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Short communication
Dendritic spine dysgenesis in neuropathic pain Andrew M. Tan a,b,∗ , Stephen G. Waxman a,b a b
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA Department of Neurology and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA
a r t i c l e
i n f o
Article history: Received 26 September 2014 Received in revised form 12 November 2014 Accepted 15 November 2014 Available online xxx Keywords: Neuropathic pain Dendritic spine SCI Rac1 Diabetes Nerve injury Plasticity Nociception Spinal cord
a b s t r a c t Neuropathic pain is a significant unmet medical need in patients with variety of injury or disease insults to the nervous system. Neuropathic pain often presents as a painful sensation described as electrical, burning, or tingling. Currently available treatments have limited effectiveness and narrow therapeutic windows for safety. More powerful analgesics, e.g., opioids, carry a high risk for chemical dependence. Thus, a major challenge for pain research is the elucidation of the mechanisms that underlie neuropathic pain and developing targeted strategies to alleviate pathological pain. The mechanistic link between dendritic spine structure and circuit function could explain why neuropathic pain is difficult to treat, since nociceptive processing pathways are adversely “hard-wired” through the reorganization of dendritic spines. Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in neuropathic pain. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease, which accompany chronic intractable pain: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presents as a mushroomshaped spine. Given the important functional implications of spine distribution, density, and shape for synaptic and neuronal function, the study of dendritic spine abnormality may provide a new perspective for investigating pain, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies. Published by Elsevier Ireland Ltd.
Neuropathic pain is a significant unmet medical need in patients with a variety of disease and injury insults to the nervous system, including spinal cord injury (SCI) or diabetic neuropathy. Individuals with neuropathic pain often describe their pain sensation as electrical, burning, tingling, or crushing. The severity of neuropathic pain can be so great that sufferers may contemplate or even commit suicide [66,82]. Currently available treatment options have limited effectiveness and small margin of safety; more powerful analgesics, e.g., opioids, carry a high risk of dependence [62,75]. Thus, a major challenge for pain research is the elucidation of the mechanisms that underlie neuropathic pain and development of new therapeutic strategies that target abnormal pain-associated mechanisms to alleviate neuropathic pain.
∗ Corresponding author at: Center for Neuroscience and Regeneration Research (127A), 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA. Tel.: +1 203 932 5711x3663; fax: +1 203 937 3801. E-mail address: [email protected] (A.M. Tan).
1. Pain pathway from the PNS to CNS Normal pain perception begins with a stimulus detected by sensory receptors located in the skin, internal organs, or other peripheral regions of the body [90]. Painful input is transduced and action potentials are electrically propagated along these peripheral nerves toward and through the heterogeneous cell populations of the dorsal root ganglia (DRG). Primary afferents from DRG neurons project into the spinal cord where they terminate within different laminae depending on the type of sensory modality. For example, high threshold mechanical pain or heat stimulus carried by unmyelinated C-fibers or thinly myelinated A-fibers terminate within superficial dorsal horn laminae [5]. Low-threshold tactile sensations carried through larger diameter myelinated A-fibers may synapse upon secondary nociceptors located in the deeper intermediate zone of the spinal cord [92,93]. A particular focus of many pain studies is a class of “convergent” neurons in the spinal cord called wide dynamic range (WDR) neurons [46]. WDR neurons are generally located in deeper laminae of the dorsal horn (i.e., 4–6) and respond to all somatosensory modalities, including thermal and mechanical stimuli. WDR neurons send
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Fig. 1. Dendritic spines develop and mature to influence synaptic function. Larger, mature spines appear as mushroom-shaped structures, generally contain increased glutamatergic receptor density, e.g., AMPA or NMDA receptors, and represent stronger and more stable synapses. In contrast, thin or filopodia dendritic spines are associated with absent, weaker, or less mature synaptic connections [68].
ascending projections through the spinothalamic tract, a major pain pathway to the brain, and thus, act as intermediate relay points or “gateway” neurons for nociception. A unique characteristic of WDR neurons is that they increase their firing rates as the intensity of peripheral stimulation increases. For example, as a light, innocuous brushing of the skin transitions to noxious pinching or poking stimuli, WDR neurons will increase their action potential firing frequency. Thus, electrophysiological recordings of WDR neurons provide a powerful empirical readout of the global nociceptive activity within the CNS. Importantly, abnormally increased WDR neuron responsiveness, i.e., hyperexcitability, to stimulation is associated with neuropathic pain [75,90]. 2. Synaptic basis for neuropathic pain Multiple mechanisms along the PNS–CNS neuraxis contribute to hyperexcitability of nociceptive neurons, including WDR neurons, associated with neuropathic pain after injury or disease. These mechanisms include the loss of inhibitory inputs [44,96,98,99], inflammation [27,50,76,89,101,], dysregulation of potassium-chloride co-transporter 2 (KCC2) activity [13,28,55], and sodium channel misexpression [14,26,100]. Emerging evidence demonstrates that learning and memory mechanisms share mechanistic similarities with pain [45,60,74,94]. Traditionally studied in the cortex, the most well understood and established biological concept for learning and memory is the synaptic model of long-term potentiation (LTP). LTP is defined as the increase in synaptic efficacy as a result of synchronous activity between neurons [22,30,42]. In the early phase of LTP following an activity-dependent induction event, there are two general changes in the postsynaptic membrane including (1) an increase in the number and clustering of glutamatergic receptors, e.g., AMPA receptors, in the postsynaptic membrane, and (2) a post-translational increase in postsynaptic receptor activity. Because early phases of LTP are translational-independent (i.e., do not require protein synthesis), increased synaptic strength via LTP can develop over the course of minutes. Interestingly, others have shown that LTP can occur rapidly within spinal cord pain pathways in vivo [16,31,60,61]. High frequency stimulation (e.g., tetanic stimulation) and inflammation can lead to LTP induction between primary C-fiber afferents and nociceptive neurons in the superficial dorsal horn and widedynamic range (WDR) neurons located in the intermediate zone [67]. Further evidence demonstrates that nervous system injury
