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Gliopathy Ensures Persistent Inflammation and Chronic Pain after Spinal Cord Injury
Hulsebosch, Claire E.
Experimental neurology
Research focused on improving recovery of function, including the reduction of central neuropathic pain (CNP) after spinal cord injury (SCI) is essential. After SCI, regional neuropathic pain syndromes above, at and below the level or spinal injury develop and are thought to have different mechanisms, but may share common dysfunctional glial mechanisms. Detloff et al, 2008 describes events in the lumbar region of the spinal cord after a midthoracic SCI injury, the so called "below-level" pain and compares the findings to peripheral nerve lesion findings. This commentary briefly reviews glial contributions and intracellular signaling mechanisms, both neuronal and glial, that provide the substrate for CNP after SCI, including the persistent glial production of factors that can maintain sensitization of dorsal horn neurons in segments remote from the spinal injury; ie. dorsal horn hyperexcitability to formerly non noxious stimuli that become noxious after SCI resulting in allodynia. The term "gliopathy" is proposed to describe the dysfunctional and maladaptive response of glial cells, specifically astrocytes and microglia, to neural injury that is initiated by the sudden injury induced increase in extracellular concentrations of glutamate and concomitant production of several proinflammatory molecules. It is important to understand the roles that different glia play in "gliopathy," a condition that appears to persist after SCI. Furthermore, targeted treatment of gliopathy will attenuate mechanical allodynia in both central and peripheral neuropathic pain syndromes.
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Herpes simplex virus vector-mediated expression of interleukin-10 reduces below-level central neuropathic pain after spinal cord injury
Lau, Darryl
Harte, Steven E.
Morrow, Thomas J.
Wang, Shiyong
Mata, Marina
Fink, David J.
Neurorehabilitation and neural repair
Neuroimmune activation in the spinal dorsal horn plays an important role in the pathogenesis of chronic pain after peripheral nerve injury.
We wanted to examine the role of neuroimmune activation in below level neuropathic pain after traumatic spinal cord injury (SCI).
Right hemilateral SCI was created in male Sprague Dawley rats by controlled blunt impact through a T12 laminectomy. Pain related behaviors were assessed using both evoked reflex responses and an operant conflict-avoidance test. Neuroimmune activation was blocked by the anti-inflammatory cytokine interleukin-10 (IL-10) delivered by a non-replicating herpes simplex virus (HSV)-based gene transfer vector (vIL10). Markers of neuroimmune activation were assessed using immunohistochemistry and Western blot.
One week after SCI, injured animals demonstrated mechanical allodynia, thermal hyperalgesia, and mechanical hyperalgesia in the hind limbs below the level of injury. Animals inoculated with vIL10 had a statistically significant reduction in all of these measures compared to injured rats or injured rats inoculated with control vector. Conflict-avoidance behavior of injured rats inoculated with vIL10 was consistent with significantly reduced pain compared to injured rats injected with control vector. These behavioral results correlated with a significant decrease in spinal tumor necrosis factor α (mTNFα) expression assessed by Western blot and astrocyte activation assessed by glial fibrillary acidic protein immunohistochemistry.
Below level pain after SCI is characterized by neuroimmune activation (increase mTNFα and astrocyte activation). Blunting of the neuroimmune response by HSV-mediated delivery of IL-10 reduced pain-related behaviors, and may represent a potential novel therapeutic agent.
spinal cord injury; pain; gene therapy; herpes virus; interleukin-10; neuroinflammation
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Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury
Carlton, Susan M.
Du, Junhui
Tan, Huai Yu
Nesic, Olivera
Hargett, Gregory L.
Bopp, Anne C.
Yamani, Ammar
Lin, Qing
Willis, William D.
Hulsebosch, Claire E.
Central neuropathic pain (CNP) developing after spinal cord injury (SCI) is described by the region affected: above-level, at-level and below-level pain occurs in dermatomes rostral, at/near, or below the SCI level, respectively. People with SCI and rodent models of SCI develop above-level pain characterized by mechanical allodynia and thermal hyperalgesia. Mechanisms underlying this pain are unknown and the goals of this study were to elucidate components contributing to the generation of above-level CNP. Following a thoracic (T10) contusion, forelimb nociceptors had enhanced spontaneous activity and were sensitized to mechanical and thermal stimulation of the forepaws 35 days post-injury. Cervical dorsal horn neurons showed enhanced responses to non-noxious and noxious mechanical stimulation as well as thermal stimulation of receptive fields. Immunostaining dorsal root ganglion (DRG) cells and cord segments with activating transcription factor 3 (ATF3, a marker for neuronal injury) ruled out neuronal damage as a cause for above-level sensitization since few C8 DRG cells expressed AFT3 and cervical cord segments had few to no ATF3-labeled cells. Finally, activated microglia and astrocytes were present in thoracic and cervical cord at 35 days post-SCI, indicating a rostral spread of glial activation from the injury site. Based on these data, we conclude that peripheral and central sensitization as well as reactive glia in the uninjured cervical cord contribute to CNP. We hypothesize that reactive glia in the cervical cord release pro-inflammatory substances which drive chronic CNP. Thus a complex cascade of events spanning many cord segments underlies above-level CNP.
