1 Nature Medicine 2010 Vol: 16(11):1258-1266. DOI: 10.1038/nm.2231

Central mechanisms of pathological pain

Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.

Mentions
Figures
Figure 1: Pain circuits.(a,b) A schematic overview of the main circuits mediating physiological pain (a) and some manifestations of chronic pain (b). Figure 2: Disease-induced functional and structural plasticity in neural substrates of pain.(a) Different levels of activity-dependent functional plasticity. Molecules may become functionally sensitized (top), synaptic transmission may become potentiated by presynaptic mechanisms (second row, arrow to the left) or by postsynaptic plasticity (arrow to the right), cells may respond to noxious stimuli with increased activity and expanded receptive fields after injury (third row) and network function may change so that more cell ensembles respond to noxious stimuli, collectively leading to a higher net spinal output after injury or inflammation (bottom). (b) Examples of nociceptive activity-induced structural plasticity. From the top, synaptic spines may increase in size and density; axons may sprout or degenerate; and cells may atrophy (for example, loss of inhibitory interneurons) or proliferate (for example, microglia and astrocytes). Figure 3: Spinal mechanisms of physiological pain and disease-induced pain hypersensitivity.(a,b) The diagrams show a few prominent of many possible mediators and cell-cell interactions in the spinal cord dorsal horn in physiological states (a) and disease states (b). Putative changes in pathological states include mechanisms involving suppression of inhibition, potentiation of presynaptic release and postsynaptic excitability, increases in synapse-to-nucleus communication and gene transcription, release of neuromodulators from activated microglia and astrocytes and a net increase in nociceptive input onto higher brain structures. Glu, glutamate; sP, substance P. Figure 4: Overview of typical signaling pathways used by pronociceptive molecules that mediate disease-induced pain hypersensitivity.Shown are typical ligands and the types of receptors and signaling mediators that they use to induce changes in the expression or function of target proteins, thereby leading to characteristic functional changes over diverse timescales. 5HT, serotonin; CGRP: calcitonin gene-related peptide; CRF, corticotrophin releasing factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IP3R, inositol 1,4,5-triphosphate receptor; DAG, diacylglycerol; P2X3, ATP-gated ion channel; 5-HT3, serotonin-gated ion channel; NK1: neurokinin receptor-1; PAR1-4, protease-activated receptors 1-4; ETA, endothelin receptor A; EP1, prostaglandin receptor-1; CCK, cholecystokinin; TrkA, neurotrophin receptor A; TrkB, neurotrophin receptor B; G-/GM-CSFR, G-CSF receptor and GM-CSF receptor pJAK, phosphorylated Janus-activated kinase; pSTAT, phosphorylated signal transducer and activator of transcription; PI3-K, phosphoinositol 3-kinase; pAKT, phosphoprotein kinase B; sGC, soluble guanylyl cyclase; PIP2, phosphoinositol diphosphate.
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References
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    • . . . These serine proteases include members of the coagulation cascade (for example, thrombin factor, plasminogen and tissue plasminogen activator), proteases from inflammatory cells (for example, cathepsin G) and proteases from epithelial tissues and neurons (for example, trypsin)34, 35, 36, 37, 38, 39 (Fig. 3b) . . .
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    • . . . Another intriguing mechanism for disinhibition of spinal neurons is related to a nerve injury–induced collapse of the chloride gradient, which is coupled with enhanced excitability in postsynaptic neurons52 . . .
    • . . . Loss of the postsynaptic potassium chloride exporter KCC2 mediates this phenomenon and leads to a reduction in GABA-mediated inhibitory postsynaptic currents52, a process that is aided by bone-derived neurotrophic factor (BDNF) released from microglia53 (Fig. 3b) . . .
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    • . . . Loss of the postsynaptic potassium chloride exporter KCC2 mediates this phenomenon and leads to a reduction in GABA-mediated inhibitory postsynaptic currents52, a process that is aided by bone-derived neurotrophic factor (BDNF) released from microglia53 (Fig. 3b) . . .