or disease can contribute to adverse changes in synaptic reorganization by engaging similar synaptic-based plasticity mechanisms in spinal cord pain pathways. Injuries, such as SCI or peripheral nerve injury, increase glutamate signaling, release of neuromodulator substance-P, and neurotrophic factors, i.e., BDNF. The signaling of these molecules operates downstream through an elevation of intracellular calcium, which consequently leads to synaptic potentiation [15,29,34,36]. Taken together, synaptic reorganization in spinal cord pain circuitry is a well-known phenomenon that can partially explain central sensitization (i.e., amplified excitability of neurons and circuits in nociceptive pathways) associated with neuropathic pain [33]. Dendritic spines represent sites of synaptic contact and are found throughout the nervous system primarily on “spiny” neurons that receive convergent input, such as hippocampal neurons, pyramidal neurons in the cortex, and dorsal horn neurons in the spinal cord [24,35,75]. To maintain synaptic efficacy in the longterm, dendritic spines may develop, reorganize, and mature (Fig. 1). Activation of downstream kinases, such as PKA, PKC, and extracellular signal-related kinase (ERK), ultimately lead to the prerequisite events, i.e., gene transcription, protein synthesis, actin cytoskeletal reorganization, that contribute to dendritic spine remodeling [1,8,32,43,77,95]. Thus, the architecture of dendritic spines is highly regulated by multiple molecular signaling pathways. A single neuron may contain hundreds of dendritic spines of varied shapes and geometries, which have been generally categorized using simple descriptors, including “mushroom”, “thin or filopodia”, or “stubby” [3,6] (Fig. 2A). The morphology of individual dendritic spines directly contributes to regulating local synaptic function [19,83]. Large, mushroom-shaped dendritic spines are associated with mature, stabilized synapses (which have increased glutamaterigic receptor density) and memory formation, whereas thin or filopodia-like spines are associated with weaker or developing, less-mature synapses (Fig. 1). At the cellular level, an increase in dendritic spine density also represents an increase in excitatory inputs upon a postsynaptic neuron, which may increase the overall excitability of a neural circuit [7]. Taken together, dendritic spine remodeling provides a structural-based mechanism for modifying and maintaining long-term synaptic function. The chronicity of neuropathic pain underscores the importance of understanding the contribution of dendritic spine dysgenesis within nociceptive pathways [4,65,71]. The mechanistic link
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hyperalgesia, in which heat-pain thresholds decrease. More specifically, WDR neurons display increased evoked action potential firing rates that are more than 50% greater than uninjured animals without pain [74]. Interestingly, the increased excitability and electrical properties of WDR neurons in vivo are analogous to the predictions made by computer simulations, which showed that changes in dendritic spine morphology alone can alter electrical function of neurons [71]. Together, these findings in SCI first revealed support for a mechanistic relationship between abnormal dendritic spines and dysfunctional nociception. 4. Dendritic spines in peripheral nerve injury
Fig. 2. (A) Dendritic spines vary in shape. Common descriptors include stubby, filopodia or thin, and mushroom spines. (B) Abnormal dendritic spine morphologies on WDR neurons are associated with abnormal nociceptive function, including behavioral and electrophysiological evidence of neuropathic pain. Following injury or disease, dendritic spines on WDR neurons generally increase in density, redistribute to locations along dendrite branches closer to the cell body, and exhibit increased spine head diameter, e.g., indicating stronger and stable or mature synapses (red dots = mushroom spines; blue dots = thin spines). For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.
between dendritic spine structure and circuit function could explain why neuropathic pain is difficult to treat, since nociceptive processing pathways are adversely “hard-wired” through the reorganization of dendritic spines. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presented as a mushroom-shaped spine [72,75] (Fig. 2B). These changes in the morphological characteristics of dendritic spines accompany nociceptive hyperexcitability and behavioral symptoms of neuropathic pain. Given the important functional implications of spine distribution, density, and shape for neuronal function [54,56,71], a more thorough understanding of dendritic spine changes within nociceptive circuits is likely to advance our understanding of pathological chronic pain. Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in mechanisms underlying neuropathic pain. 3. Dendritic spines in spinal cord injury Dendritic spine morphologies change significantly on WDR neurons after spinal cord injury (SCI) [74]. Dendritic spine density increases and redistributes along dendritic branches in regions closer to the cell body. The shape of dendritic spines also changes, increasing in length and spine head diameter. Abnormal physiological and behavioral effects accompany abnormal dendritic spine structure following SCI; with WDR neurons exhibiting hyperexcitability in response to both evoked innocuous and noxious stimulation in electrophysiological recordings. SCI animals also demonstrate evidence of neuropathic tactile allodynia, in which non-painful touch stimuli are perceived as painful, and heat
Peripheral nerve injury models are well established and widely used tools for investigations of neuropathic pain [85]. A peripheral nerve injury, such as chronic constriction or transection of the sciatic nerves in the hindlimb, induces primary afferent plasticity, which may have a role in the development of neuropathic pain. Robust plasticity of neurons within nociceptive circuits in the spinal cord following peripheral nerve injury is less understood. As with SCI, recent work has shown that WDR neurons ipsilateral to a chronic constriction injury (CCI) to the sciatic nerve show a significant increase in dendritic spine density and an altered spine distribution ten days after injury [70]. WDR neurons in the areas innervated by the injured nerves also exhibit hyperexcitability and increased responsiveness (i.e., elevated firing rate) to low and highthreshold stimuli applied to these neurons’ cutaneous receptive fields. These findings are particularly intriguing because the trauma began in the PNS, and the pathological changes transition into the CNS. This observation suggests the existence of a putative PNS–CNS signal that participates in structural reorganization within the spinal cord nociceptive system. Potential candidates for such a transneuronal signal may include remote neuroimmune signals, e.g., cytokine release [59,81,102]. Microglia may also have a role as they become activated, i.e., microgliosis, following nerve injury as part of the inflammatory response within the spinal cord. Activated microglia and astrocytes have both been implicated in central sensitization after peripheral nerve injury [63]. Importantly, these observations are relevant to dendritic spine behavioral and physiology: as demonstrated by high-resolution electron microscopy of the hippocampus, microglial processes directly contact synaptic dendritic spine structures, and in live time-lapse studies, astrocytes have been shown to readily extend processes that interact with dendritic spines. In the latter, astrocyte-spine dynamic interactions were most coordinated at sites of more stable, larger mature dendritic spines [25,49]. Taken together, evidence suggests the involvement of non-neuronal cell populations in mechanisms regulating dendritic spine structure that contribute to injury-induced neuropathic pain. 5. Dendritic spines in thermal cutaneous burn injury The mechanisms underlying chronic pain following cutaneous burn injury have been largely unexplored. This is in part due to the complexity of burn injuries, which can be of varying location, size, and severity, e.g., burn degree scale. Nonetheless, in more common models of moderate burn injury (i.e., second degree, partial skin-thickness burns) there is an acute primary hyperalgesia, which presents rapidly within the cutaneous field of the burn injury site. This is followed by a progressive expansion of the secondary tactile allodynia response to the surrounding uninjured areas of the skin [2,21,86]. The inflammatory response within the skin, nerves, and spinal cord, e.g., microglia, MAPK activation has been shown to contribute to the burn injury-induced pain phenotype. Pain after burn injury also develop as a result of injury to peripheral nerve endings, which are highly sensitized to
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stimuli. Indeed, maladaptive structural plasticity within the CNS has also been cited as an explanation for the notorious opioid resistance observed in human burn patients [37]. In a study using adult rats, similar to earlier findings in pain models, unilateral seconddegree burn injury on the hind paw resulted in abnormal dendritic spine changes on ipsilateral WDR neurons, including increased spine density, redistribution, and more mature mushroom shapes [73]. These structural profiles accompanied an expansion of the cutaneous receptive fields, increased nociceptive hyperexcitability, and the development of tactile allodynia. While this study did not include a time-course investigation to examine the transition from acute inflammatory pain to chronic pain following burn injury, the main findings strongly support a link between the presence of abnormal dendritic spines and abnormal pain after thermal burn injury.