neuroplasticity; primary afferents; nociception; microglia activation; astrocyte activation
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Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury induced neuropathic pain states
Boroujerdi, Amin
Zeng, Jun
Sharp, Kelli
Kim, Donghyun
Steward, Oswald
Luo, Z. David
Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and or hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage gated calcium channel alpha-2-delta-1 subunit (Cavα2δ-1) proteins is effective in the management of SCI induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Cavα2δ-1 in dorsal spinal cord (DSC). To test this hypothesis, we examined if SCI-induced dysregulation of spinal Cavα2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Cavα2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hindpaw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI induced Cavα2δ-1 protein upregulation by intrathecal Cavα2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI induced Cavα2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain development and selectively targeting this pathway may provide effective pain relief for SCI patients.
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Spatial and Temporal Activation of Spinal Glial Cells: Role of Gliopathy in Central Neuropathic Pain Following Spinal Cord Injury in Rats
Gwak, Young S.
Kang, Jonghoon
Unabia, Geda C.
Hulsebosch, Claire. E.
Experimental Neurology
In the spinal cord, neurons and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion channels and also produce similar neurotransmitters and cytokines. The neuroanatomical and neurochemical similarities work synergistically to maintain physiological homeostasis in the normal spinal cord. However, in trauma or disease states, spinal glia become activated, dorsal horn neurons become hyperexcitable contributing to sensitized neuronal-glial circuits. The maladaptive spinal circuits directly affect synaptic excitability, including activation of intracellular downstream cascades that result in enhanced evoked and spontaneous activity in dorsal horn neurons with the result that abnormal pain syndromes develop.
Recent literature reported that spinal cord injury produces glial activation in the dorsal horn; however, the majority of glial activation studies after SCI have focused on transient and/or acute time points, from a few hours to one month, and peri-lesion sites, a few millimeters rostral and caudal to the lesion site. In addition, thoracic spinal cord injury produces activation of astrocytes and microglia that contributes to dorsal horn neuronal hyperexcitability and central neuropathic pain in above-level, at-level and below-level segments remote from the lesion in the spinal cord. The cellular and molecular events of glial activation are not a simple event, rather it is the consequence of a combination of several neurochemical and neurophysiological changes following SCI. The ionic imbalances, neuroinflammation and alterations of cell cycle proteins after SCI are predominant components for neuroanatomical and neurochemical changes that result in glial activation. More importantly, SCI induced release of glutamate, proinfloammatory cytokines, ATP, reactive oxygen species (ROS) and neurotrophic factors trigger activation of postsynaptic neurons and glial cells via their own receptors and channels that, in turn, contribute to neuronal-neuronal and neuronal-glial interaction as well as microglia-astrocytic interactions. However, a systematic review of temporal and spatial glial activation following SCI has not been done.
In this review, we describe time and regional dependence of glial activation and describe activation mechanisms in various SCI models in rats. These data are placed in the broader context of glial activation mechanisms and chronic pain states. Our work in the context of work by others in SCI models demonstrate that dysfunctional glia, a condition called "gliopathy", are key contributors in the underlying cellular mechanisms contributing to neuropathic pain.
Central Neuropathic Pain; Glial Activation; Gliopathy; Hyperexcitability; Spinal Cord Injury
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Adenoviral-Mediated Glial Cell Line–Derived Neurotrophic Factor Gene Transfer Has a Protective Effect on Sciatic Nerve Following Constriction-Induced Spinal Cord Injury
Chou, An-Kuo
Yang, Ming-Chang
Tsai, Hung-Pei
Chai, Chee-Yin
Tai, Ming-Hong
Kwan, Aij-Li
Hong, Yi-Ren
PLoS ONE
Neuropathic pain due to peripheral nerve injury may be associated with abnormal central nerve activity. Glial cell-line-derived neurotrophic factor (GDNF) can help attenuate neuropathic pain in different animal models of nerve injury. However, whether GDNF can ameliorate neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced peripheral nerve injury remains unknown. We investigated the therapeutic effects of adenoviral-mediated GDNF on neuropathic pain behaviors, microglial activation, pro-inflammatory cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study, neuropathic pain was produced by CCI on the ipsilateral SCDH. Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1, IL6, IL1β, AIF, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, cleaved PARP, SPECTRIN, cleaved SPECTRIN, Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by GDNF. Results showed that administrating GDNF began to attenuate both allodynia and thermal hyperalgesia at day 7. CCI-rats were found to have lower GDNF and GDNFRa-1 expression compared to controls, and GDNF re-activated their expression. Also, GDNF significantly down-regulated CCI-induced protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of GDNF might be associated with anti-inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that GDNF reduced CCI-induced neuronal apoptosis. In sum, GDNF enhanced the neurotrophic effect by inhibiting microglia activation and cytokine production via p38 and PKC signaling. GDNF could be a good therapeutic tool to attenuate programmed cell death, including apoptosis and autophagy, consequent to CCI-induced peripheral nerve injury.
