from internal stores in hippocampal dendritic spines. Neuron22(1):115–24.
58.
ErschbamerMKHofstetterCPOlsonL. 2005. RhoA, RhoB, RhoC, Rac1, Cdc42, and Tc10 mRNA levels in spinal cord, sensory ganglia, and corticospinal tract neurons and long-lasting specific changes following spinal cord injury. J Comp Neurol484(2):224–33.
59.
FifkovaE. 1985. A possible mechanism of morphometric changes in dendritic spines induced by stimulation. Cell Mol Neurobiol5(1–2):47–63.
60.
FischerTZWaxmanSG. 2012. Extraterritorial temperature pain threshold abnormalities in subjects with healed thermal injury. J Rehabil Res Dev49(4):515–22.
61.
FreySFreyJU. 2008. ‘Synaptic tagging’ and ‘cross-tagging’ and related associative reinforcement processes of functional plasticity as the cellular basis for memory formation. Prog Brain Res169:117–43.
62.
FukazawaYSaitohYOzawaFOhtaYMizunoKInokuchiK. 2003. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron38(3):447–60.
63.
GaoYDickersonJBGuoFZhengJZhengY. 2004. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A101(20): 7618–23.
64.
GomezMKioussisDCantrellDA. 2001. The GTPase Rac-1 controls cell fate in the thymus by diverting thymocytes from positive to negative selection. Immunity15(5):703–13.
65.
Gonzalez-BillaultCMunoz-LlancaoPHenriquezDRWojnackiJCondeCCaceresA. 2012. The role of small GTPases in neuronal morphogenesis and polarity. Cytoskeleton (Hoboken)69(7):464–85.
66.
GosselinRDSuterMRJiRRDecosterdI. 2010. Glial cells and chronic pain. Neuroscientist16(5):519–31.
67.
GotoABotaAMiyaKWangJTsukamotoSJiangX, and others. 2021. Stepwise synaptic plasticity events drive the early phase of memory consolidation. Science374(6569): 857–63.
68.
Gruber-SchoffneggerDDrdla-SchuttingRHonigspergerCWunderbaldingerGGassnerMSandkuhlerJ. 2013. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J Neurosci33(15):6540–51.
69.
GuanZKuhnJAWangXColquittBSolorzanoCVamanS, and others. 2016. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci19(1):94–101.
70.
GuoYBensonCHillMHenrySEffraimPWaxmanSG, and others. 2018. Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury. Mol Pain14:1744806918788648.
71.
HaberMZhouLMuraiKK. 2006. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J Neurosci26(35):8881–91.
72.
HainsBCKleinJPSaabCYCranerMJBlackJAWaxmanSG. 2003. Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci23(26):8881–92.
73.
HainsBCWaxmanSG. 2006. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci26(16):4308–17.
74.
HalpainSSpencerKGraberS. 2005. Dynamics and pathology of dendritic spines. Prog Brain Res147:29–37.
75.
HasbargenTAhmedMMMiranpuriGLiLKahleKTResnickD, and others. 2010. Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury. Ann N Y Acad Sci1198:168–72.
76.
HayashiKOhshimaTHashimotoMMikoshibaK. 2007. Pak1 regulates dendritic branching and spine formation. Dev Neurobiol67(5):655–69.
77.
Hayashi-TakagiAYagishitaSNakamuraMShiraiFWuYILoshbaughAL, and others. 2015. Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature525(7569):333–8.
78.
HirokawaYArnoldMNakajimaHZalcbergJMarutaH. 2005. Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. Cancer Biol Ther4(9):956–60.
79.
HoltmaatASvobodaK. 2009. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci10(9):647–58.
80.
HoppeADSwansonJA. 2004. Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell15(8):3509–19.
81.
HsiehTHLeeHHCHameedMQPascual-LeoneAHenschTKRotenbergA. 2017. Trajectory of parvalbumin cell impairment and loss of cortical inhibition in traumatic brain injury. Cereb Cortex27(12):5509–24.
82.
HughesDIScottDTToddAJRiddellJS. 2003. Lack of evidence for sprouting of Abeta afferents into the superficial laminas of the spinal cord dorsal horn after nerve section. J Neurosci23(29):9491–9.
83.
HummelMLuPCummonsTAWhitesideGT. 2008. The persistence of a long-term negative affective state following the induction of either acute or chronic pain. Pain140(3): 436–45.
84.
IkedaHAsaiTMuraseK. 2000. Robust changes of afferent-induced excitation in the rat spinal dorsal horn after conditioning high-frequency stimulation. J Neurophysiol83(4):2412–20.