6. Dendritic spines in diabetic mellitus Mechanisms underlying diabetic neuropathic pain have been particularly elusive due to the complexity of metabolic diseases, which affect the entire body. Mechanisms that may contribute to diabetic neuropathic pain, include peripheral neuropathy, i.e., nerve damage as a result of secondary vascular disease, dysfunctional KCC2, and sodium channel misexpression in DRG neurons [14,20,38,80]. As with many other diseases that contribute to the development of neuropathic pain, maladaptive neuroplasticity within nociceptive circuits may also be a mechanism underlying diabetic neuropathic pain. Although most diabetic pain studies focus on the PNS as the source of pain, abnormal changes within the CNS may further account for diabetic neuropathic pain [20]. In a streptozotocin (STZ)-induced diabetic neuropathic pain model, dendritic spine reorganization occurred on WDR neurons in the spinal cord [72]. STZ is a specific toxin for insulin-producing pancreatic beta cells and administration of the compound significantly increases blood
glucose levels (i.e., hyperglycemia) to produce a model of type 1 diabetes [47]. In contrast to other injury-pain models, the study of STZ-induced neuropathic pain revealed the existence of a time window wherein hyperglycemic animals (soon after STZ-induction) had both near-normal dendritic spine profiles and normal pain thresholds [72]. This was followed by spine dysgenesis, which developed with a time-course paralleling that of behavioral signs of pain. These observations share two important implications: first, there is temporal relationship between the dendritic spine structure and pain phenotype, and second that the presence of maladaptive dendritic spines predicts the manifestation of neuropathic pain. This structure-function relationship in diabetic disease suggests that there is a therapeutic window for intervention (e.g., targeting mechanisms of dendritic spine remodeling) in early-diabetes that could prevent the transition from pre-diabetic conditions to the establishment of intractable neuropathic pain. As yet, it is not known whether dendritic spine changes in diabetes are a direct result of the hyperglycemic condition, secondary inflammation [53,69], or changes in presynaptic elements [72,87].
7. Regulation of dendritic spine dysgenesis The Rac1 kinase is one of the most well-studied regulatory molecules that govern dendritic spine behavior [12,57,64,79]. Rac1 is a small intracellular protein (∼21 kDa) in the family of Rho GTPases [58], which regulates a host of cellular functions, including actin cytoskeletal organization and glutamaterigc AMPA receptor clustering in the postsynaptic membrane of dendritic spines [97]. In the hippocampus, dominant negative expression of Rac1 (mutant RacN17) decreases spine density and inhibits spine maturation [48,78]; whereas constitutively activated Rac1 increases the rate of spine turnover, density, and increases spine volume. Importantly, in animal models of stress or neurotrauma, Rac1 mRNA expression and activation increase after SCI, remaining elevated for up to three months [17,18].
Fig. 3. (A) Representative silhouette renderings of Golgi-stained spinal cord tissue summarize the morphological effect on dendritic spines from several injury/disease models of neuropathic pain (black color) as compared with normal (gray color). These abnormal dendritic spine profiles accompany behavioral symptoms and electrophysiological signs of neuropathic pain. However, following Rac1-inhibitor treatment, there is a reduction in injury/disease-induced abnormal spine profiles (gray with outline) and attenuated pain phenotype. (B) Quantitation of mushroom-shaped spine density demonstrated a significant reduction in spine density, which was within near-normal ranges, after Rac1-inhibitor treatment [70,72–74]. Note that this figure should be taken as a qualitative overview of previous findings, and a retrospective comparison across injury/disease effects on dendritic spines was not performed.