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Mechanisms of Chronic Central Neuropathic Pain after Spinal Cord Injury
Hulsebosch, Claire E.
Hains, Bryan C.
Crown, Eric D.
Carlton, Susan M.
Brain research reviews
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 kdyne, 1 sec dwell) devices to model spinal cord injury (SCI). Both of these devices and injury parameters, if done correctly, will result in animals with above level (forelimb), at level (trunk) and below level (hindlimb) mechanical allodynia that model the changes in evoked somatosensation experienced by the majority of people with SCI. The sections are as follows: 1) Mechanisms of Remote Microglial Activation and Pain Signaling in "Below-Level" Central Pain 2) Intracellular Signaling Mechanisms in Central Sensitization in "At-Level" Pain 3) Peripheral Sensitization Contributes to "Above Level" Injury Pain Following Spinal Cord Injury and 4) Role of Reactive Oxygen Species in Central Sensitization in Regional Neuropathic Pain Following SCI. To summarize, differential regional mechanisms contribute to the regional chronic pain states. We propose the importance of understanding the mechanisms in the differential regional pain syndromes after SCI in the chronic condition. Targeting regional mechanisms will be of enormous benefit to the SCI population that suffer chronic pain, and will contribute to better treatment strategies for other chronic pain syndromes.
Reactive Oxygen Species; cytokines; Central Sensitization; Peripheral Sensitization; Pain; Chronic Pain; Regional Pain Syndrome
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Vascular Endothelial Growth Factor and Spinal Cord Injury Pain
Nesic, Olivera
Sundberg, Laura M.
Herrera, Juan J.
Mokkapati, Venkata U.L.
Lee, Julieann
Narayana, Ponnada A.
Journal of Neurotrauma
Vascular endothelial growth factor (VEGF)-A mRNA was previously identified as one of the significantly upregulated transcripts in spinal cord injured tissue from adult rats that developed allodynia. To characterize the role of VEGF-A in the development of pain in spinal cord injury (SCI), we analyzed mechanical allodynia in SCI rats that were treated with either vehicle, VEGF-A isoform 165 (VEGF165), or neutralizing VEGF165-specific antibody. We have observed that exogenous administration of VEGF165 increased both the number of SCI rats that develop persistent mechanical allodynia, and the level of hypersensitivity to mechanical stimuli. Our analysis identified excessive and aberrant growth of myelinated axons in dorsal horns and dorsal columns of chronically injured spinal cords as possible mechanisms for both SCI pain and VEGF165-induced amplification of SCI pain, suggesting that elevated endogenous VEGF165 may have a role in the development of allodynia after SCI. However, the neutralizing VEGF165 antibody showed no effect on allodynia or axonal sprouting after SCI. It is possible that another endogenous VEGF isoform activates the same signaling pathway as the exogenously-administered 165 isoform and contributes to SCI pain. Our transcriptional analysis revealed that endogenous VEGF188 is likely to be the isoform involved in the development of allodynia after SCI. To the best of our knowledge, this is the first study to suggest a possible link between VEGF, nonspecific sprouting of myelinated axons, and mechanical allodynia following SCI.
microarray analysis; myelinated axon sprouting; neuropathic pain; rat spinal cord injury; vascular endothelial growth factor
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Calcium/Calmodulin Dependent Kinase II Plays a Role in Persistent Central Neuropathic Pain Following Spinal Cord Injury
Crown, Eric D
Gwak, Young S.
Ye, Zaiming
Tan, Huaiyu
Johnson, Kathia M
Xu, Guo-Ying
McAdoo, David J
Hulsebosch, Claire E
Chronic central neuropathic pain following CNS injuries remains refractory to therapeutic interventions. A novel approach would be to target key intracellular signaling proteins that are known to contribute to continued activation by phosphorylation of kinases, transcription factors, and/or receptors that contribute to changes in membrane excitability. We demonstrate that one signaling kinase, calcium/calmodulin-dependent kinase II (CaMKII), is critical in maintaining aberrant dorsal horn neuron hyperexcitability in the neuropathic pain condition following spinal cord injury (SCI). Following T10 contusion SCI, activated CaMKII (phosphorylated, pCAMKII) expression is significantly upregulated in the T7/8 spinal dorsal horn in neurons, but not glial cells, and in oligodendrocytes in the dorsal column in the same rats that displayed at-level mechanical allodynia. Furthermore, identified spinothalamic neurons demonstrated significant increases of pCaMKII after SCI compared to sham controls. However, neither astrocytes nor microglia showed pCaMKII expression in either sham or SCI rats. To demonstrate causality, treatment of SCI rats with KN-93, which prevents CaMKII activation, significantly attenuated at-level mechanical allodynia and aberrant WDR neuronal activity evoked by brush, pressure, pinch stimuli and a graded series of von Frey stimuli, respectively. This is the first evidence that persistent CaMKII activation contributes to chronic central neuropathic pain by mechanisms that involve maintained hyperexcitability of WDR dorsal horn neurons. Furthermore, targeting key signaling proteins is a novel, useful therapeutic strategy for treating chronic central neuropathic pain.