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    • . . . Depletion of KCC2 has also been implicated in the pathogenesis of pain associated with spinal cord injury54, diabetic neuropathy55 and other forms of chronic pain . . .
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    • . . . Depletion of KCC2 has also been implicated in the pathogenesis of pain associated with spinal cord injury54, diabetic neuropathy55 and other forms of chronic pain . . .
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    • . . . Collateral sprouting of low-threshold Aβ fibers on to 'nociceptive' second-order neurons in the spinal dorsal horn has been observed after peripheral injury61, but this might not occur consistently or in a sufficiently large magnitude62 . . .
  62. Bao, L. Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord Eur. J. Neurosci. 16, 175-185 (2002) .
    • . . . Collateral sprouting of low-threshold Aβ fibers on to 'nociceptive' second-order neurons in the spinal dorsal horn has been observed after peripheral injury61, but this might not occur consistently or in a sufficiently large magnitude62 . . .
  63. Zhang, Z.; Hefferan, M.P.; Loomis, C.W. Topical bicuculline to the rat spinal cord induces highly localized allodynia that is mediated by spinal prostaglandins Pain 92, 351-361 (2001) .
    • . . . Furthermore, the fact that disinhibition of spinal networks by acute blockade of spinal GABAergic or glycinergic transmission can induce immense tactile allodynia within minutes63 suggests that there must be a hard-wired pathway already in place that is normally under strong inhibitory control . . .
  64. Baba, H. Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn Mol. Cell. Neurosci. 24, 818-830 (2003) .
    • . . . Electrophysiological studies show that whereas only high-threshold monosynaptic inputs are found on pain- and temperature-sensitive spinal projection neurons under normal circumstances, blockade of local inhibition uncovers substantial Aβ, low-threshold fiber inputs, which are polysynaptic and require NMDA receptor activation to be functional64, 65. . . .
  65. Torsney, C.; Anderson, R.L.; Ryce-Paul, K.A.; MacDermott, A.B. Characterization of sensory neuron subpopulations selectively expressing green fluorescent protein in phosphodiesterase 1C BAC transgenic mice Mol. Pain 2, 17 (2006) .
    • . . . Electrophysiological studies show that whereas only high-threshold monosynaptic inputs are found on pain- and temperature-sensitive spinal projection neurons under normal circumstances, blockade of local inhibition uncovers substantial Aβ, low-threshold fiber inputs, which are polysynaptic and require NMDA receptor activation to be functional64, 65. . . .
    • . . . Interestingly, rats with arthritic pain show enhanced transmission at synapses in the CeA with afferents that bring nociceptive inputs from the parabrachial nucleus as well as those that bring polymodal sensory inputs from the basolateral amygdala65 . . .
  66. Kolhekar, R.; Murphy, S.; Gebhart, G.F. Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat Pain 71, 31-40 (1997) .
    • . . . Thalamic relay nuclei have a key role in gating, filtering and processing sensory information en route to the cerebral cortex and are subject to similar activity-induced plasticity processes as the spinal cord46, 66 . . .
  67. Cheong, E. Tuning thalamic firing modes via simultaneous modulation of T- and L-type Ca2+ channels controls pain sensory gating in the thalamus J. Neurosci. 28, 13331-13340 (2008) .
    • . . . The mGluR1/mGluR5-PLCβ pathway increases burst firing and decreases tonic firing in thalamocortical neurons by concurrently regulating T-type and L-type calcium currents67, and this process is associated with reduced visceral pain responses, suggesting that switching between the firing modes of thalamocortical neurons is a key mechanism for gating of incoming sensory nociceptive inputs. . . .
  68. Jeon, D. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC Nat. Neurosci. 13, 482-488 (2010) .
    • . . . The ACC mediates key emotional-aversive aspects of pain68 and may also have a mnemonic role in which it allows transient storage of information during pain processing . . .