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A Rac1-specific inhibitor, NSC23766, has been a powerful tool for understanding the role of Rac1-regulation of dendritic spines and neuropathic pain [23] (Fig. 3). NSC23766 blocks Trio and Tiam1, guanine exchange factors, without interrupting with related GTPases cdc42 or Rho-GEF; importantly, NSC23766 does not affect Rac1 binding to its effector PAK1 [23]. Treatment with NSC23766 of spinal cord dorsal horn neurons in vitro effectively decreases dendritic spine density [70]. In vivo, intrathecal administration of NSC23766 in rats with SCI reduces protein levels of postsynaptic density marker, PSD-95, without affecting the presynaptic terminal-associated protein, synaptophysin [74], suggesting that NSC23766 administration has a preferential effect on postsynaptic elements. Treatment with NSC23766 over three days restores a near-normal dendritic spine profile on WDR neurons following SCI: including a normalization of dendritic spine density, spine length, and spine head diameter. Along with these structural changes, NSC23766 treatment in SCI animals increases mechanical and thermal pain thresholds and evoked-WDR neuron electrical responses back to near-normal levels [74]. Similarly, in a peripheral nerve injury and a thermal burn-injury pain model, NSC23766 inhibition of Rac1 disrupts abnormal dendritic spine remodeling and attenuates physiological evidence of neuropathic pain [70]. Previous studies have demonstrated that inhibitors of RhoA/Rho kinases (ROCK inhibitors) may have effectiveness in treating diabetic neuropathic pain [52]. In agreement, NSC23766 treatment in an STZ-induced diabetic neuropathic pain model also resulted in a reduction in neuropathic mechanical allodynia and attenuated WDR neuron hyperexcitability [72]. Close-to-normal dendritic spine profiles accompanied these physiological effects of NSC23766 (Fig. 3). However, unlike the effects of the compound in SCI, NSC23766 failed to restore heat pain thresholds to normal levels in peripheral nerve- or burn-injury pain or diabetic neuropathic pain models, suggesting that Rac1-inhibition has a differential action on mechanical and thermal sensory modalities, at least under these injury/disease-induced painful conditions. It is unknown whether dendritic spine profiles change on other cell-types within the nociceptive system, e.g., lamina II. Aberrant dendritic spine profiles on different spinal cord neurons could explain discrepancies in neuropathic pain responses. Moreover, NSC23766 treatment only partly restores mechanical pain thresholds in these studies, which suggests that other factors contribute to neuropathic pain phenotype [10,11,41,70,72,73]. The mode and action of pharmacological Rac1 inhibition is not clear. NSC23766 treatment alleviates SCI-induced pain without affecting gross locomotor behavior [74], suggesting that the compound fails to significantly affect the spinal cord motor system when used at an effective analgesic dosage. Although microgliosis contributes to chronic pain and Rac1-activity regulates microglial lamellipodia formation and membrane ruffling [51], NSC23766 treatment did not affect levels of elevated microglial-immunoreactivity in the spinal cord dorsal horn following peripheral nerve injury [70]. Treatment with NSC23766 in uninjured animals had no observable effect on electrical or behavioral outcomes in nociceptive assessments [72]. Despite these observations, systemic effects of drug administration in vivo are likely to have yet to be reported off-target actions; thus, genomic tools, e.g., genetic manipulation or transgenic mice, may provide more powerful tools for understanding mechanisms that underlie dendritic spine remodeling in neuropathic pain. 8. Implications and horizons The mechanistic link between dendritic spine structure and nociceptive function in the spinal cord extends into other CNS modalities. Hyperreflexia and spasticity are common after SCI, multiple sclerosis, and stroke. Although mechanisms of injury
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or disease-induced increased excitability of spinal reflex circuits include ion channel misexpression and disinhibition [39,40,84], a spinal cord memory mechanism has been proposed and may contribute to dysfunctional motor control [9,88,91]. Taken together, emerging evidence suggests that dendritic spine remodeling is a novel mechanism that may contribute to spasticity as well as neuropathic pain. The study of dendritic spine abnormality may provide a new perspective for investigating chronic disease, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies. Conflict of interest None Acknowledgements The work presented is supported by grants from the Paralyzed Veterans of America (PVA) and the Department of Veterans Affairs (VA) Medical Research Service and Rehabilitation Research Service. Andrew M. Tan is funded by the PVA Research Foundation and a VA Career Development Award (1 IK2 RX001123-01A2). We thank Lakshmi Bangalore for her excellent editorial and intellectual contribution. References [1] M. Ackermann, A. Matus, Activity-induced targeting of profilin and stabilization of dendritic spine morphology, Nat. Neurosci. 6 (2003) 1194–1200. [2] J.W. Allen, T.L. Yaksh, Tissue injury models of persistent nociception in rats, Methods Mol. Med. 99 (2004) 25–34. [3] V.A. Alvarez, B.L. Sabatini, Anatomical and physiological plasticity of dendritic spines, Annu. Rev. Neurosci. 30 (2007) 79–97. [4] A.V. Apkarian, M.N. Baliki, P.Y. Geha, Towards a theory of chronic pain, Prog. Neurobiol. 87 (2009) 81–97. [5] R. Baron, Peripheral neuropathic pain: from mechanisms to symptoms, Clin. J. Pain 16 (2000) S12–S20. [6] T. Bonhoeffer, R. Yuste, Spine motility. Phenomenology, mechanisms, and function, Neuron 35 (2002) 1019–1027. [7] J. Bourne, K.M. Harris, Do thin spines learn to be mushroom spines that remember? Curr. Opin. Neurobiol. 17 (2007) 381–386. [8] C.R. Bramham, Local protein synthesis actin dynamics, and LTP consolidation, Curr. Opin. Neurobiol. 18 (2008) 524–531. [9] J.S. Carp, A.M. Tennissen, X.Y. Chen, J.R. Wolpaw, H-reflex operant conditioning in mice, J. Neurophysiol. 96 (2006) 1718–1727. [10] Y.W. Chang, A. Tan, C. Saab, S. Waxman, Unilateral focal burn injury is followed by long-lasting bilateral allodynia and neuronal hyperexcitability in spinal cord dorsal horn, J. Pain 11 (2010) 119–130. [11] Y.W. Chang, S.G. Waxman, Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury, J. Pain 11 (2010) 1146–1154. [12] S. Corbetta, S. Gualdoni, G. Ciceri, M. Monari, E. Zuccaro, V.L. Tybulewicz, I. de Curtis, Essential role of Rac1 and Rac3 GTPases in neuronal development, FASEB J. 23 (2009) 1347–1357. [13] S.W. Cramer, C. Baggott, J. Cain, J. Tilghman, B. Allcock, G. Miranpuri, S. Rajpal, D. Sun, D. Resnick, The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury, Mol. Pain 4 (36) (2008) 36–43. [14] M.J. Craner, J.P. Klein, M. Renganathan, J.A. Black, S.G. Waxman, Changes of sodium channel expression in experimental painful diabetic neuropathy, Ann. Neurol. 52 (2002) 786–792. [15] R. Deumens, G.L. Mazzone, G. Taccola, Early spread of hyperexcitability to caudal dorsal horn networks after a chemically-induced lesion of the rat spinal cord in vitro, Neuroscience 229 (2013) 155–163. [16] R. Drdla, J. Sandkuhler, Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo, Mol. Pain 4 (18) (2008) 18–25. [17] C.I. Dubreuil, M.J. Winton, L. McKerracher, Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system, J. Cell Biol. 162 (2003) 233–243. [18] M.K. Erschbamer, C.P. Hofstetter, L. Olson, 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. Neurol. 484 (2005) 224–233. [19] E. Fifkova, A possible mechanism of morphometric changes in dendritic spines induced by stimulation, Cell. Mol. Neurobiol. 5 (1985) 47–63.