85.
IkedaHStarkJFischerHWagnerMDrdlaRJagerT, and others. 2006. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science312(5780):1659–62.
86.
ImpeySDavareMLesiakAFortinDAndoHVarlamovaO, and others. 2010. An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAK signaling. Mol Cell Neurosci43(1):146–56.
87.
JiRRKohnoTMooreKAWoolfCJ. 2003. Central sensitization and LTP: do pain and memory share similar mechanisms?Trends Neurosci26(12):696–705.
88.
JiRRWoolfCJ. 2001. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis8(1):1–10.
89.
KerrBJBradburyEJBennettDLTrivediPMDassanPFrenchJ, and others. 1999. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci19(12): 5138–48.
90.
KichinaJVGocAAl-HuseinBSomanathPRKandelES. 2010. PAK1 as a therapeutic target. Expert Opin Ther Targets14(7):703–25.
91.
KimBGDaiHNMcAteeMViciniSBregmanBS. 2006. Remodeling of synaptic structures in the motor cortex following spinal cord injury. Exp Neurol198(2):401–15.
92.
KimSKNabekuraJ. 2011. Rapid synaptic remodeling in the adult somatosensory cortex following peripheral nerve injury and its association with neuropathic pain. J Neurosci31(14):5477–82.
93.
KnottGWHoltmaatAWilbrechtLWelkerESvobodaK. 2006. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat Neurosci9(9):1117–24.
94.
LaGraizeSCLabudaCJRutledgeMAJacksonRLFuchsPN. 2004. Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Exp Neurol188(1):139–48.
95.
LaiKOIpNY. 2013. Structural plasticity of dendritic spines: the underlying mechanisms and its dysregulation in brain disorders. Biochim Biophys Acta1832(12):2257–63.
96.
LaMotteRHThalhammerJG. 1982. Response properties of high-threshold cutaneous cold receptors in the primate. Brain Res244(2):279–87.
97.
LangCBarcoAZablowLKandelERSiegelbaumSAZakharenkoSS. 2004. Transient expansion of synaptically connected dendritic spines upon induction of hippocampal long-term potentiation. Proc Natl Acad Sci U S A101(47):16665–70.
98.
LedeboerASloaneEMMilliganEDFrankMGMahonyJHMaierSF, and others. 2005. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain115(1–2): 71–83.
99.
LeeSJEscobedo-LozoyaYSzatmariEMYasudaR. 2009. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature458(7236):299–304.
100.
LiLZYinNLiXYMiaoYChengSLiF, and others. 2019. Rac1 modulates excitatory synaptic transmission in mouse retinal ganglion cells. Neurosci Bull35(4):673–87.
101.
LiuWTHanYLiHCAdamsBZhengJHWuYP, and others. 2009a. An in vivo mouse model of long-term potentiation at synapses between primary afferent C-fibers and spinal dorsal horn neurons: essential role of EphB1 receptor. Mol Pain5:29.
102.
LiuXGZhouLJ. 2015. Long-term potentiation at spinal C-fiber synapses: a target for pathological pain. Curr Pharm Des21(7):895–905.
103.
LiuYBromanJZhangMEdvinssonL. 2009b. Brainstem and thalamic projections from a craniovascular sensory nervous centre in the rostral cervical spinal dorsal horn of rats. Cephalalgia29(9):935–48.
104.
LiuYZhouLJWangJLiDRenWJPengJ, and others. 2017. TNF-alpha differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci37(4):871–81.
105.
LuYChristianKLuB. 2008. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?Neurobiol Learn Mem89(3):312–23.
106.
LuscherCNicollRAMalenkaRCMullerD. 2000. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat Neurosci3(6):545–50.
107.
MaQLYangFFrautschySAColeGM. 2012. PAK in Alzheimer disease, Huntington disease and X-linked mental retardation. Cell Logist2(2):117–25.
108.
MajewskaABrownERossJYusteR. 2000. Mechanisms of calcium decay kinetics in hippocampal spines: role of spine calcium pumps and calcium diffusion through the spine neck in biochemical compartmentalization. J Neurosci20(5):1722–34.
109.
MalcangioMRamerMSJonesMGMcMahonSB. 2000. Abnormal substance P release from the spinal cord following injury to primary sensory neurons. Eur J Neurosci12(1):397–9.
110.
MalenkaRC. 2003. The long-term potential of LTP. Nat Rev Neurosci4(11):923–6.
111.
