Rac1-regulated dendritic spine remodeling contributes to neuropathic pain after peripheral nerve injury.

Although prior studies have implicated maladaptive remodeling of dendritic spines on wide-dynamic range dorsal horn neurons as a contributor to pain after spinal cord injury, there have been no studies on dendritic spines after peripheral nerve injury. To determine whether dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain after peripheral nerve injury, we analyzed dendritic spine morphology and functional influence in lamina IV-V dorsal horn neurons after sham, chronic constriction injury (CCI) of the sciatic nerve, and CCI treatment with NSC23766, a selective inhibitor of Rac1, which has been implicated in dendritic spine development. 10 days after CCI, spine density increased with mature, mushroom-shaped spines preferentially distributed along dendritic branch regions closer to the cell body.

Dendritic spine remodeling after spinal cord injury alters neuronal signal processing.

Central sensitization, a prolonged hyperexcitability of dorsal horn nociceptive neurons, is a major contributor to abnormal pain processing after spinal cord injury (SCI). Dendritic spines are micron-sized dendrite protrusions that can regulate the efficacy of synaptic transmission. Here we used a computational approach to study whether changes in dendritic spine shape, density, and distribution can individually, or in combination, adversely modify the input-output function of a postsynaptic neuron to create a hyperexcitable neuronal state.

Early microglial inhibition preemptively mitigates chronic pain development after experimental spinal cord injury.

Spinal cord injury (SCI) results in the development of chronic pain syndromes that can persist indefinitely and cause reductions in quality of life. Treatment of chronic pain after SCI remains extremely challenging; thus, an important research goal is to determine whether early treatments can attenuate the subsequent development of pain conditions. The current study examined the hypothesis that early administration of the microglial-inhibiting drug minocycline could ameliorate the development of pain after SCI.

Mechanisms of chronic central neuropathic pain after spinal cord injury.

Not all spinal contusions result in mechanical allodynia, in which non-noxious stimuli become noxious. The studies presented use the NYU impactor at 12.5 mm drop or the Infinite Horizons Impactor (150 kdyn, 1 s dwell) devices to model spinal cord injury (SCI).

Remote neuroimmune signaling: a long-range mechanism of nociceptive network plasticity.

Chronic pain secondary to neuronal injury is actively and continuously modulated at multiple locations along the sensory neuraxis. Here, we describe how nociceptive neurons of the spinal cord and thalamus process and communicate nociceptive information in terms of precisely calibrated firing patterns. We then discuss how several cell types with immunogenic properties (e.

Neuropathic pain memory is maintained by Rac1-regulated dendritic spine remodeling after spinal cord injury.

Localized increases in synaptic strength constitute a synaptic basis for learning and memory in the CNS and may also contribute to the maintenance of neuropathic pain after spinal cord injury (SCI) through the de novo formation or elaboration of postsynaptic dendritic structures. To determine whether SCI-induced dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain, we analyzed spine morphometry, localization, and functional influence in dorsal horn (DH) neurons in adult rats 1 month after sham surgery, contusion SCI, and SCI treated with a selective inhibitor of Rac1 activation, NSC23766. After SCI, DH neurons located in lamina IV-V exhibited increased spine density, redistributed spines, and mature spines compared with control neurons, which was associated with enhancement of EPSCs in computer simulations and hyperexcitable responsiveness to innocuous and noxious peripheral stimuli in unit recordings in vivo.

Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis.

Purpose: Central nervous system plasticity is essential for normal function, but can also reinforce abnormal network behavior, leading to epilepsy and other disorders. The role of altered ion channel expression in abnormal plasticity has not been thoroughly investigated. Nav1.

Alarm or curse? The pain of neuroinflammation.

The nociceptive nervous system and the immune system serve to defend and alarm the host of imminent or actual damage. However, persistent or recurring exposure of neurons to activated immune cells is associated with an increase in painful behavior following experimental neuropathic injuries. Our understanding of the functional consequences of immune cell-neuron interaction is still incomplete.