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Short communication
Dendritic spine dysgenesis in neuropathic pain Andrew M. Tan a,b,∗ , Stephen G. Waxman a,b a b
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA Department of Neurology and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA
a r t i c l e
i n f o
Article history: Received 26 September 2014 Received in revised form 12 November 2014 Accepted 15 November 2014 Available online xxx Keywords: Neuropathic pain Dendritic spine SCI Rac1 Diabetes Nerve injury Plasticity Nociception Spinal cord
a b s t r a c t Neuropathic pain is a significant unmet medical need in patients with variety of injury or disease insults to the nervous system. Neuropathic pain often presents as a painful sensation described as electrical, burning, or tingling. Currently available treatments have limited effectiveness and narrow therapeutic windows for safety. More powerful analgesics, e.g., opioids, carry a high risk for chemical dependence. Thus, a major challenge for pain research is the elucidation of the mechanisms that underlie neuropathic pain and developing targeted strategies to alleviate pathological pain. The mechanistic link between dendritic spine structure and circuit function could explain why neuropathic pain is difficult to treat, since nociceptive processing pathways are adversely “hard-wired” through the reorganization of dendritic spines. Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in neuropathic pain. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease, which accompany chronic intractable pain: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presents as a mushroomshaped spine. Given the important functional implications of spine distribution, density, and shape for synaptic and neuronal function, the study of dendritic spine abnormality may provide a new perspective for investigating pain, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies. Published by Elsevier Ireland Ltd.
Neuropathic pain is a significant unmet medical need in patients with a variety of disease and injury insults to the nervous system, including spinal cord injury (SCI) or diabetic neuropathy. Individuals with neuropathic pain often describe their pain sensation as electrical, burning, tingling, or crushing. The severity of neuropathic pain can be so great that sufferers may contemplate or even commit suicide [66,82]. Currently available treatment options have limited effectiveness and small margin of safety; more powerful analgesics, e.g., opioids, carry a high risk of dependence [62,75]. Thus, a major challenge for pain research is the elucidation of the mechanisms that underlie neuropathic pain and development of new therapeutic strategies that target abnormal pain-associated mechanisms to alleviate neuropathic pain.
∗ Corresponding author at: Center for Neuroscience and Regeneration Research (127A), 950 Campbell Avenue, Building 34, West Haven, CT 06516, USA. Tel.: +1 203 932 5711x3663; fax: +1 203 937 3801. E-mail address: [email protected] (A.M. Tan).
1. Pain pathway from the PNS to CNS Normal pain perception begins with a stimulus detected by sensory receptors located in the skin, internal organs, or other peripheral regions of the body [90]. Painful input is transduced and action potentials are electrically propagated along these peripheral nerves toward and through the heterogeneous cell populations of the dorsal root ganglia (DRG). Primary afferents from DRG neurons project into the spinal cord where they terminate within different laminae depending on the type of sensory modality. For example, high threshold mechanical pain or heat stimulus carried by unmyelinated C-fibers or thinly myelinated A-fibers terminate within superficial dorsal horn laminae [5]. Low-threshold tactile sensations carried through larger diameter myelinated A-fibers may synapse upon secondary nociceptors located in the deeper intermediate zone of the spinal cord [92,93]. A particular focus of many pain studies is a class of “convergent” neurons in the spinal cord called wide dynamic range (WDR) neurons [46]. WDR neurons are generally located in deeper laminae of the dorsal horn (i.e., 4–6) and respond to all somatosensory modalities, including thermal and mechanical stimuli. WDR neurons send
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Fig. 1. Dendritic spines develop and mature to influence synaptic function. Larger, mature spines appear as mushroom-shaped structures, generally contain increased glutamatergic receptor density, e.g., AMPA or NMDA receptors, and represent stronger and more stable synapses. In contrast, thin or filopodia dendritic spines are associated with absent, weaker, or less mature synaptic connections [68].
ascending projections through the spinothalamic tract, a major pain pathway to the brain, and thus, act as intermediate relay points or “gateway” neurons for nociception. A unique characteristic of WDR neurons is that they increase their firing rates as the intensity of peripheral stimulation increases. For example, as a light, innocuous brushing of the skin transitions to noxious pinching or poking stimuli, WDR neurons will increase their action potential firing frequency. Thus, electrophysiological recordings of WDR neurons provide a powerful empirical readout of the global nociceptive activity within the CNS. Importantly, abnormally increased WDR neuron responsiveness, i.e., hyperexcitability, to stimulation is associated with neuropathic pain [75,90]. 2. Synaptic basis for neuropathic pain Multiple mechanisms along the PNS–CNS neuraxis contribute to hyperexcitability of nociceptive neurons, including WDR neurons, associated with neuropathic pain after injury or disease. These mechanisms include the loss of inhibitory inputs [44,96,98,99], inflammation [27,50,76,89,101,], dysregulation of potassium-chloride co-transporter 2 (KCC2) activity [13,28,55], and sodium channel misexpression [14,26,100]. Emerging evidence demonstrates that learning and memory mechanisms share mechanistic similarities with pain [45,60,74,94]. Traditionally studied in the cortex, the most well understood and established biological concept for learning and memory is the synaptic model of long-term potentiation (LTP). LTP is defined as the increase in synaptic efficacy as a result of synchronous activity between neurons [22,30,42]. In the early phase of LTP following an activity-dependent induction event, there are two general changes in the postsynaptic membrane including (1) an increase in the number and clustering of glutamatergic receptors, e.g., AMPA receptors, in the postsynaptic membrane, and (2) a post-translational increase in postsynaptic receptor activity. Because early phases of LTP are translational-independent (i.e., do not require protein synthesis), increased synaptic strength via LTP can develop over the course of minutes. Interestingly, others have shown that LTP can occur rapidly within spinal cord pain pathways in vivo [16,31,60,61]. High frequency stimulation (e.g., tetanic stimulation) and inflammation can lead to LTP induction between primary C-fiber afferents and nociceptive neurons in the superficial dorsal horn and widedynamic range (WDR) neurons located in the intermediate zone [67]. Further evidence demonstrates that nervous system injury