ManserEChongCZhaoZSLeungTMichaelGHallC, and others. 1995. Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family. J Biol Chem270(42):25070–8.
112.
MareiHMalliriA. 2017. Rac1 in human diseases: the therapeutic potential of targeting Rac1 signaling regulatory mechanisms. Small GTPases8(3):139–63.
113.
MartielJLMouchetPBoissierMD. 1994. Modeling the integrative properties of dendrites: application to the striatal spiny neuron. Synapse16(4):269–79.
114.
MarutaH. 2011. Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1. Drug Discov Ther5(6):266–78.
115.
MarutaHHeH. 2020. PAK1-blockers: potential therapeutics against COVID-19. Med Drug Discov6:100039.
116.
MarutaHKittakaA. 2020. Chemical evolution for taming the ‘pathogenic kinase’ PAK1. Drug Discov Today25(6):959–64.
117.
MatsushitaTLankfordKLArroyoEJSasakiMNeyaziMRadtkeC, and others. 2015. Diffuse and persistent blood-spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells. Exp Neurol267:152–64.
118.
MatsuzakiMEllis-DaviesGCNemotoTMiyashitaYIinoMKasaiH. 2001. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci4(11):1086–92.
119.
MatsuzakiMHonkuraNEllis-DaviesGCKasaiH. 2004. Structural basis of long-term potentiation in single dendritic spines. Nature429(6993):761–6.
120.
MendellLM. 1966. Physiological properties of unmyelinated fiber projection to the spinal cord. Exp Neurol16(3):316–32.
121.
MikiHSuetsuguSTakenawaT. 1998. WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. EMBO J17(23):6932–41.
122.
MiyamotoAWakeHIshikawaAWEtoKShibataKMurakoshiH, and others. 2016. Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun7:12540.
123.
MogilJS. 2020. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat Rev Neurosci21(7):353–65.
124.
MorgadoCSilvaLPereira-TerraPTavaresI. 2011. Changes in serotoninergic and noradrenergic descending pain pathways during painful diabetic neuropathy: the preventive action of IGF1. Neurobiol Dis43(1):275–84.
125.
NairDHosyEPetersenJDConstalsAGiannoneGChoquetD, and others. 2013. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J Neurosci33(32):13204–24.
126.
NakayamaAYHarmsMBLuoL. 2000. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J Neurosci20(14):5329–38.
127.
NguyenPTDormanLCPanSVainchteinIDHanRTNakao-InoueH, and others. 2020. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell182(2):388–403.e15.
128.
NikolicM. 2008. The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain. Mol Neurobiol37(2–3):187–202.
129.
NoguchiJNagaokaAWatanabeSEllis-DaviesGCKitamuraKKanoM, and others. 2011. In vivo two-photon uncaging of glutamate revealing the structure-function relationships of dendritic spines in the neocortex of adult mice. J Physiol589(Pt 10):2447–57.
130.
OhDHanSSeoJLeeJRChoiJGroffenJ, and others. 2010. Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins. J Neurosci30(42):14134–44.
131.
PanFAldridgeGMGreenoughWTGanWB. 2010. Dendritic spine instability and insensitivity to modulation by sensory experience in a mouse model of fragile X syndrome. Proc Natl Acad Sci U S A107(41):17768–73.
132.
ParkerEMKindjaNLCheethamCEJSweetRA. 2020. Sex differences in dendritic spine density and morphology in auditory and visual cortices in adolescence and adulthood. Sci Rep10(1):9442.
133.
PatwaSBensonCADyerLOlsonKLBangaloreLHillM, and others. 2019. Spinal cord motor neuron plasticity accompanies second-degree burn injury and chronic pain. Physiol Rep7(23):e14288.
134.
Perez-AlvarezANavarreteMCoveloAMartinEDAraqueA. 2014. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J Neurosci34(38):12738–44.
135.
PriceTJCerveroFGoldMSHammondDLPrescottSA. 2009. Chloride regulation in the pain pathway. Brain Res Rev60(1):149–70.
136.
PriceTJGhoshS. 2013. ZIPping to pain relief: the role (or not) of PKMzeta in chronic pain. Mol Pain9:6.
137.
PriceTJRashidMHMillecampsMSanojaREntrenaJMCerveroF. 2007. Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci27(51):13958–67.
138.
RaemaekersTPericABaatsenPSannerudRDeclerckIBaertV, and others. 2012. ARF6-mediated endosomal transport of telencephalin affects dendritic filopodia-to-spine maturation. EMBO J31(15):3252–69.
139.
RajaSNCarrDBCohenMFinnerupNBFlorHGibsonS, and others. 2020. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain161(9):1976–82.
