The Experts below are selected from a list of 9075 Experts worldwide ranked by ideXlab platform

Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.

  • correlation of nav1 8 and nav1 9 Sodium Channel Expression with neuropathic pain in human subjects with lingual nerve neuromas
    Molecular Pain, 2013
    Co-Authors: Emma V Bird, Stephen G Waxman, Joel A Black, P P Robinson, Claire R Christmas, Alison R Loescher, Keith G Smith, Fiona M Boissonade
    Abstract:

    Background Voltage-gated Sodium Channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The Expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the Expression of these ion Channels and the presence or absence of dysaesthesia investigated.

  • Sodium Channel Expression within chronic multiple sclerosis plaques
    Journal of Neuropathology and Experimental Neurology, 2007
    Co-Authors: Joel A Black, Jia Newcombe, Bruce D Trapp, Stephen G Waxman
    Abstract:

    Multiple sclerosis (MS) is characterized by focal destruction of myelin sheaths, gliotic scars, and axonal damage that contributes to the accumulation of nonremitting clinical deficits. Previous studies have demonstrated coExpression of Sodium Channel Nav1.6 and the Sodium-calcium exchanger (NCX), together with beta-amyloid precursor protein (beta-APP), a marker of axonal damage, in degenerating axons within acute MS lesions. Axonal degeneration is less frequent within chronic MS lesions than in acute plaques, although current evidence suggests that axonal loss in chronic lesions ("slow burn") is a major contributor to accumulating disability. It is not known, however, whether axonal degenerations in chronic and acute lesions share common mechanisms, despite radically differing extracellular milieus. In this study, the Expression of Sodium Channels Nav1.2 and Nav1.6 and of NCX was examined in chronic MS plaques within the spinal cord. Nav1.2 immunostaining was not observed along demyelinated axons in chronic lesions but was expressed by scar and reactive astrocytes within the plaque. Nav1.6 immunoreactivity, which was intense at nodes of Ranvier in normal appearing white matter in the same sections, was present in approximately one-third of the demyelinated axons within these plaques in a patchy rather than continuous distribution. NCX was not detected in demyelinated axons within chronic lesions, although it was clearly present within the scar astrocytes surrounding the demyelinated axons. beta-APP accumulation occurred in a small percentage of axons within chronic lesions within the spinal cord, but beta-APP was not preferentially present in axons that expressed Nav1.6. These observations suggest that different mechanisms underlie axonal degeneration in acute and chronic MS lesions, with axonal injury occurring at sites of coExpression of Nav1.6 and NCX in acute lesions but independent of coExpression of these 2 molecules in chronic lesions.

  • Sodium Channel Expression and the molecular pathophysiology of pain after sci
    Progress in Brain Research, 2007
    Co-Authors: Bryan C. Hains, Stephen G Waxman
    Abstract:

    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. Our results have shown increased Expression of the Nav1.3 Sodium Channel in the spinal cord and thalamus. Nav1.3 upregulation allows dorsal horn neurons to generate ramp currents, enhanced persistent currents, and shifts in steady-state activation and inactivation. Further downstream, Nav1.3 causes increased spontaneous and evoked firing of neurons in the ventroposterior lateral (VPL) nucleus of the thalamus. Nav1.3 also underlies changes in burst firing properties of VPL neurons. The combination of spinal and thalamic generation and amplification of pain by Nav1.3 dysregulation contributes to post-SCI chronic pain. If proven to be similar in humans, targeting of this system after SCI may offer hope for treatment of clinical pain.

  • Sodium Channel Expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury
    Molecular Pain, 2006
    Co-Authors: Peng Zhao, Stephen G Waxman, Bryan C. Hains
    Abstract:

    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. To test this hypothesis, adult male Sprague-Dawley rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, when allodynia and hyperalgesia were evident, in situ hybridization and immunocytochemical analysis revealed up-regulation of Nav1.3 mRNA, but no changes in Expression of Nav1.1, Nav1.2, or Nav1.6 in VPL neurons, and unit recordings demonstrated increased background firing, which persisted after spinal cord transection, and evoked hyperresponsiveness to peripheral stimuli. These results demonstrate that injury to the peripheral nervous system induces alterations in Sodium Channel Expression within higher-order VPL neurons, and suggest that misExpression of the Nav1.3 Sodium Channel increases the excitability of VPL neurons injury, contributing to neuropathic pain.