or disease can contribute to adverse changes in synaptic reorganization by engaging similar synaptic-based plasticity mechanisms in spinal cord pain pathways. Injuries, such as SCI or peripheral nerve injury, increase glutamate signaling, release of neuromodulator substance-P, and neurotrophic factors, i.e., BDNF. The signaling of these molecules operates downstream through an elevation of intracellular calcium, which consequently leads to synaptic potentiation [15,29,34,36]. Taken together, synaptic reorganization in spinal cord pain circuitry is a well-known phenomenon that can partially explain central sensitization (i.e., amplified excitability of neurons and circuits in nociceptive pathways) associated with neuropathic pain [33]. Dendritic spines represent sites of synaptic contact and are found throughout the nervous system primarily on “spiny” neurons that receive convergent input, such as hippocampal neurons, pyramidal neurons in the cortex, and dorsal horn neurons in the spinal cord [24,35,75]. To maintain synaptic efficacy in the longterm, dendritic spines may develop, reorganize, and mature (Fig. 1). Activation of downstream kinases, such as PKA, PKC, and extracellular signal-related kinase (ERK), ultimately lead to the prerequisite events, i.e., gene transcription, protein synthesis, actin cytoskeletal reorganization, that contribute to dendritic spine remodeling [1,8,32,43,77,95]. Thus, the architecture of dendritic spines is highly regulated by multiple molecular signaling pathways. A single neuron may contain hundreds of dendritic spines of varied shapes and geometries, which have been generally categorized using simple descriptors, including “mushroom”, “thin or filopodia”, or “stubby” [3,6] (Fig. 2A). The morphology of individual dendritic spines directly contributes to regulating local synaptic function [19,83]. Large, mushroom-shaped dendritic spines are associated with mature, stabilized synapses (which have increased glutamaterigic receptor density) and memory formation, whereas thin or filopodia-like spines are associated with weaker or developing, less-mature synapses (Fig. 1). At the cellular level, an increase in dendritic spine density also represents an increase in excitatory inputs upon a postsynaptic neuron, which may increase the overall excitability of a neural circuit [7]. Taken together, dendritic spine remodeling provides a structural-based mechanism for modifying and maintaining long-term synaptic function. The chronicity of neuropathic pain underscores the importance of understanding the contribution of dendritic spine dysgenesis within nociceptive pathways [4,65,71]. The mechanistic link
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hyperalgesia, in which heat-pain thresholds decrease. More specifically, WDR neurons display increased evoked action potential firing rates that are more than 50% greater than uninjured animals without pain [74]. Interestingly, the increased excitability and electrical properties of WDR neurons in vivo are analogous to the predictions made by computer simulations, which showed that changes in dendritic spine morphology alone can alter electrical function of neurons [71]. Together, these findings in SCI first revealed support for a mechanistic relationship between abnormal dendritic spines and dysfunctional nociception. 4. Dendritic spines in peripheral nerve injury
Fig. 2. (A) Dendritic spines vary in shape. Common descriptors include stubby, filopodia or thin, and mushroom spines. (B) Abnormal dendritic spine morphologies on WDR neurons are associated with abnormal nociceptive function, including behavioral and electrophysiological evidence of neuropathic pain. Following injury or disease, dendritic spines on WDR neurons generally increase in density, redistribute to locations along dendrite branches closer to the cell body, and exhibit increased spine head diameter, e.g., indicating stronger and stable or mature synapses (red dots = mushroom spines; blue dots = thin spines). For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.
between dendritic spine structure and circuit function could explain why neuropathic pain is difficult to treat, since nociceptive processing pathways are adversely “hard-wired” through the reorganization of dendritic spines. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presented as a mushroom-shaped spine [72,75] (Fig. 2B). These changes in the morphological characteristics of dendritic spines accompany nociceptive hyperexcitability and behavioral symptoms of neuropathic pain. Given the important functional implications of spine distribution, density, and shape for neuronal function [54,56,71], a more thorough understanding of dendritic spine changes within nociceptive circuits is likely to advance our understanding of pathological chronic pain. Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in mechanisms underlying neuropathic pain. 3. Dendritic spines in spinal cord injury Dendritic spine morphologies change significantly on WDR neurons after spinal cord injury (SCI) [74]. Dendritic spine density increases and redistributes along dendritic branches in regions closer to the cell body. The shape of dendritic spines also changes, increasing in length and spine head diameter. Abnormal physiological and behavioral effects accompany abnormal dendritic spine structure following SCI; with WDR neurons exhibiting hyperexcitability in response to both evoked innocuous and noxious stimulation in electrophysiological recordings. SCI animals also demonstrate evidence of neuropathic tactile allodynia, in which non-painful touch stimuli are perceived as painful, and heat
Peripheral nerve injury models are well established and widely used tools for investigations of neuropathic pain [85]. A peripheral nerve injury, such as chronic constriction or transection of the sciatic nerves in the hindlimb, induces primary afferent plasticity, which may have a role in the development of neuropathic pain. Robust plasticity of neurons within nociceptive circuits in the spinal cord following peripheral nerve injury is less understood. As with SCI, recent work has shown that WDR neurons ipsilateral to a chronic constriction injury (CCI) to the sciatic nerve show a significant increase in dendritic spine density and an altered spine distribution ten days after injury [70]. WDR neurons in the areas innervated by the injured nerves also exhibit hyperexcitability and increased responsiveness (i.e., elevated firing rate) to low and highthreshold stimuli applied to these neurons’ cutaneous receptive fields. These findings are particularly intriguing because the trauma began in the PNS, and the pathological changes transition into the CNS. This observation suggests the existence of a putative PNS–CNS signal that participates in structural reorganization within the spinal cord nociceptive system. Potential candidates for such a transneuronal signal may include remote neuroimmune signals, e.g., cytokine release [59,81,102]. Microglia may also have a role as they become activated, i.e., microgliosis, following nerve injury as part of the inflammatory response within the spinal cord. Activated microglia and astrocytes have both been implicated in central sensitization after peripheral nerve injury [63]. Importantly, these observations are relevant to dendritic spine behavioral and physiology: as demonstrated by high-resolution electron microscopy of the hippocampus, microglial processes directly contact synaptic dendritic spine structures, and in live time-lapse studies, astrocytes have been shown to readily extend processes that interact with dendritic spines. In the latter, astrocyte-spine dynamic interactions were most coordinated at sites of more stable, larger mature dendritic spines [25,49]. Taken together, evidence suggests the involvement of non-neuronal cell populations in mechanisms regulating dendritic spine structure that contribute to injury-induced neuropathic pain. 5. Dendritic spines in thermal cutaneous burn injury The mechanisms underlying chronic pain following cutaneous burn injury have been largely unexplored. This is in part due to the complexity of burn injuries, which can be of varying location, size, and severity, e.g., burn degree scale. Nonetheless, in more common models of moderate burn injury (i.e., second degree, partial skin-thickness burns) there is an acute primary hyperalgesia, which presents rapidly within the cutaneous field of the burn injury site. This is followed by a progressive expansion of the secondary tactile allodynia response to the surrounding uninjured areas of the skin [2,21,86]. The inflammatory response within the skin, nerves, and spinal cord, e.g., microglia, MAPK activation has been shown to contribute to the burn injury-induced pain phenotype. Pain after burn injury also develop as a result of injury to peripheral nerve endings, which are highly sensitized to
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stimuli. Indeed, maladaptive structural plasticity within the CNS has also been cited as an explanation for the notorious opioid resistance observed in human burn patients [37]. In a study using adult rats, similar to earlier findings in pain models, unilateral seconddegree burn injury on the hind paw resulted in abnormal dendritic spine changes on ipsilateral WDR neurons, including increased spine density, redistribution, and more mature mushroom shapes [73]. These structural profiles accompanied an expansion of the cutaneous receptive fields, increased nociceptive hyperexcitability, and the development of tactile allodynia. While this study did not include a time-course investigation to examine the transition from acute inflammatory pain to chronic pain following burn injury, the main findings strongly support a link between the presence of abnormal dendritic spines and abnormal pain after thermal burn injury.