140.
RexCSChenLYSharmaALiuJBabayanAHGallCM, and others. 2009. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol186(1):85–97.
141.
RidleyAJ. 2006. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol16(10):522–9.
142.
RisherWCKimNKohSChoiJEMitevPSpenceEF, and others. 2018. Thrombospondin receptor alpha2delta-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol217(10):3747–65.
143.
SaabCYWaxmanSGHainsBC. 2008. Alarm or curse? The pain of neuroinflammation. Brain Res Rev58(1):226–35.
144.
SaberiRZadehAGAfsharMJAFakharMKeighobadiMMohtasebiS, and others. 2021. In vivo anti-leishmanial activity of concocted herbal topical preparation against Leishmania major (MRHO/IR/75/ER). Ann Parasitol67(3):483–8.
145.
Sanchez-VenturaJGimenez-LlortLPenasCUdinaE. 2021. Voluntary wheel running preserves lumbar perineuronal nets, enhances motor functions and prevents hyperreflexia after spinal cord injury. Exp Neurol336:113533.
146.
SandkuhlerJ. 2007. Understanding LTP in pain pathways. Mol Pain3:9.
147.
SaneyoshiTMatsunoHSuzukiAMurakoshiHHedrickNGAgnelloE, and others. 2019. Reciprocal activation within a kinase-effector complex underlying persistence of structural LTP. Neuron102(6):1199–210.e6.
148.
ScholzJWoolfCJ. 2007. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci10(11):1361–8.
149.
SchwechterBRosenmundCToliasKF. 2013. RasGRF2 Rac-GEF activity couples NMDA receptor calcium flux to enhanced synaptic transmission. Proc Natl Acad Sci U S A110(35):14462–7.
150.
SharmaKFongDKCraigAM. 2006. Postsynaptic protein mobility in dendritic spines: long-term regulation by synaptic NMDA receptor activation. Mol Cell Neurosci31(4):702–12.
151.
SoderlingSHBinnsKLWaymanGADaveeSMOngSHPawsonT, and others. 2002. The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling. Nat Cell Biol4(12):970–5.
152.
SokengSDTallaESakavaPFokam TagneMAHenoumontCSophieL, and others. 2020. Anti-inflammatory and analgesic effect of arachic acid ethyl ester isolated from propolis. Biomed Res Int2020:8797284.
153.
StrattonHJKhannaR. 2020. Sculpting dendritic spines during initiation and maintenance of neuropathic pain. J Neurosci40(40):7578–89.
154.
SvendsenFTjolsenAGjerstadJHoleK. 1999. Long term potentiation of single WDR neurons in spinalized rats. Brain Res816(2):487–92.
TanAMSamadOALiuSBandaruSZhaoPWaxmanSG. 2013. Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis. Exp Neurol248:509–19.
160.
TanAMStamboulianSChangYWZhaoPHainsABWaxmanSG, and others. 2008. Neuropathic pain memory is maintained by Rac1-regulated dendritic spine remodeling after spinal cord injury. J Neurosci28(49):13173–83.
TanAMWaxmanSG. 2015. Dendritic spine dysgenesis in neuropathic pain. Neurosci Lett601:54–60.
163.
TanakaJHoriikeYMatsuzakiMMiyazakiTEllis-DaviesGCKasaiH. 2008. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science319(5870):1683–7.
164.
TashiroAYusteR. 2004. Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility. Mol Cell Neurosci26(3):429–40.
165.
TashiroAYusteR. 2008. Role of Rho GTPases in the morphogenesis and motility of dendritic spines. Methods Enzymol439:285–302.
166.
ThompsonSWBennettDLKerrBJBradburyEJMcMahonSB. 1999. Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci U S A96(14):7714–8.
167.
ToddAJ. 2010. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci11(12):823–36.
168.
ToliasKFBikoffJBKaneCGToliasCSHuLGreenbergME. 2007. The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci U S A104(17):7265–70.
169.
TreedeRDHoheiselUWangDMagerlW. 2022. Central sensitization: clinical utility of a physiological concept for the International Statistical Classification of Diseases and Related Health Problems and for nociplastic pain. Pain163(Suppl 1):S99–S107.
170.
TremblayME. 2011. The role of microglia at synapses in the healthy CNS: novel insights from recent imaging studies. Neuron Glia Biol7(1):67–76.
171.
TremblayMELoweryRLMajewskaAK. 2010. Microglial interactions with synapses are modulated by visual experience. PLoS Biol8(11):e1000527.