CaMKII; central neuropathic pain; electrophysiology; immunocytochemistry; mechanical allodynia; Western Immunoblotting
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Activation of p38 MAP Kinase is Involved in Central Neuropathic Pain Following Spinal Cord Injury
Crown, Eric D
Gwak, Young Seob
Ye, Zaiming
Johnson, Kathia M
Hulsebosch, Claire E
Experimental neurology
Recent work regarding chronic central neuropathic pain (CNP) following spinal cord injury (SCI) suggests that activation of key signaling molecules such as members of the mitogen activated protein kinase (MAPK) family play a role in the expression of at-level mechanical allodynia. Specifically, Crown and colleagues (2005, 2006) have shown that the development of at-level CNP following moderate spinal cord injury is correlated with increased expression of the activated (and thus phosphorylated) forms of the MAPKs extracellular signal related kinase and p38 MAPK. The current study extends this work by directly examining the role of p38 MAPK in the maintenance of at-level CNP following spinal cord injury. Using a combination of behavioral, immunocytochemical, and electrophysiological measures we demonstrate that increased activation of p38 MAPK occurs in the spinal cord just rostral to the site of injury in rats that develop at-level mechanical allodynia after moderate SCI. Immunocytochemical analyses indicate that the increases in p38 MAPK activation occurred in astrocytes, microglia, and dorsal horn neurons in the spinal cord rostral to the site of injury. Inhibiting the enzymatic activity of p38 MAPK dose dependently reverses the behavioral expression of at-level mechanical allodynia and also decreases the hyperexcitability seen in thoracic dorsal horn neurons after moderate SCI. Taken together, these novel data are the first to demonstrate causality that increased activation of p38 MAPK in multiple cell types play an important role in the maintenance of at-level CNP following spinal cord injury.
p38 MAPK; electrophysiology; at-level mechanical allodynia; girdling; Western Immunoblotting; immunocytochemistry; central neuropathic pain
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Influence of intrathecal delivery of bone marrow-derived mesenchymal stem cells on spinal inflammation and pain hypersensitivity in a rat model of peripheral nerve injury
Schäfer, Sabrina
Berger, Julie V
Deumens, Ronald
Goursaud, Stéphanie
Hanisch, Uwe-Karsten
Hermans, Emmanuel
Journal of Neuroinflammation
Multipotent mesenchymal stem (stromal) cells (MSCs) have been credited with immunomodulative properties, supporting beneficial outcomes when transplanted into a variety of disease models involving inflammation. Potential mechanisms include the secretion of paracrine factors and the establishment of a neurotrophic microenvironment. To test the hypothesis that MSCs release soluble mediators that can attenuate local inflammation, we here analysed the influence of MSCs on the activation of microglia cells, as well as on inflammatory parameters and pain behaviour in a surgical rat model of neuropathic pain.
We focussed on an experimental model of partial sciatic nerve ligation (PSNL), characterised by a rapid and persistent inflammation in the dorsal lumbar spinal cord where sensory inputs from the sciatic nerve are processed. Via indwelling intrathecal catheters, MSCs were repetitively grafted into the intrathecal lumbar space. Animals were evaluated for mechanical and thermal hypersensitivity over a period of 21 days after PSNL. Afterwards, spinal cords were processed for immunohistochemical analysis of the microglial marker ionized calcium-binding adapter molecule 1 (Iba1) and quantification of inflammatory markers in ipsilateral dorsal horns. We hypothesised that injections on postsurgical days 2 to 4 would interfere with microglial activation, leading to a reduced production of pro-inflammatory cytokines and amelioration of pain behaviour.
PSNL-induced mechanical allodynia or heat hyperalgesia were not influenced by MSC transplantation, and spinal cord inflammatory processes remained largely unaffected. Indeed, the early microglial response to PSNL characterised by increased Iba1 expression in the lumbar dorsal horn was not significantly altered and cytokine levels in the spinal cord at 21 days after surgery were similar to those found in vehicle-injected animals. Grafted MSCs were detected close to the pia mater, but were absent within the spinal cord parenchyma.