6. Dendritic spines in diabetic mellitus Mechanisms underlying diabetic neuropathic pain have been particularly elusive due to the complexity of metabolic diseases, which affect the entire body. Mechanisms that may contribute to diabetic neuropathic pain, include peripheral neuropathy, i.e., nerve damage as a result of secondary vascular disease, dysfunctional KCC2, and sodium channel misexpression in DRG neurons [14,20,38,80]. As with many other diseases that contribute to the development of neuropathic pain, maladaptive neuroplasticity within nociceptive circuits may also be a mechanism underlying diabetic neuropathic pain. Although most diabetic pain studies focus on the PNS as the source of pain, abnormal changes within the CNS may further account for diabetic neuropathic pain [20]. In a streptozotocin (STZ)-induced diabetic neuropathic pain model, dendritic spine reorganization occurred on WDR neurons in the spinal cord [72]. STZ is a specific toxin for insulin-producing pancreatic beta cells and administration of the compound significantly increases blood
glucose levels (i.e., hyperglycemia) to produce a model of type 1 diabetes [47]. In contrast to other injury-pain models, the study of STZ-induced neuropathic pain revealed the existence of a time window wherein hyperglycemic animals (soon after STZ-induction) had both near-normal dendritic spine profiles and normal pain thresholds [72]. This was followed by spine dysgenesis, which developed with a time-course paralleling that of behavioral signs of pain. These observations share two important implications: first, there is temporal relationship between the dendritic spine structure and pain phenotype, and second that the presence of maladaptive dendritic spines predicts the manifestation of neuropathic pain. This structure-function relationship in diabetic disease suggests that there is a therapeutic window for intervention (e.g., targeting mechanisms of dendritic spine remodeling) in early-diabetes that could prevent the transition from pre-diabetic conditions to the establishment of intractable neuropathic pain. As yet, it is not known whether dendritic spine changes in diabetes are a direct result of the hyperglycemic condition, secondary inflammation [53,69], or changes in presynaptic elements [72,87].
7. Regulation of dendritic spine dysgenesis The Rac1 kinase is one of the most well-studied regulatory molecules that govern dendritic spine behavior [12,57,64,79]. Rac1 is a small intracellular protein (∼21 kDa) in the family of Rho GTPases [58], which regulates a host of cellular functions, including actin cytoskeletal organization and glutamaterigc AMPA receptor clustering in the postsynaptic membrane of dendritic spines [97]. In the hippocampus, dominant negative expression of Rac1 (mutant RacN17) decreases spine density and inhibits spine maturation [48,78]; whereas constitutively activated Rac1 increases the rate of spine turnover, density, and increases spine volume. Importantly, in animal models of stress or neurotrauma, Rac1 mRNA expression and activation increase after SCI, remaining elevated for up to three months [17,18].
Fig. 3. (A) Representative silhouette renderings of Golgi-stained spinal cord tissue summarize the morphological effect on dendritic spines from several injury/disease models of neuropathic pain (black color) as compared with normal (gray color). These abnormal dendritic spine profiles accompany behavioral symptoms and electrophysiological signs of neuropathic pain. However, following Rac1-inhibitor treatment, there is a reduction in injury/disease-induced abnormal spine profiles (gray with outline) and attenuated pain phenotype. (B) Quantitation of mushroom-shaped spine density demonstrated a significant reduction in spine density, which was within near-normal ranges, after Rac1-inhibitor treatment [70,72–74]. Note that this figure should be taken as a qualitative overview of previous findings, and a retrospective comparison across injury/disease effects on dendritic spines was not performed.