  • changes in electrophysiological properties and Sodium Channel nav1 3 Expression in thalamic neurons after spinal cord injury
    Brain, 2005
    Co-Authors: Bryan C. Hains, Carl Y Saab, Stephen G Waxman
    Abstract:

    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. In this study we hypothesized that, following SCI, neurons in the thalamus undergo electrophysiological changes linked to aberrant Expression of Na(v)1.3. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 thoracic level. Four weeks post-SCI, Na(v)1.3 protein was upregulated within thalamic neurons in ventroposterior lateral (VPL) and ventroposterior medial nuclei, where extracellular unit recordings revealed increased spontaneous discharge, afterdischarge, hyperresponsiveness to innocuous and noxious peripheral stimuli, and expansion of peripheral receptive fields. Altered electrophysiological properties of VPL neurons persisted after interruption of ascending spinal barrage by spinal cord transection above the level of the injury. Lumbar intrathecal administration of specific antisense oligodeoxynucleotides generated against Na(v)1.3 caused a significant reduction in Na(v)1.3 Expression in thalamic neurons and reversed electrophysiological alterations. These results show, for the first time, a change in Sodium Channel Expression within neurons in the thalamus after injury to the spinal cord, and suggest that these changes contribute to altered processing of somatosensory information after SCI.

Joel A Black - One of the best experts on this subject based on the ideXlab platform.

  • correlation of nav1 8 and nav1 9 Sodium Channel Expression with neuropathic pain in human subjects with lingual nerve neuromas
    Molecular Pain, 2013
    Co-Authors: Emma V Bird, Stephen G Waxman, Joel A Black, P P Robinson, Claire R Christmas, Alison R Loescher, Keith G Smith, Fiona M Boissonade
    Abstract:

    Background Voltage-gated Sodium Channels Nav1.8 and Nav1.9 are expressed preferentially in small diameter sensory neurons, and are thought to play a role in the generation of ectopic activity in neuronal cell bodies and/or their axons following peripheral nerve injury. The Expression of Nav1.8 and Nav1.9 has been quantified in human lingual nerves that have been previously injured inadvertently during lower third molar removal, and any correlation between the Expression of these ion Channels and the presence or absence of dysaesthesia investigated.

  • voltage gated Sodium Channel Expression in rat and human epidermal keratinocytes evidence for a role in pain
    Pain, 2008
    Co-Authors: Peng Zhao, Joel A Black, Sulayman D Dibhajj, Travis P Barr, Quanzhi Hou, Phillip J Albrecht, Karin L Petersen, Elon Eisenberg, James Wymer, Frank L Rice
    Abstract:

    Keratinocytes are implicated in sensory transduction and can influence nociception, but whether these contribute to chronic pain is not known. In neurons, voltage-gated Sodium Channels (Na(v)) are involved in neuropathic pain and are activated by depolarization. Since keratinocytes can also show changes in membrane potential, we used RT-PCR, in situ hybridization, and immunohistochemistry to investigate the Expression of Sodium Channels in these cells. Na(v)1.1, Na(v)1.6, and Na(v)1.8 were localized within keratinocytes in rat epidermis. In addition, Sodium Channels contribute to the release of ATP from rat keratinocytes in response to increased [K(+)](o), implicating Sodium Channels in keratinocyte ligand release and nociception. To examine whether keratinocytes may contribute to human pain states, we analyzed Sodium Channel Expression in human skin biopsies from subjects with complex regional pain syndrome Type 1 (CRPS) and post-herpetic neuralgia (PHN) using immunohistochemistry. Control skin exhibited immunolabeling for Na(v)1.5, Na(v)1.6 and Na(v)1.7. In contrast, painful skin from CRPS and PHN subjects displayed Na(v)1.1, Na(v)1.2, and Na(v)1.8 immunolabeling, in addition to substantially increased signal for Na(v)1.5, Na(v)1.6, Na(v)1.7. These observations lead us to propose that pathological increases in keratinocyte Sodium Channel Expression may contribute to pain by increasing epidermal ATP release, resulting in excessive activation of P2X receptors on primary sensory axons. Consistent with this hypothesis, animal models of neuropathic pain exhibit increases in subcutaneous ATP release and activity of primary sensory neurons, and peripheral administration of P2X antagonists has been shown to reduce neuropathic pain in humans.