172.
TremblayMEMajewskaAK. 2011. A role for microglia in synaptic plasticity?Commun Integr Biol4(2):220–2.
173.
UhlMSchmeisserMJSchumannS. 2022. The sexual dimorphic synapse: from spine density to molecular composition. Front Mol Neurosci15:818390.
174.
Van SteenwinckelJReaux-Le GoazigoAPommierBMauborgneADansereauMAKitabgiP, and others. 2011. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J Neurosci31(15):5865–75.
175.
WangLHDingWQSunYG. 2022. Spinal ascending pathways for somatosensory information processing. Trends Neurosci45(8):594–607.
176.
WangSMOoiLLHuiKM. 2011. Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma. Clin Cancer Res17(18):6040–51.
177.
WangYLuYFLiCLSunWLiZWangRR, and others. 2016. Involvement of Rac1 signalling pathway in the development and maintenance of acute inflammatory pain induced by bee venom injection. Br J Pharmacol173(5):937–50.
178.
WaxmanSGDib-HajjSCumminsTRBlackJA. 1999. Sodium channels and pain. Proc Natl Acad Sci U S A96(14):7635–9.
179.
WaxmanSGHainsBC. 2006. Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci29(4):207–15.
180.
WaxmanSGKocsisJDBlackJA. 1994. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol72(1):466–70.
181.
WegnerAMNebhanCAHuLMajumdarDMeierKMWeaverAM, and others. 2008. N-wasp and the arp2/3 complex are critical regulators of actin in the development of dendritic spines and synapses. J Biol Chem283(23): 15912–20.
182.
WellsCMWalmsleyMOoiSTybulewiczVRidleyAJ. 2004. Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci117(Pt 7):1259–68.
183.
WiensKMLinHLiaoD. 2005. Rac1 induces the clustering of AMPA receptors during spinogenesis. J Neurosci25(46): 10627–36.
184.
WoolfCJ. 1983. Evidence for a central component of post-injury pain hypersensitivity. Nature306(5944):686–8.
185.
WoolfCJKingAE. 1987. Physiology and morphology of multireceptive neurons with C-afferent fiber inputs in the deep dorsal horn of the rat lumbar spinal cord. J Neurophysiol58(3):460–79.
186.
WoolfCJKingAE. 1990. Dynamic alterations in the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat spinal cord. J Neurosci10(8):2717–26.
187.
WuZWangSWuIMataMFinkDJ. 2015. Activation of TLR-4 to produce tumour necrosis factor-alpha in neuropathic pain caused by paclitaxel. Eur J Pain19(7):889–98.
188.
XieZSrivastavaDPPhotowalaHKaiLCahillMEWoolfreyKM, and others. 2007. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron56(4):640–56.
189.
XuMAitaMChavkinC. 2008. Partial infraorbital nerve ligation as a model of trigeminal nerve injury in the mouse: behavioral, neural, and glial reactions. J Pain9(11):1036–48.
190.
YangHMattinglyRR. 2006. The Ras-GRF1 exchange factor coordinates activation of H-Ras and Rac1 to control neuronal morphology. Mol Biol Cell17(5):2177–89.
191.
YangYLiuJJ. 2022. Structural LTP: Signal transduction, actin cytoskeleton reorganization, and membrane remodeling of dendritic spines. Curr Opin Neurobiol74:102534.
192.
YusteRBonhoefferT. 2004. Genesis of dendritic spines: insights from ultrastructural and imaging studies. Nat Rev Neurosci5(1):24–34.
193.
YusteRMajewskaAHolthoffK. 2000. From form to function: calcium compartmentalization in dendritic spines. Nat Neurosci3(7):653–9.
194.
ZhaoPHillMLiuSChenLBangaloreLWaxmanSG, and others. 2016. Dendritic spine remodeling following early and late Rac1 inhibition after spinal cord injury: evidence for a pain biomarker. J Neurophysiol115(6):2893–910.
195.
ZhaoPWaxmanSGHainsBC. 2007. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci27(9):2357–68.
196.
ZhouLJPengJXuYNZengWJZhangJWeiX, and others. 2019. Microglia are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain. Cell Rep27(13): 3844–59.e6.
197.
ZhouQHommaKJPooMM. 2004. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron44(5):749–57.
198.
ZhouYQLiuDQChenSPSunJZhouXRLuoF, and others. 2017. Cellular and molecular mechanisms of calcium/calmodulin-dependent protein kinase II in chronic pain. J Pharmacol Exp Ther363(2):176–83.