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A Rac1-specific inhibitor, NSC23766, has been a powerful tool for understanding the role of Rac1-regulation of dendritic spines and neuropathic pain [23] (Fig. 3). NSC23766 blocks Trio and Tiam1, guanine exchange factors, without interrupting with related GTPases cdc42 or Rho-GEF; importantly, NSC23766 does not affect Rac1 binding to its effector PAK1 [23]. Treatment with NSC23766 of spinal cord dorsal horn neurons in vitro effectively decreases dendritic spine density [70]. In vivo, intrathecal administration of NSC23766 in rats with SCI reduces protein levels of postsynaptic density marker, PSD-95, without affecting the presynaptic terminal-associated protein, synaptophysin [74], suggesting that NSC23766 administration has a preferential effect on postsynaptic elements. Treatment with NSC23766 over three days restores a near-normal dendritic spine profile on WDR neurons following SCI: including a normalization of dendritic spine density, spine length, and spine head diameter. Along with these structural changes, NSC23766 treatment in SCI animals increases mechanical and thermal pain thresholds and evoked-WDR neuron electrical responses back to near-normal levels [74]. Similarly, in a peripheral nerve injury and a thermal burn-injury pain model, NSC23766 inhibition of Rac1 disrupts abnormal dendritic spine remodeling and attenuates physiological evidence of neuropathic pain [70]. Previous studies have demonstrated that inhibitors of RhoA/Rho kinases (ROCK inhibitors) may have effectiveness in treating diabetic neuropathic pain [52]. In agreement, NSC23766 treatment in an STZ-induced diabetic neuropathic pain model also resulted in a reduction in neuropathic mechanical allodynia and attenuated WDR neuron hyperexcitability [72]. Close-to-normal dendritic spine profiles accompanied these physiological effects of NSC23766 (Fig. 3). However, unlike the effects of the compound in SCI, NSC23766 failed to restore heat pain thresholds to normal levels in peripheral nerve- or burn-injury pain or diabetic neuropathic pain models, suggesting that Rac1-inhibition has a differential action on mechanical and thermal sensory modalities, at least under these injury/disease-induced painful conditions. It is unknown whether dendritic spine profiles change on other cell-types within the nociceptive system, e.g., lamina II. Aberrant dendritic spine profiles on different spinal cord neurons could explain discrepancies in neuropathic pain responses. Moreover, NSC23766 treatment only partly restores mechanical pain thresholds in these studies, which suggests that other factors contribute to neuropathic pain phenotype [10,11,41,70,72,73]. The mode and action of pharmacological Rac1 inhibition is not clear. NSC23766 treatment alleviates SCI-induced pain without affecting gross locomotor behavior [74], suggesting that the compound fails to significantly affect the spinal cord motor system when used at an effective analgesic dosage. Although microgliosis contributes to chronic pain and Rac1-activity regulates microglial lamellipodia formation and membrane ruffling [51], NSC23766 treatment did not affect levels of elevated microglial-immunoreactivity in the spinal cord dorsal horn following peripheral nerve injury [70]. Treatment with NSC23766 in uninjured animals had no observable effect on electrical or behavioral outcomes in nociceptive assessments [72]. Despite these observations, systemic effects of drug administration in vivo are likely to have yet to be reported off-target actions; thus, genomic tools, e.g., genetic manipulation or transgenic mice, may provide more powerful tools for understanding mechanisms that underlie dendritic spine remodeling in neuropathic pain. 8. Implications and horizons The mechanistic link between dendritic spine structure and nociceptive function in the spinal cord extends into other CNS modalities. Hyperreflexia and spasticity are common after SCI, multiple sclerosis, and stroke. Although mechanisms of injury
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or disease-induced increased excitability of spinal reflex circuits include ion channel misexpression and disinhibition [39,40,84], a spinal cord memory mechanism has been proposed and may contribute to dysfunctional motor control [9,88,91]. Taken together, emerging evidence suggests that dendritic spine remodeling is a novel mechanism that may contribute to spasticity as well as neuropathic pain. The study of dendritic spine abnormality may provide a new perspective for investigating chronic disease, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies. Conflict of interest None Acknowledgements The work presented is supported by grants from the Paralyzed Veterans of America (PVA) and the Department of Veterans Affairs (VA) Medical Research Service and Rehabilitation Research Service. Andrew M. Tan is funded by the PVA Research Foundation and a VA Career Development Award (1 IK2 RX001123-01A2). We thank Lakshmi Bangalore for her excellent editorial and intellectual contribution. References [1] M. Ackermann, A. Matus, Activity-induced targeting of profilin and stabilization of dendritic spine morphology, Nat. Neurosci. 6 (2003) 1194–1200. [2] J.W. Allen, T.L. Yaksh, Tissue injury models of persistent nociception in rats, Methods Mol. Med. 99 (2004) 25–34. [3] V.A. Alvarez, B.L. Sabatini, Anatomical and physiological plasticity of dendritic spines, Annu. Rev. Neurosci. 30 (2007) 79–97. [4] A.V. Apkarian, M.N. Baliki, P.Y. Geha, Towards a theory of chronic pain, Prog. Neurobiol. 87 (2009) 81–97. [5] R. Baron, Peripheral neuropathic pain: from mechanisms to symptoms, Clin. J. Pain 16 (2000) S12–S20. [6] T. Bonhoeffer, R. Yuste, Spine motility. Phenomenology, mechanisms, and function, Neuron 35 (2002) 1019–1027. [7] J. Bourne, K.M. Harris, Do thin spines learn to be mushroom spines that remember? Curr. Opin. Neurobiol. 17 (2007) 381–386. [8] C.R. Bramham, Local protein synthesis actin dynamics, and LTP consolidation, Curr. Opin. Neurobiol. 18 (2008) 524–531. [9] J.S. Carp, A.M. Tennissen, X.Y. Chen, J.R. Wolpaw, H-reflex operant conditioning in mice, J. Neurophysiol. 96 (2006) 1718–1727. [10] Y.W. Chang, A. Tan, C. Saab, S. Waxman, Unilateral focal burn injury is followed by long-lasting bilateral allodynia and neuronal hyperexcitability in spinal cord dorsal horn, J. Pain 11 (2010) 119–130. [11] Y.W. Chang, S.G. Waxman, Minocycline attenuates mechanical allodynia and central sensitization following peripheral second-degree burn injury, J. Pain 11 (2010) 1146–1154. [12] S. Corbetta, S. Gualdoni, G. Ciceri, M. Monari, E. Zuccaro, V.L. Tybulewicz, I. de Curtis, Essential role of Rac1 and Rac3 GTPases in neuronal development, FASEB J. 23 (2009) 1347–1357. [13] S.W. Cramer, C. Baggott, J. Cain, J. Tilghman, B. Allcock, G. Miranpuri, S. Rajpal, D. Sun, D. Resnick, The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury, Mol. Pain 4 (36) (2008) 36–43. [14] M.J. Craner, J.P. Klein, M. Renganathan, J.A. Black, S.G. Waxman, Changes of sodium channel expression in experimental painful diabetic neuropathy, Ann. Neurol. 52 (2002) 786–792. [15] R. Deumens, G.L. Mazzone, G. Taccola, Early spread of hyperexcitability to caudal dorsal horn networks after a chemically-induced lesion of the rat spinal cord in vitro, Neuroscience 229 (2013) 155–163. [16] R. Drdla, J. Sandkuhler, Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo, Mol. Pain 4 (18) (2008) 18–25. [17] C.I. Dubreuil, M.J. Winton, L. McKerracher, Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system, J. Cell Biol. 162 (2003) 233–243. [18] M.K. Erschbamer, C.P. Hofstetter, L. Olson, 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. Neurol. 484 (2005) 224–233. [19] E. Fifkova, A possible mechanism of morphometric changes in dendritic spines induced by stimulation, Cell. Mol. Neurobiol. 5 (1985) 47–63.
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Please cite this article in press as: A.M. Tan, S.G. Waxman, Dendritic spine dysgenesis in neuropathic pain, Neurosci. Lett. (2014), http://dx.doi.org/10.1016/j.neulet.2014.11.024