  • Sodium Channel Expression within chronic multiple sclerosis plaques
    Journal of Neuropathology and Experimental Neurology, 2007
    Co-Authors: Joel A Black, Jia Newcombe, Bruce D Trapp, Stephen G Waxman
    Abstract:

    Multiple sclerosis (MS) is characterized by focal destruction of myelin sheaths, gliotic scars, and axonal damage that contributes to the accumulation of nonremitting clinical deficits. Previous studies have demonstrated coExpression of Sodium Channel Nav1.6 and the Sodium-calcium exchanger (NCX), together with beta-amyloid precursor protein (beta-APP), a marker of axonal damage, in degenerating axons within acute MS lesions. Axonal degeneration is less frequent within chronic MS lesions than in acute plaques, although current evidence suggests that axonal loss in chronic lesions ("slow burn") is a major contributor to accumulating disability. It is not known, however, whether axonal degenerations in chronic and acute lesions share common mechanisms, despite radically differing extracellular milieus. In this study, the Expression of Sodium Channels Nav1.2 and Nav1.6 and of NCX was examined in chronic MS plaques within the spinal cord. Nav1.2 immunostaining was not observed along demyelinated axons in chronic lesions but was expressed by scar and reactive astrocytes within the plaque. Nav1.6 immunoreactivity, which was intense at nodes of Ranvier in normal appearing white matter in the same sections, was present in approximately one-third of the demyelinated axons within these plaques in a patchy rather than continuous distribution. NCX was not detected in demyelinated axons within chronic lesions, although it was clearly present within the scar astrocytes surrounding the demyelinated axons. beta-APP accumulation occurred in a small percentage of axons within chronic lesions within the spinal cord, but beta-APP was not preferentially present in axons that expressed Nav1.6. These observations suggest that different mechanisms underlie axonal degeneration in acute and chronic MS lesions, with axonal injury occurring at sites of coExpression of Nav1.6 and NCX in acute lesions but independent of coExpression of these 2 molecules in chronic lesions.

  • upregulation and colocalization of p75 and nav1 8 in purkinje neurons in experimental autoimmune encephalomyelitis
    Neuroscience Letters, 2004
    Co-Authors: Tina G Damarjian, Matthew J. Craner, Joel A Black, Stephen G Waxman
    Abstract:

    Recent studies have indicated that, in addition to demyelination and axonal degeneration, a third factor, dysregulated ion Channel Expression, contributes to the pathophysiology of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Consistent with this suggestion, upregulated Expression of Sodium Channel Na(v)1.8 is observed in Purkinje neurons in EAE and MS, and biophysical studies indicate that aberrant Expression of Na(v)1.8 produces abnormal Purkinje cell firing which may contribute to the development of cerebellar ataxia. However, the molecular mechanisms that contribute to the upregulation of Na(v)1.8 in Purkinje cells in EAE and MS have not yet been determined. Previous studies have shown that neurotrophic factors can modulate Sodium Channel Expression and that elevated levels of NGF are present in EAE and MS. Using immunocytochemical methods, we examined the relationship between the upregulation of Na(v)1.8 and the Expression of the NGF receptors p75 and TrkA in EAE. Here we demonstrate that upregulation of Na(v)1.8 is associated with Expression of p75 and low levels of TrkA in the majority of Purkinje cells in EAE. These findings, together with previous studies demonstrating a modulatory role of NGF on Sodium Channel Expression, suggest that NGF acting via p75 contributes to the upregulation of Na(v)1.8 in Purkinje cells in EAE.

  • upregulation of Sodium Channel nav1 3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury
    The Journal of Neuroscience, 2003
    Co-Authors: Bryan C Hains, Matthew J. Craner, Joel A Black, Joshua P Klein, Carl Y Saab, Stephen G Waxman
    Abstract:

    Spinal cord injury (SCI) can result in hyperexcitability of dorsal horn neurons and central neuropathic pain. We hypothesized that these phenomena are consequences, in part, of dysregulated Expression of voltage-gated Sodium Channels. Because the rapidly repriming TTX-sensitive Sodium Channel Nav1.3 has been implicated in peripheral neuropathic pain, we investigated its role in central neuropathic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal contusion injury. Four weeks after injury when extracellular recordings demonstrated hyperexcitability of L3-L5 dorsal horn multireceptive nociceptive neurons, and when pain-related behaviors were evident, quantitative RT-PCR, in situ hybridization, and immunocytochemistry revealed an upregulation of Nav1.3 in dorsal horn nociceptive neurons. Intrathecal administration of antisense oligodeoxynucleotides (ODNs) targeting Nav1.3 resulted in decreased Expression of Nav1.3 mRNA and protein, reduced hyperexcitability of multireceptive dorsal horn neurons, and attenuated mechanical allodynia and thermal hyperalgesia after SCI. Expression of Nav1.3 protein and hyperexcitability in dorsal horn neurons as well as pain-related behaviors returned after cessation of antisense delivery. Responses to normally noxious stimuli and motor function were unchanged in SCI animals administered Nav1.3 antisense, and administration of mismatch ODNs had no effect. These results demonstrate for the first time that Nav1.3 is upregulated in second-order dorsal horn sensory neurons after nervous system injury, showing that SCI can trigger changes in Sodium Channel Expression, and suggest a functional link between Nav1.3 Expression and neuronal hyperexcitability associated with central neuropathic pain.

Bryan C. Hains - One of the best experts on this subject based on the ideXlab platform.

  • Sodium Channel Expression and the molecular pathophysiology of pain after sci
    Progress in Brain Research, 2007
    Co-Authors: Bryan C. Hains, Stephen G Waxman
    Abstract:

    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. Our results have shown increased Expression of the Nav1.3 Sodium Channel in the spinal cord and thalamus. Nav1.3 upregulation allows dorsal horn neurons to generate ramp currents, enhanced persistent currents, and shifts in steady-state activation and inactivation. Further downstream, Nav1.3 causes increased spontaneous and evoked firing of neurons in the ventroposterior lateral (VPL) nucleus of the thalamus. Nav1.3 also underlies changes in burst firing properties of VPL neurons. The combination of spinal and thalamic generation and amplification of pain by Nav1.3 dysregulation contributes to post-SCI chronic pain. If proven to be similar in humans, targeting of this system after SCI may offer hope for treatment of clinical pain.

  • Sodium Channel Expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury
    Molecular Pain, 2006
    Co-Authors: Peng Zhao, Stephen G Waxman, Bryan C. Hains
    Abstract:

    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. To test this hypothesis, adult male Sprague-Dawley rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, when allodynia and hyperalgesia were evident, in situ hybridization and immunocytochemical analysis revealed up-regulation of Nav1.3 mRNA, but no changes in Expression of Nav1.1, Nav1.2, or Nav1.6 in VPL neurons, and unit recordings demonstrated increased background firing, which persisted after spinal cord transection, and evoked hyperresponsiveness to peripheral stimuli. These results demonstrate that injury to the peripheral nervous system induces alterations in Sodium Channel Expression within higher-order VPL neurons, and suggest that misExpression of the Nav1.3 Sodium Channel increases the excitability of VPL neurons injury, contributing to neuropathic pain.

  • changes in electrophysiological properties and Sodium Channel nav1 3 Expression in thalamic neurons after spinal cord injury
    Brain, 2005
    Co-Authors: Bryan C. Hains, Carl Y Saab, Stephen G Waxman
    Abstract:

    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. In this study we hypothesized that, following SCI, neurons in the thalamus undergo electrophysiological changes linked to aberrant Expression of Na(v)1.3. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 thoracic level. Four weeks post-SCI, Na(v)1.3 protein was upregulated within thalamic neurons in ventroposterior lateral (VPL) and ventroposterior medial nuclei, where extracellular unit recordings revealed increased spontaneous discharge, afterdischarge, hyperresponsiveness to innocuous and noxious peripheral stimuli, and expansion of peripheral receptive fields. Altered electrophysiological properties of VPL neurons persisted after interruption of ascending spinal barrage by spinal cord transection above the level of the injury. Lumbar intrathecal administration of specific antisense oligodeoxynucleotides generated against Na(v)1.3 caused a significant reduction in Na(v)1.3 Expression in thalamic neurons and reversed electrophysiological alterations. These results show, for the first time, a change in Sodium Channel Expression within neurons in the thalamus after injury to the spinal cord, and suggest that these changes contribute to altered processing of somatosensory information after SCI.