    • . . . Peripheral nerve injury triggers long-term changes in excitatory synaptic transmission in layer 2/3 neurons in the ACC, recruiting both pre- and postsynaptic mechanisms of potentiation9, 69, which involve GluR-A–containing AMPARs, activation of ERK1 and ERK2 and the calcium-stimulated adenylyl cyclase-1 (refs. 68,69). . . .
  69. Cao, H. Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction and expression of affective pain J. Neurosci. 29, 3307-3321 (2009) .
    • . . . Peripheral nerve injury triggers long-term changes in excitatory synaptic transmission in layer 2/3 neurons in the ACC, recruiting both pre- and postsynaptic mechanisms of potentiation9, 69, which involve GluR-A–containing AMPARs, activation of ERK1 and ERK2 and the calcium-stimulated adenylyl cyclase-1 (refs. 68,69). . . .
  70. Fu, Y.; Neugebauer, V. Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior J. Neurosci. 28, 3861-3876 (2008) .
    • . . . This enhanced transmission is mediated by G protein signaling through mGluR1 and mGluR5 and corticotrophin-releasing factor receptors70, 71 . . .
  71. Neugebauer, V.; Li, W.; Bird, G.C.; Bhave, G.; Gereau, R.W. Synaptic plasticity in the amygdala in a model of arthritic pain: differential roles of metabotropic glutamate receptors 1 and 5 J. Neurosci. 23, 52-63 (2003) .
    • . . . This enhanced transmission is mediated by G protein signaling through mGluR1 and mGluR5 and corticotrophin-releasing factor receptors70, 71 . . .
  72. Delaney, A.J.; Crane, J.W.; Sah, P. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism Neuron 56, 880-892 (2007) .
    • . . . Furthermore, at glutamatergic synapses between CeA neurons and nociceptive inputs from the pontine parabrachial nuclues, endogenously released noradrenaline acting at presynaptic α2 receptors decreases the number of active release sites for glutamate with no change in release probability, suggesting that the CeA might be an important target region for the antinociceptive actions of noradrenaline72. . . .
  73. Eippert, F. Activation of the opioidergic descending pain control system underlies placebo analgesia Neuron 63, 533-543 (2009) .
    • . . . Such inhibitory mechanisms have evolutionary value because they can enable the organism to ignore pain in critical situations, such as flight or fight, and serve as a mechanistic basis for placebo-induced analgesia73 . . .
  74. Porreca, F.; Ossipov, M.H.; Gebhart, G.F. Chronic pain and medullary descending facilitation Trends Neurosci. 25, 319-325 (2002) .
    • . . . Converging lines of evidence from anatomical, electrophysiological and pharmacological studies show that the axis of the periaqueductal gray (PAG) and rostroventral medulla (RVM) can inhibit or facilitate sensory processing in the spinal dorsal horn74 . . .
    • . . . Pharmacological manipulations that increase synaptic levels of serotonin and noradrenaline, such as the use of tricyclic antidepressants and other classes of antidepressant, have gained prominence in the clinical management of chronic pain, particularly in therapy-resistant states such as neuropathic pain and fibromyalgia74, 75 . . .
    • . . . Recent years have brought substantial advances in the understanding of descending facilitation of pain by the PAG-RVM axis74 . . .
    • . . . Site-specific microinjections of local anaesthetics and lesion studies have helped to work out the circuitry that underlies this process and its functional role in mediating the facilitatory influences of supraspinal sites74, 75 . . .
    • . . . It is intriguing to note that in conditions of tissue injury or persistent activation of nociceptors, a phenotypic switch is seen in RVM neurons such that the incidence of on and off cells in the population increases, coupled with a corresponding decrease in neutral cells74, 75 . . .
  75. Heinricher, M.M.; Tavares, I.; Leith, J.L.; Lumb, B.M. Descending control of nociception: specificity, recruitment and plasticity Brain Res. Rev. 60, 214-225 (2009) .