We conclude that intrathecal administration is not an appropriate route to deliver cells for treatment of acute spinal cord inflammation as it leads to entrapment of grafted cells within the pia mater. We propose that the early inflammatory response triggered by PSNL in the lumbar spinal cord failed to effectively recruit MSCs or was insufficient to disturb the tissue integrity so as to allow MSCs to penetrate the spinal cord parenchyma.
Mesenchymal stem cells; Neuroinflammation; Microglia; PSNL; Pain
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Remote Astrocytic and Microglial Activation Modulate Neuronal Hyperexcitability and Below-Level Neuropathic Pain after Spinal Injury in Rat
Gwak, Young Seob
Hulsebosch, Claire E.
In this study, we evaluated whether astrocytic and microglial activation mediates below-level neuropathic pain following spinal cord injury. Male Sprague-Dawley (225–250 g) rats were given low thoracic (T13) spinal transverse hemisection and behavioral, electrophysiological and immunohistochemical methods were used to examine the development and maintenance of below-level neuropathic pain. On post operation day 28, both hindlimbs showed significantly decreased paw withdrawal thresholds and thermal latencies as well as hyperexcitability of lumbar (L4-5) spinal wide dynamic range (WDR) neurons on both sides of spinal dorsal horn compared to sham controls (*p<0.05). Intrathecal treatment with propentofylline (PPF, 10 mM) for 7 consecutive days immediately after spinal injury attenuated the development of mechanical allodynia and thermal hyperalgesia in both hindlimbs in a dose related reduction compared to vehicle treatments (*p<0.05). Intrathecal treatment with single injections of PPF at 28 days after spinal injury, attenuated the existing mechanical allodynia and thermal hyperalgesia in both hindlimbs in a dose related reduction (*p<0.05). In electrophysiological studies, topical treatment of 10 mM PPF onto the spinal surface attenuated the neuronal hyperexcitability in response to mechanical stimuli. In immunohistochemical studies, astrocytes and microglia in rats with spinal hemisection showed significantly increased GFAP and OX-42 expression in both superficial and deep dorsal horns in the lumbar spinal dorsal horn compared to sham controls (*p<0.05) that was prevented in a dose related manner by PPF. In conclusion, our present data support astrocytic and microglial activation that contributes to below-level central neuropathic pain following spinal cord injury.
allodynia; hyperexcitability; spinal cord injury; spinal glia; WDR neuron
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Injury Discharges Regulate Calcium Channel Alpha-2-Delta-1 Subunit Upregulation in the Dorsal Horn that Contributes to Initiation of Neuropathic Pain
Boroujerdi, Amin
Kim, Hee Kee
Lyu, Yeoung Su
Kim, Doo-Sik
Figueroa, Katherine W.
Chung, Jin Mo
Luo, Z. David
Previous studies have shown that peripheral nerve injury in rats induces increased expression of the voltage gated calcium channel (VGCC) alpha-2-delta-1 subunit (Cavα2δ1) in spinal dorsal horn and sensory neurons in dorsal root ganglia (DRG) that correlates to established neuropathic pain states. To determine if injury discharges trigger Cavα2δ1 induction that contributes to neuropathic pain initiation, we examined allodynia onset and Cavα2δ1 levels in DRG and spinal dorsal horn of spinal nerve ligated rats after blocking injury induced neural activity with a local brief application of lidocaine on spinal nerves before the ligation. The lidocaine pretreatment blocked ligation-induced discharges in a dose-dependent manner. Similar pretreatment with the effective concentration of lidocaine diminished injury-induced increases of the Cavα2δ1 in DRG and abolished that in spinal dorsal horn specifically, and resulted in a delayed onset of tactile allodynia post injury. Both dorsal horn Cavα2δ1 upregulation and tactile allodynia in the lidocaine pretreated rats returned to levels similar to that in saline pretreated controls two weeks post the ligation injury. In addition, preemptive intrathecal Cavα2δ1 antisense treatments blocked concurrently injury-induced allodynia onset and Cavα2δ1 upregulation in dorsal spinal cord. These findings indicate that injury induced discharges regulate Cavα2δ1 expression in the spinal dorsal horn that is critical for neuropathic allodynia initiation. Thus, preemptive blockade of injury-induced neural activity or Cavα2δ1 upregulation may be a beneficial option in neuropathic pain management.
Nerve injury; spinal neuroplasticity; neuropathic pain; allodynia initiation
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Chronic At- and Below-Level Pain after Moderate Unilateral Cervical Spinal Cord Contusion in Rats
Detloff, Megan Ryan
Wade, Rodel E.
Houlé, John D.