  • altered Sodium Channel Expression in second order spinal sensory neurons contributes to pain after peripheral nerve injury
    The Journal of Neuroscience, 2004
    Co-Authors: Bryan C. Hains, Matthew J. Craner, Carl Y Saab, Joshua P. Klein, Stephen G Waxman
    Abstract:

    Peripheral nerve injury is known to upregulate the rapidly repriming Na v 1.3 Sodium Channel within first-order spinal sensory neurons. In this study, we hypothesized that (1) after peripheral nerve injury, second-order dorsal horn neurons abnormally express Na v 1.3, which (2) contributes to the responsiveness of these dorsal horn neurons and to pain-related behaviors. To test these hypotheses, adult rats underwent chronic constriction injury (CCI) of the sciatic nerve. Ten days after CCI, allodynia and hyperalgesia were evident. In situ hybridization, quantitative reverse transcription-PCR, and immunocytochemical analysis revealed upregulation of Na v 1.3 in dorsal horn nociceptive neurons but not in astrocytes or microglia, and unit recordings demonstrated hyperresponsiveness of dorsal horn sensory neurons. Intrathecal antisense oligodeoxynucleotides targeting Na v 1.3 decreased the Expression of Na v 1.3 mRNA and protein, reduced the hyperresponsiveness of dorsal horn neurons, and attenuated pain-related behaviors after CCI, all of which returned after cessation of antisense delivery. These results demonstrate for the first time that Sodium Channel Expression is altered within higher-order spinal sensory neurons after peripheral nerve injury and suggest a link between misExpression of the Na v 1.3 Sodium Channel and central mechanisms that contribute to neuropathic pain after peripheral nerve injury.

  • primary motor neurons fail to up regulate voltage gated Sodium Channel nav1 3 brain type iii following axotomy resulting from spinal cord injury
    Journal of Neuroscience Research, 2002
    Co-Authors: Bryan C. Hains, Joel A Black, Stephen G Waxman
    Abstract:

    Epilepsy occurs in a small proportion of patients with spinal cord injury (SCI), but whether it is due to concomitant traumatic head injury or to changes in cortical motor neurons secondary to axotomy within the spinal cord is not known. Na(v)1.3/brain type III Sodium Channel Expression is up-regulated following peripheral axotomy of dorsal root ganglion (DRG) and facial motor neurons, but, to date, Na(v)1.3 Expression has not been examined in upper (cortical) motor neurons following axotomy associated with SCI. In the present study, we examine Na(v)1.3 Expression in upper motor neurons within rat primary motor cortex following midthoracic (T9) dorsal column transection, which severs the axons of those cells. Axotomized pyramidal cells were identified by retrograde transport of fluorogold. Immunolabeled cells were confined to layer V of the primary motor cortex and exhibited low levels of Na(v)1.3 staining. After axotomy, no significant changes were detected in Na(v)1.3 density or distribution in injured or uninjured cells, compared with control brains, in contrast to up-regulation of Na(v)1.3 in ipsilateral DRG neurons after sciatic nerve transection. These results do not preclude a role for voltage-gated Sodium Channels in post-SCI epilepsy but suggest that up-regulated Expression of Na(v)1.3 Channel is not involved.

Sulayman D Dibhajj - One of the best experts on this subject based on the ideXlab platform.

  • voltage gated Sodium Channel Expression in rat and human epidermal keratinocytes evidence for a role in pain
    Pain, 2008
    Co-Authors: Peng Zhao, Joel A Black, Sulayman D Dibhajj, Travis P Barr, Quanzhi Hou, Phillip J Albrecht, Karin L Petersen, Elon Eisenberg, James Wymer, Frank L Rice
    Abstract:

    Keratinocytes are implicated in sensory transduction and can influence nociception, but whether these contribute to chronic pain is not known. In neurons, voltage-gated Sodium Channels (Na(v)) are involved in neuropathic pain and are activated by depolarization. Since keratinocytes can also show changes in membrane potential, we used RT-PCR, in situ hybridization, and immunohistochemistry to investigate the Expression of Sodium Channels in these cells. Na(v)1.1, Na(v)1.6, and Na(v)1.8 were localized within keratinocytes in rat epidermis. In addition, Sodium Channels contribute to the release of ATP from rat keratinocytes in response to increased [K(+)](o), implicating Sodium Channels in keratinocyte ligand release and nociception. To examine whether keratinocytes may contribute to human pain states, we analyzed Sodium Channel Expression in human skin biopsies from subjects with complex regional pain syndrome Type 1 (CRPS) and post-herpetic neuralgia (PHN) using immunohistochemistry. Control skin exhibited immunolabeling for Na(v)1.5, Na(v)1.6 and Na(v)1.7. In contrast, painful skin from CRPS and PHN subjects displayed Na(v)1.1, Na(v)1.2, and Na(v)1.8 immunolabeling, in addition to substantially increased signal for Na(v)1.5, Na(v)1.6, Na(v)1.7. These observations lead us to propose that pathological increases in keratinocyte Sodium Channel Expression may contribute to pain by increasing epidermal ATP release, resulting in excessive activation of P2X receptors on primary sensory axons. Consistent with this hypothesis, animal models of neuropathic pain exhibit increases in subcutaneous ATP release and activity of primary sensory neurons, and peripheral administration of P2X antagonists has been shown to reduce neuropathic pain in humans.