    • . . . Pharmacological manipulations that increase synaptic levels of serotonin and noradrenaline, such as the use of tricyclic antidepressants and other classes of antidepressant, have gained prominence in the clinical management of chronic pain, particularly in therapy-resistant states such as neuropathic pain and fibromyalgia74, 75 . . .
    • . . . Site-specific microinjections of local anaesthetics and lesion studies have helped to work out the circuitry that underlies this process and its functional role in mediating the facilitatory influences of supraspinal sites74, 75 . . .
    • . . . It is intriguing to note that in conditions of tissue injury or persistent activation of nociceptors, a phenotypic switch is seen in RVM neurons such that the incidence of on and off cells in the population increases, coupled with a corresponding decrease in neutral cells74, 75 . . .
  76. Zhao, Z.Q. Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs J. Neurosci. 27, 6045-6053 (2007) .
    • . . . However, mice lacking a LIM homeobox transcription factor called Lmx1b, which lack serotonergic neurons in the adult CNS, show markedly reduced analgesia in response to opioids and antidepressants, suggesting that central serotonergic neurons constitute an important part of the descending pain modulatory circuitry that mediates analgesia induced by opioids and antidepressants76, 77. . . .
    • . . . Mice that genetically lack serotonergic neurons76 show enhanced inflammatory pain, which is attenuated by spinal delivery of serotonin, but also show decreased sensitivity to mechanical painful stimuli in basal (naive) conditions . . .
    • . . . One interpretation of these findings is that descending serotonergic pathways facilitate mechanical sensitivity in circumstances of acute pain, but that in inflammatory conditions the inhibitory influences of descending serotonergic neurons prevail76 . . .
  77. Zhao, Z.Q. Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward Proc. Natl. Acad. Sci. USA 104, 14519-14524 (2007) .
    • . . . However, mice lacking a LIM homeobox transcription factor called Lmx1b, which lack serotonergic neurons in the adult CNS, show markedly reduced analgesia in response to opioids and antidepressants, suggesting that central serotonergic neurons constitute an important part of the descending pain modulatory circuitry that mediates analgesia induced by opioids and antidepressants76, 77. . . .
  78. Zhang, W. Neuropathic pain is maintained by brainstem neurons co-expressing opioid and cholecystokinin receptors Brain 132, 778-787 (2009) .
    • . . . Neurons in the RVM that express both cholecystokinin receptor 2 and the μ-opioid receptor, which are directly activated by cholecystokinin input to the RVM, are important for descending facilitation and their ablation markedly reduces the duration of neuropathic pain78 . . .
  79. Wei, F.; Guo, W.; Zou, S.; Ren, K.; Dubner, R. Supraspinal glial-neuronal interactions contribute to descending pain facilitation J. Neurosci. 28, 10482-10495 (2008) .
    • . . . Persistent afferent inputs that arise from peripheral injury or inflammation produce neuroplastic changes in the RVM, such as activation and proliferation of microglia and astrocytes, phosphorylation of the p38 MAP kinase, release of BDNF and upregulation of NMDAR subunits79, 80 . . .
  80. Guo, W. Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation J. Neurosci. 26, 126-137 (2006) .
    • . . . Persistent afferent inputs that arise from peripheral injury or inflammation produce neuroplastic changes in the RVM, such as activation and proliferation of microglia and astrocytes, phosphorylation of the p38 MAP kinase, release of BDNF and upregulation of NMDAR subunits79, 80 . . .
  81. Suzuki, R.; Morcuende, S.; Webber, M.; Hunt, S.P.; Dickenson, A.H. Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways Nat. Neurosci. 5, 1319-1326 (2002) .
    • . . . Interestingly, the ablation of lamina 1 projection neurons, which express neurokinin 1 receptors, leads to a decrease in activity-induced activation of serotonergic neurons in the brain stem and to loss of descending facilitation81 . . .
  82. Fields, H.L. Pain modulation: expectation, opioid analgesia and virtual pain Prog. Brain Res. 122, 245-253 (2000) .
    • . . . A widely accepted theory proposes that two distinct populations of neurons in the brainstem, 'on cells' and 'off cells', are differentially recruited by higher brain structures in conditions of chronic pain, stress or fear to facilitate or inhibit pain at the spinal level82 . . .