Journal of Neurotrauma
Chronic neuropathic pain is a significant consequence of spinal cord injury (SCI) that is associated with evoked pain, including allodynia and/or hyperalgesia. Allodynia is defined as a painful response to normally innocuous stimuli, and hyperalgesia occurs when there is an amplified pain response to normally noxious stimuli. We describe a model of a unilateral cervical level (C5) contusion injury where sensory recovery was assessed weekly for 6 weeks in 32 adult, female, Sprague-Dawley rats. Bilateral thermal hyperalgesia and tactile allodynia are detectable in the fore- and hindpaws as early as 7 days post-injury (dpi) and persist for at least 42 days. Paw withdrawal latency in response to a noxious thermal stimulus significantly intra-animal pre-operative values. Change in paw withdrawal latency plateaued at 21 dpi. Interestingly, bilateral forepaw allodynia develops in fewer than 40% of rats as measured by von Frey monofilament testing. Similar results occur in the hindpaws, where bilateral allodynia occurs in 46% of rats with SCI. The contralesional forepaw and both hindpaws of rats showed a slight increase in paw withdrawal threshold to tactile stimuli acutely after SCI, corresponding to ipsilesional forelimb motor deficits that resolve over time. That there is no difference among allodynic and non-allodynic groups in overall spared tissue or specifically of the dorsal column or ventrolateral white matter where ascending sensory tracts reside suggests that SCI-induced pain does not depend solely on the size or extent of the lesion, but that other mechanisms are in play. These observations provide a valid model system for future testing of therapeutic interventions to prevent the onset or to reduce the debilitating effects of chronic neuropathic pain after SCI.
central pain; mechanical allodynia; spinal cord injury; thermal hyperalgesia
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Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury
Suter, Marc R
Berta, Temugin
Gao, Yong-Jing
Decosterd, Isabelle
Ji, Ru-Rong
Molecular Pain
After peripheral nerve injury, spontaneous ectopic activity arising from the peripheral axons plays an important role in inducing central sensitization and neuropathic pain. Recent evidence indicates that activation of spinal cord microglia also contributes to the development of neuropathic pain. In particular, activation of p38 mitogen-activated protein kinase (MAPK) in spinal microglia is required for the development of mechanical allodynia. However, activity-dependent activation of microglia after nerve injury has not been fully addressed. To determine whether spontaneous activity from C- or A-fibers is required for microglial activation, we used resiniferatoxin (RTX) to block the conduction of transient receptor potential vanilloid subtype 1 (TRPV1) positive fibers (mostly C- and Aδ-fibers) and bupivacaine microspheres to block all fibers of the sciatic nerve in rats before spared nerve injury (SNI), and observed spinal microglial changes 2 days later.
SNI induced robust mechanical allodynia and p38 activation in spinal microglia. SNI also induced marked cell proliferation in the spinal cord, and all the proliferating cells (BrdU+) were microglia (Iba1+). Bupivacaine induced a complete sensory and motor blockade and also significantly inhibited p38 activation and microglial proliferation in the spinal cord. In contrast, and although it produced an efficient nociceptive block, RTX failed to inhibit p38 activation and microglial proliferation in the spinal cord.
(1) Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers) is not enough to prevent nerve injury-induced spinal microglial activation. (2) Peripheral input from large myelinated fibers is important for microglial activation. (3) Microglial activation is associated with mechanical allodynia.
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Below Level Central Pain Induced by Discrete Dorsal Spinal Cord Injury
Wieseler, Julie
Ellis, Amanda L.
McFadden, Andrew
Brown, Kimberley
Starnes, Charlotte
Maier, Steven F.
Watkins, Linda R.
Falci, Scott
Journal of Neurotrauma
Central neuropathic pain occurs with multiple sclerosis, stroke, and spinal cord injury (SCI). Models of SCI are commonly used to study central neuropathic pain and are excellent at modeling gross physiological changes. Our goal was to develop a rat model of central neuropathic pain by traumatizing a discrete region of the dorsal spinal cord, thereby avoiding issues including paralysis, urinary tract infection, and autotomy. To this end, dorsal root avulsion was pursued. The model was developed by first determining the number of avulsed dorsal roots sufficient to induce below-level hindpaw mechanical allodynia. This was optimally achieved by unilateral T13 and L1 avulsion, which resulted in tissue damage confined to Lissauer's tract, dorsal horn, and dorsal columns, at the site of avulsion, with no gross physical changes at other spinal levels. Behavior following avulsion was compared to that following rhizotomy of the T13 and L1 dorsal roots, a commonly used model of neuropathic pain. Avulsion induced below-level allodynia that was more robust and enduring than that seen after rhizotomy. This, plus the lack of direct spinal cord damage associated with rhizotomy, suggests that avulsion is not synonymous with rhizotomy, and that avulsion (but not rhizotomy) is a model of central neuropathic pain. The new model described here is the first to use discrete dorsal horn damage by dorsal root avulsion to create below-level bilateral central neuropathic pain.