  • patterned electrical activity modulates Sodium Channel Expression in sensory neurons
    Journal of Neuroscience Research, 2003
    Co-Authors: Joshua P. Klein, Sulayman D Dibhajj, Elisabetta A Tendi, Douglas R Fields, Stephen G Waxman
    Abstract:

    Peripheral nerve injury induces changes in the level of gene Expression for Sodium Channels Nav1.3, Nav1.8, and Nav1.9 within dorsal root ganglion (DRG) neurons, which may contribute to the development of hyperexcitability, ectopic neuronal discharge, and neuropathic pain. The mechanism of this change in Sodium Channel Expression is unclear. Decreased availability of neurotrophic factors following axotomy contributes to these changes in gene transcription, but the question of whether changes in intrinsic neuronal activity levels alone can trigger changes in the Expression of these Sodium Channels has not been addressed. We examined the effect of electrical stimulation on the Expression of Nav1.3, Nav1.8, and Nav1.9 by using cultured embryonic mouse sensory neurons under conditions in which nerve growth factor (NGF) was not limiting. Expression of Nav1.3 was not significantly changed following stimulation. In contrast, we observed activity-dependent down-regulation of Nav1.8 and Nav1.9 mRNA and protein levels after stimulation, as demonstrated by quantitative polymerase chain reaction and immunocytochemistry. These results show that a change in neuronal activity can alter the Expression of Sodium Channel genes in a subtype-specific manner, via a mechanism independent of NGF withdrawal.

  • sensory neuron specific Sodium Channel sns is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: J A Black, Sulayman D Dibhajj, Jia Newcombe, David Baker, M L Cuzner, Stephen G Waxman
    Abstract:

    Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and/or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion Channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific Sodium Channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" Sodium Channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that Sodium Channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein Expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in Sodium Channel Expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion Channel Expression may contribute to clinical abnormalities such as ataxia in these disorders.

  • plasticity of Sodium Channel Expression in drg neurons in the chronic constriction injury model of neuropathic pain
    Pain, 1999
    Co-Authors: Sulayman D Dibhajj, Theodore R Cummins, Jenny Fjell, Kaj Fried, Zheng Zheng, Robert H Lamotte, Joel A Black
    Abstract:

    Previous studies have shown that transection of the sciatic nerve induces dramatic changes in Sodium currents of axotomized dorsal root ganglion (DRG) neurons, which are paralleled by significant changes in the levels of transcripts of several Sodium Channels expressed in these neurons. Sodium currents that are resistant to tetrodotoxin (TTX-R) and the transcripts of two TTX-R Sodium Channels are significantly attenuated, while a rapidly repriming tetrodotoxin-sensitive (TTX-S) current emerges and the transcripts of α-III Sodium Channel, which produce a TTX-S current when expressed in oocytes, are up-regulated. We report here on changes in Sodium currents and Sodium Channel transcripts in DRG neurons in the chronic constriction injury (CCI) model of neuropathic pain. CCI-induced changes in DRG neurons, 14 days post-surgery, mirror those of axotomy. Transcripts of NaN and SNS, two sensory neuron-specific TTX-R Sodium Channels, are significantly down-regulated as is the TTX-R Sodium current, while transcripts of the TTX-S α-III Sodium Channel and a rapidly repriming TTX-S Na current are up-regulated in small diameter DRG neurons. These changes may provide at least a partial basis for the hyperexcitablity of DRG neurons that contributes to hyperalgesia in this model.