Locomotor dysfunction and pain: the scylla and charybdis of fiber sprouting after spinal cord injury.

Injury to the spinal cord (SCI) can produce a constellation of problems including chronic pain, autonomic dysreflexia, and motor dysfunction. Neuroplasticity in the form of fiber sprouting or the lack thereof is an important phenomenon that can contribute to the deleterious effects of SCI. Aberrant sprouting of primary afferent fibers and synaptogenesis within incorrect dorsal horn laminae leads to the development and maintenance of chronic pain as well as autonomic dysreflexia.

Disruption of cAMP and prostaglandin E2 transport by multidrug resistance protein 4 deficiency alters cAMP-mediated signaling and nociceptive response.

Multidrug resistance protein 4 (MRP4; ABCC4) is a member of the MRP/ATP-binding cassette family serving as a transmembrane transporter involved in energy-dependent efflux of anticancer/antiviral nucleotide agents and of physiological substrates, including cyclic nucleotides and prostaglandins (PGs). Phenotypic consequences of mrp4 deficiency were investigated using mrp4-knockout mice and derived immortalized mouse embryonic fibroblast (MEF) cells. Mrp4 deficiency caused decreased extracellular and increased intracellular levels of cAMP in MEF cells under normal and forskolin-stimulated conditions.

Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21.

Spinal cord injury (SCI) results in the generation and amplification of pain caused in part by injury-induced changes in neuronal excitability at multiple levels along the sensory neuraxis. We have previously shown that activated microglia, through an ERK (extracellular signal-regulated kinase)-regulated PGE(2) (prostaglandin E(2)) signaling mechanism, maintain neuronal hyperexcitability in the lumbar dorsal horn. Here, we examined whether microglial cells in the thalamus contribute to the modulation of chronic pain after SCI, and whether microglial activation is governed by spinally mediated increases in the microglial activator cysteine-cysteine chemokine ligand 21 (CCL21).

Sodium channel expression and the molecular pathophysiology of pain after SCI.

The chronic pain that develops as a result of spinal cord injury (SCI) is extremely debilitating and remains largely unmanageable by current therapeutic strategies. Voltage-gated sodium channels regulate the biophysical properties, and thus firing characteristics, of neurons. After SCI the repertoire of sodium channels produced by dorsal horn nociceptive neurons is altered, enabling neurons to fire at higher than normal rates in response to unchanged peripheral stimuli as well as to generate spontaneous discharges in the absence of stimuli, resulting in the genesis of neuropathic pain.

In silico modeling of axonal reconnection within a discrete fiber tract after spinal cord injury.

Following spinal cord injury (SCI), descending axons that carry motor commands from the brain to the spinal cord are injured or transected, producing chronic motor dysfunction and paralysis. Reconnection of these axons is a major prerequisite for restoration of function after SCI. Thus far, only modest gains in motor function have been achieved experimentally or in the clinic after SCI, identifying the practical limitations of current treatment approaches.

Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury.

Many patients with traumatic spinal cord injury (SCI) report pain that persists indefinitely and is resistant to available therapeutic approaches. We recently showed that microglia become activated after experimental SCI and dynamically maintain hyperresponsiveness of spinal cord nociceptive neurons and pain-related behaviors. Mechanisms of signaling between microglia and neurons that help to maintain abnormal pain processing are unknown.

Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE.

Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied.

Sodium channel expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury.

Peripheral nerve injury is known to up-regulate the expression of rapidly-repriming Nav1.3 sodium channel within first-order dorsal root ganglion neurons and second-order dorsal horn nociceptive neurons, but it is not known if pain-processing neurons higher along the neuraxis also undergo changes in sodium channel expression. In this study, we hypothesized that after peripheral nerve injury, third-order neurons in the ventral posterolateral (VPL) nucleus of the thalamus undergo changes in expression of sodium channels.

Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury.

Traumatic spinal cord injury (SCI) results not only in motor impairment, but also in chronic central neuropathic pain, which often is refractory to conventional treatment approaches. Upregulated expression of sodium channel Nav1.3 has been observed within the spinal dorsal horn neurons after SCI, and appears to contribute to neuronal hyperresponsiveness and pain-related behaviors.

Activated microglia contribute to the maintenance of chronic pain after spinal cord injury.

Traumatic spinal cord injury (SCI) results not only in motor impairment but also in chronic central pain, which can be refractory to conventional treatment approaches. It has been shown recently that in models of peripheral nerve injury, spinal cord microglia can become activated and contribute to development of pain. Considering their role in pain after peripheral injury, and because microglia are known to become activated after SCI, we tested the hypothesis that activated microglia contribute to chronic pain after SCI.

Fire and phantoms after spinal cord injury: Na+ channels and central pain.

Neuropathic pain and phantom phenomena occur commonly after spinal cord injury (SCI) but their molecular basis is not yet fully understood. Recent findings demonstrate abnormal expression of the Nav1.3 Na(+) channel within second-order spinal cord dorsal horn neurons and third-order thalamic neurons along the pain pathway after SCI, and suggest that this change makes these neurons hyperexcitable so that they act as pain amplifiers and generators.

Alterations in burst firing of thalamic VPL neurons and reversal by Na(v)1.3 antisense after spinal cord injury.

We recently showed that spinal cord contusion injury (SCI) at the thoracic level induces pain-related behaviors and increased spontaneous discharges, hyperresponsiveness to innocuous and noxious peripheral stimuli, and enlarged receptive fields in neurons in the ventral posterolateral (VPL) nucleus of the thalamus. These changes are linked to the abnormal expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel.

Protection of corticospinal tract neurons after dorsal spinal cord transection and engraftment of olfactory ensheathing cells.

Transplantation of olfactory ensheathing cells (OECs) into the damaged rat spinal cord leads to directed elongative axonal regeneration and improved functional outcome. OECs are known to produce a number of neurotrophic molecules. To explore the possibility that OECs are neuroprotective for injured corticospinal tract (CST) neurons, we transplanted OECs into the dorsal transected spinal cord (T9) and examined primary motor cortex (M1) to assess apoptosis and neuronal loss at 1 and 4 weeks post-transplantation.

Neuroprotection by sodium channel blockade with phenytoin in an experimental model of glaucoma.

Purpose: Sustained influx of intracellular sodium through voltage-gated sodium channels is an important event in the cascade leading to degeneration of axons. This study tested the hypothesis that sodium channel blockade with phenytoin would result in neuroprotection of retinal ganglion cells (RGCs) and optic nerve axons in an experimental model of glaucoma.

Methods: Chronic elevation of rat intraocular pressure (IOP) leading to optic nerve damage was induced using the episcleral vein occlusion model.

Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury.

Spinal cord contusion injury (SCI) is known to induce pain-related behaviour, as well as hyperresponsiveness in lumbar dorsal horn nociceptive neurons associated with the aberrant expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel. Many of these second-order dorsal horn neurons project to third-order neurons in the ventrobasal complex of the thalamus.

Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.

Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal sodium channels can trigger axonal degeneration, recent studies have tested sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, sodium channel blockers may also interfere with inflammatory mechanisms.

Effect of age at time of spinal cord injury on behavioral outcomes in rat.

Spinal cord injury (SCI) often leads to chronic central pain (CCP) syndromes such as allodynia and hyperalgesia. Although several experimental animal models for CCP studies exist, little is known about the effect of age on the development of CCP following SCI. In this study, we evaluated behavioral responses to mechanical and thermal stimuli following SCI using three different age groups of adult Sprague-Dawley rats: young (40 days), adult (60 days), and middle-age (12 months).