avulsion; central pain; rhizotomy; spinal cord injury
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Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury
Xu, Zhen-Zhong
Berta, Temugin
Ji, Ru-Rong
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
Accumulating evidence indicates that activation of spinal cord microglia plays an important role in the genesis of neuropathic pain. Resolvin E1 (E1) is derived from omega-3 polyunsaturated fatty acid and exhibits potent anti-inflammatory, pro-resolution, and anti-nociceptive effects. We further examined whether RvE1 could reduce neuropathic pain and modulate spinal cord microglial activation. Intrathecal pre-treatment of RvE1 (100 ng) daily for 3 days partially prevented the development of nerve injury-induced mechanical allodynia and up-regulation of IBA-1 (microglial marker) and TNF-α in the spinal cord dorsal horn. Furthermore, intrathecal post-treatment of RvE1 (100 ng), 3 weeks after nerve injury, transiently reduced mechanical allodynia and heat hyperalgesia. Finally, RvE1 blocked lipopolisaccharide-induced microgliosis and TNF-α release in primary micoglial cultures. Our data suggest that RvE1 may attenuate neuropathic pain via inhibiting microglial signaling. Targeting the anti-inflammatory and pro-resolution lipid mediators may offer new options for preventing and treating neuropathic pain.
Eicosapentaenoic acid (EPA); Tumor necrosis factor-alpha TNF-α; lipopolisacride (LPS); nerve injury; omega-3 poly unsaturated fatty acids; spinal cord
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Stress Exacerbates Neuropathic Pain via Glucocorticoid and NMDA Receptor Activation
Alexander, Jessica K.
DeVries, A. Courtney
Kigerl, Kristina A.
Dahlman, Jason M.
G.Popovich, Phillip
Brain, behavior, and immunity
There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g. corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, a GR antagonist, prevented the stress-induced increase in allodynia whereas exogenous administration of CORT to non-stressed mice reproduced the allodynic response caused by stress. Since nerve injury-induced microglial activation has been implicated in the onset and propagation of neuropathic pain, we evaluated cellular and molecular indices of microglial activation in the context of stress. Activation of dorsal horn microglia was accelerated by stress; however, this effect was transient and was not associated with the onset or maintenance of a pro-inflammatory phenotype. Stress-enhanced allodynia was associated with increased dorsal horn extracellular signal-regulated kinase phosphorylation (pERK). ERK activation could indicate a stress-mediated increase in glutamatergic signaling, therefore mice were treated prior to SNI and stress with memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist. Memantine prevented stress-induced enhancement of allodynia after SNI. These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress.
pain; glucocorticoids; inflammation; microglia; glutamate; ERK
Related Articles
Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy
Talbot, Sébastien
Chahmi, Emna
Dias, Jenny Pena
Couture, Réjean
Journal of Neuroinflammation
The pro-nociceptive kinin B1 receptor (B1R) is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ)-diabetic rat. This study aims at defining the role of microglial kinin B1R in diabetic pain neuropathy.
Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p.), and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p.) were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR) of B1R and pro-inflammatory markers. Spinal B1R binding sites ((125I)-HPP-desArg10-Hoe 140) were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B1R agonist (des-Arg9-BK) and antagonists (SSR240612 and R-715) were measured on neuropathic pain manifestations.
STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B1R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg9-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B1R, IL-1β, TNF-α, TRPV1) and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B1R binding sites were reduced by 38%.
The upregulation of kinin B1R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.
Related Articles
Intrathecal delivery of PDGF produces tactile allodynia through its receptors in spinal microglia
Masuda, Junya
Tsuda, Makoto
Tozaki-Saitoh, Hidetoshi
Inoue, Kazuhide
Molecular Pain
Neuropathic pain is a debilitating pain condition that occurs after nerve damage. Such pain is considered to be a reflection of the aberrant excitability of dorsal horn neurons. Emerging lines of evidence indicate that spinal microglia play a crucial role in neuronal excitability and the pathogenesis of neuropathic pain, but the mechanisms underlying neuron-microglia communications in the dorsal horn remain to be fully elucidated. A recent study has demonstrated that platelet-derived growth factor (PDGF) expressed in dorsal horn neurons contributes to neuropathic pain after nerve injury, yet how PDGF produces pain hypersensitivity remains unknown. Here we report an involvement of spinal microglia in PDGF-induced tactile allodynia. A single intrathecal delivery of PDGF B-chain homodimer (PDGF-BB) to naive rats produced a robust and long-lasting decrease in paw withdrawal threshold in a dose-dependent manner. Following PDGF administration, the immunofluorescence for phosphorylated PDGF β-receptor (p-PDGFRβ), an activated form, was markedly increased in the spinal dorsal horn. Interestingly, almost all p-PDGFRβ-positive cells were double-labeled with an antibody for the microglia marker OX-42, but not with antibodies for other markers of neurons, astrocytes and oligodendrocytes. PDGF-stimulated microglia in vivo transformed into a modest activated state in terms of their cell number and morphology. Furthermore, PDGF-BB-induced tactile allodynia was prevented by a daily intrathecal administration of minocycline, which is known to inhibit microglia activation. Moreover, in rats with an injury to the fifth lumbar spinal nerve (an animal model of neuropathic pain), the immunofluorescence for p-PDGFRβ was markedly enhanced exclusively in microglia in the ipsilateral dorsal horn. Together, our findings suggest that spinal microglia critically contribute to PDGF-induced tactile allodynia, and it is also assumed that microglial PDGF signaling may have a role in the pathogenesis of neuropathic pain.