  83. Edelmayer, R.M. Medullary pain facilitating neurons mediate allodynia in headache-related pain Ann. Neurol. 65, 184-193 (2009) .
    • . . . For example, application of inflammatory mediators to the dura leads to an activation of on cells and a transient inhibition of off cells in the RVM, which is associated with facial allodynia in headache-related pain83. . . .
  84. Li, P.; Zhuo, M. Silent glutamatergic synapses and nociception in mammalian spinal cord Nature 393, 695-698 (1998) .
    • . . . Importantly, serotonin applied spinally can transform silent glutamatergic synapses into functional ones by insertion of AMPARs84 . . .
  85. Wei, F. Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain J. Neurosci. 30, 8624-8636 (2010) .
    • . . . However, this notion is not fully supported by a recent study, which reports that selective depletion of serotonin in RVM neurons by local RNA interference of tryptophan hydroxylase-2, the rate-limiting enzyme in the synthesis of neuronal serotonin, attenuates tissue or nerve injury-induced allodynia and hyperalgesia85 . . .
  86. Seminowicz, D.A. Regional gray matter density changes in brains of patients with irritable bowel syndrome Gastroenterology 139, 48-57 (2010) .
    • . . . At the macroscopic anatomical level, long-term neuropathic pain in humans has widespread effects on brain anatomy related to the duration and magnitude of pain86 . . .
    • . . . Local morphological alterations in the brain, mostly representing a decrease in the brain gray matter, have been reported in people with phantom pain, chronic back pain, irritable bowel syndrome, fibromyalgia and headaches, among others86, 87 . . .
  87. May, A. Morphing voxels: the hype around structural imaging of headache patients Brain 132, 1419-1425 (2009) .
    • . . . Local morphological alterations in the brain, mostly representing a decrease in the brain gray matter, have been reported in people with phantom pain, chronic back pain, irritable bowel syndrome, fibromyalgia and headaches, among others86, 87 . . .
  88. Rodriguez-Raecke, R.; Niemeier, A.; Ihle, K.; Ruether, W.; May, A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain J. Neurosci. 29, 13746-13750 (2009) .
    • . . . Furthermore, the decrease in gray matter associated with chronic pain is at least partially reversible when pain is successfully treated, suggesting that these structural changes are a reversible consequence of frequent nociceptive inputs88 . . .
  89. Seminowicz, D.A. MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain Neuroimage 47, 1007-1014 (2009) .
    • . . . Interestingly, these changes have been modeled successfully in rats, making it possible to carry out mechanistic studies into the functional relevance of the observations made in chronic pain patients89. . . .
  90. Schweizerhof, M. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain Nat. Med. 15, 802-807 (2009) .
    • . . . Striking changes in the structure of nerves such as denervation, renervation, sprouting and hypertrophy have been reported in peripheral tissues, such as the skin, bone or visceral organs in pathological pain states in humans and experimental animals90, 91, 92, 93 (Fig. 1b) . . .
    • . . . The functional role of such morphological changes is not clear, especially as most of the morphological studies have been done on fixed tissue in biopsies, which precludes an unequivocal causal association with changes in pain perception90, 91, 92 . . .
  91. Ceyhan, G.O. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases Gastroenterology 136, 177-186 (2009) .
    • . . . Striking changes in the structure of nerves such as denervation, renervation, sprouting and hypertrophy have been reported in peripheral tissues, such as the skin, bone or visceral organs in pathological pain states in humans and experimental animals90, 91, 92, 93 (Fig. 1b) . . .
  92. Siau, C.; Xiao, W.; Bennett, G.J. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells Exp. Neurol. 201, 507-514 (2006) .
    • . . . Striking changes in the structure of nerves such as denervation, renervation, sprouting and hypertrophy have been reported in peripheral tissues, such as the skin, bone or visceral organs in pathological pain states in humans and experimental animals90, 91, 92, 93 (Fig. 1b) . . .