  • abnormal Expression of sns pn3 Sodium Channel in cerebellar purkinje cells following loss of myelin in the taiep rat
    Neuroreport, 1999
    Co-Authors: Joel A Black, Sulayman D Dibhajj, Jenny Fjell, Kaj Fried, I D Duncan, L T Oconnor, Z Gladwell, Simon Tate, Stephen G Waxman
    Abstract:

    Using in situ hybridization and immunochemical methods, we have observed an increase in the Expression of SNS/PN3 Sodium Channel mRNA and protein in cerebellar Purkinje cells of the taiep rat. These changes are present in taiep rats at 12 months of age, following loss of myelin, but not at one month, prior to loss of myelin. Increased SNS/PN3 Expression is not associated with aging per se, because it was not observed in control rats at 12 months of age. These results suggest that altered Sodium Channel Expression in Purkinje cells may contribute to the ataxia that occurs in taiep rats.

Mustafa B A Djamgoz - One of the best experts on this subject based on the ideXlab platform.

  • regulation of voltage gated Sodium Channel Expression in cancer hormones growth factors and auto regulation
    Philosophical Transactions of the Royal Society B, 2014
    Co-Authors: Scott P Fraser, Iley Ozerlatgunduz, William J Brackenbury, Elizabeth M Fitzgerald, Thomas M Campbell, Charles R Coombes, Mustafa B A Djamgoz
    Abstract:

    Although ion Channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their Expression. Here, we focus on voltage-gated Na(+) Channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC Expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional Channel Expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC Expression and regulation in cancer.

  • molecular pharmacology of voltage gated Sodium Channel Expression in metastatic disease clinical potential of neonatal nav1 5 in breast cancer
    European Journal of Pharmacology, 2009
    Co-Authors: Rustem Onkal, Mustafa B A Djamgoz
    Abstract:

    A variety of ion Channels have been detected in cancer cells. In particular, upregulation of voltage-gated Sodium Channels (VGSCs) has been associated pathophysiologically with several strongly metastatic carcinomas. This review emphasises breast cancer. Inhibiting VGSC activity in a number of independent ways, using the highly selective tetrodotoxin (TTX), gene silencing and a blocking polyclonal antibody, suppressed a range of cellular behaviors, especially directional motility and invasion, integral to the metastatic cascade. Conversely, transfecting a VGSC into a weakly invasive human prostate cancer cell line significantly increased invasiveness. In vivo, also, VGSC Expression has been correlated positively with metastatic status. It has been suggested, therefore (i) that VGSC upregulation is an early event in metastatic progression and (ii) that VGSC Expression is a 'switch,' necessary and sufficient for engaging cancer cells in a highly invasive state. Importantly, where studied, mainly prostate and breast cancers, the dominant VGSC (Nav1.7 and Nav1.5, respectively) was found to be an embryonic/neonatal splice variant, consistent with the gene Expression being "oncofoetal." In breast cancer, the molecular difference between the adult and neonatal isoforms of the VGSC/Nav1.5 is largest (31 base pairs, generating 7 amino acid differences). We propose that neonatal Nav1.5 is a novel marker with significant clinical potential for management of metastatic breast cancer and describe a number of approaches which may enable tumour-specific targeting. These include various small-molecule drugs, small-interfering RNA, monoclonal antibody and natural neurotoxins.

  • a potential novel marker for human prostate cancer voltage gated Sodium Channel Expression in vivo
    Prostate Cancer and Prostatic Diseases, 2005
    Co-Authors: James K J Diss, D Stewart, Filippo Pani, C S Foster, Marjorie M Walker, A Patel, Mustafa B A Djamgoz
    Abstract:

    Functional Expression of voltage-gated Sodium Channel alpha-subunits (VGSCalphas), specifically Nav1.7, is associated with strong metastatic potential in prostate cancer (CaP) in vitro. Furthermore, VGSC activity in vitro directly potentiates processes integral to metastasis. To investigate VGSCalpha Expression in CaP in vivo, immunohistochemistry and real-time PCR were performed on human prostate biopsies (n>20). VGSCalpha immunostaining was evident in prostatic tissues and markedly stronger in CaP vs non-CaP patients. Importantly, RT-PCRs identified Nav1.7 as the VGSCalpha most strikingly upregulated (approximately 20-fold) in CaP, and the resultant receiver-operating characteristics curve demonstrated high diagnostic efficacy for the disease. It is concluded that VGSCalpha Expression increases significantly in CaP in vivo and that Nav1.7 is a potential functional diagnostic marker.