  93. Cain, D.M. Functional interactions between tumor and peripheral nerve: changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain J. Neurosci. 21, 9367-9376 (2001) .
    • . . . Striking changes in the structure of nerves such as denervation, renervation, sprouting and hypertrophy have been reported in peripheral tissues, such as the skin, bone or visceral organs in pathological pain states in humans and experimental animals90, 91, 92, 93 (Fig. 1b) . . .
    • . . . For example, in animal models of cancer-induced pain, recurring cycles of denervation and renervation occur, which may lead to confounding results across studies depending upon which time point was examined93 . . .
  94. Hofer, S.B.; Bonhoeffer, T. Dendritic spines: the stuff that memories are made of? Curr. Biol. 20, R157-R159 (2010) .
    • . . . Perhaps the most exciting form of structural plasticity refers to activity-dependent changes in dendritic spines, which define the strength of excitatory synaptic transmission94 (Fig. 1b) . . .
  95. Saneyoshi, T.; Fortin, D.A.; Soderling, T.R. Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways Curr. Opin. Neurobiol. 20, 108-115 (2010) .
    • . . . Sensory inputs can profoundly alter both the stability and function of synaptic contacts by inducing activity-dependent changes in spines over a time scale ranging from seconds to hours or even days95 . . .
    • . . . Interestingly, several key mediators of spine stabilization and turnover, which have been studied in brain circuits95, overlap with molecules that mediate spinal pain hypersensitivity, such as AMPARs, NMDARs, CamKIIα and ephrins as well as other RTKs (Fig. 2b) . . .
  96. Yang, G.; Pan, F.; Gan, W.B. Stably maintained dendritic spines are associated with lifelong memories Nature 462, 920-924 (2009) .
    • . . . However, new evidence shows that a small fraction of new spines generated by a novel sensory experience are preserved and are associated with life-long memories96 . . .
  97. Tan, A.M. Neuropathic pain memory is maintained by Rac1-regulated dendritic spine remodeling after spinal cord injury J. Neurosci. 28, 13173-13183 (2008) .
    • . . . Neuropathic pain resulting from spinal cord injury is associated with both increased de novo formation and elaboration of dendritic spines in spinal laminae IV and V97. . . .
    • . . . Furthermore, most signaling pathways that link synaptic activity to spine morphology influence local actin dynamics97, 98 . . .
    • . . . In this context, it is interesting to note that modulation of spine morphology and density in the spinal dorsal horn induced by spinal cord injury is reversed by inhibiting Rac1, which also leads to amelioration of injury-induced hyperalgesia97 (Fig. 2b) . . .
  98. Hotulainen, P.; Hoogenraad, C.C. Actin in dendritic spines: connecting dynamics to function J. Cell Biol. 189, 619-629 (2010) .
    • . . . From studies on the brain, it is known that changes in the shape and size of dendritic spines are determined by rapid remodelling of the underlying actin cytoskeleton98 . . .
    • . . . Furthermore, most signaling pathways that link synaptic activity to spine morphology influence local actin dynamics97, 98 . . .
  99. Luo, L. Rho GTPases in neuronal morphogenesis Nat. Rev. Neurosci. 1, 173-180 (2000) .
    • . . . For example, the Rho/Rac families of GTPases transduce signals coming from extracellular stimuli (such as ephrins or glutamate) to the actin cytoskeleton and contribute to plasticity in dendritic spines99 . . .
  100. Eroglu, C. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis Cell 139, 380-392 (2009) .
    • . . . Gabapentin is an inhibitor of α2δ-1, which was proposed to be a component of voltage-sensitive calcium channels; however, it was recently found that α2δ-1 constitutes a thrombospondin receptor and gabapentin inhibits excitatory synaptogenesis in the brain by antagonizing thrombospondin binding to α2δ-1, a mechanism that has been linked to the antiepileptic actions of gabapentin100 . . .
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