Related Articles
Early Systemic Granulocyte-Colony Stimulating Factor Treatment Attenuates Neuropathic Pain after Peripheral Nerve Injury
Chao, Po-Kuan
Lu, Kwok-Tung
Lee, Yun-Lin
Chen, Jin-Chung
Wang, Hung-Li
Yang, Yi-Ling
Cheng, Mei-Yun
Liao, Ming-Feng
Ro, Long-Sun
PLoS ONE
Recent studies have shown that opioid treatment can reduce pro-inflammatory cytokine production and counteract various neuropathic pain syndromes. Granulocyte colony-stimulating factor (G-CSF) can promote immune cell differentiation by increasing leukocytes (mainly opioid-containing polymorphonuclear (PMN) cells), suggesting a potential beneficial role in treating chronic pain. This study shows the effectiveness of exogenous G-CSF treatment (200 µg/kg) for alleviating thermal hyperalgesia and mechanical allodynia in rats with chronic constriction injury (CCI), during post-operative days 1–25, compared to that of vehicle treatment. G-CSF also increases the recruitment of opioid-containing PMN cells into the injured nerve. After CCI, single administration of G-CSF on days 0, 1, and 2, but not on day 3, relieved thermal hyperalgesia, which indicated that its effect on neuropathic pain had a therapeutic window of 0–48 h after nerve injury. CCI led to an increase in the levels of interleukin-6 (IL-6) mRNA and tumor necrosis factor-α (TNF-α) protein in the dorsal root ganglia (DRG). These high levels of IL-6 mRNA and TNF-α were suppressed by a single administration of G-CSF 48–144 h and 72–144 h after CCI, respectively. Furthermore, G-CSF administered 72–144 h after CCI suppressed the CCI-induced upregulation of microglial activation in the ipsilateral spinal dorsal horn, which is essential for sensing neuropathic pain. Moreover, the opioid receptor antagonist naloxone methiodide (NLXM) reversed G-CSF-induced antinociception 3 days after CCI, suggesting that G-CSF alleviates hyperalgesia via opioid/opioid receptor interactions. These results suggest that an early single systemic injection of G-CSF alleviates neuropathic pain via activation of PMN cell-derived endogenous opioid secretion to activate opioid receptors in the injured nerve, downregulate IL-6 and TNF-α inflammatory cytokines, and attenuate microglial activation in the spinal dorsal horn. This indicates that G-CSF treatment can suppress early inflammation and prevent the subsequent development of neuropathic pain.
Related Articles
Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine
Zhuang, Zhi-Ye
Kawasaki, Yasuhiko
Tan, Ping-Heng
Wen, Yeong-Ray
Huang, Jing
Ji, Ru-Rong
Brain, behavior, and immunity
Accumulating evidence suggests that microglial cells in the spinal cord play an important role in the development of neuropathic pain. However, it remains largely unknown how glia interact with neurons in the spinal cord after peripheral nerve injury. Recent studies suggest that the chemokine fractalkine may mediate neural/microglial interaction via its sole receptor CX3CR1. We have examined how fractalkine activates microglia in a neuropathic pain condition produced by spinal nerve ligation (SNL). SNL induced an upregulation of CX3CR1 in spinal microglia that began on day 1, peaked on day 3, and maintained on day 10. Intrathecal injection of a neutralizing antibody against CX3CR1 suppressed not only mechanical allodynia but also the activation of p38 MAPK in spinal microglia following SNL. Conversely, intrathecal infusion of fractalkine produced a marked p38 activation and mechanical allodynia. SNL also induced a dramatic reduction of the membrane-bound fractalkine in the dorsal root ganglion, suggesting a cleavage and release of this chemokine after nerve injury. Finally, application of fractalkine to spinal slices did not produce acute facilitation of excitatory synaptic transmission in dorsal horn neurons, arguing against a direct action of fractalkine on spinal neurons. Collectively, our data suggest that (a) fractalkine cleavage (release) after nerve injury may play an important role in neural-glial interaction, and (b) microglial CX3CR1/p38 MAPK pathway is critical for the development of neuropathic pain.
Chemokine; MAP kinase; microglia; spinal cord; neural-glial interaction; spinal nerve ligation; intracellular signaling; neuropathic pain
Related Articles
Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons
Huang, Chung-Yu
Chen, Ying-Ling
Li, Allen H
Lu, Juu-Chin
Wang, Hung-Li
Journal of Neuroinflammation
Several lines of evidence suggest that CCL2 could initiate the hyperalgesia of neuropathic pain by causing central sensitization of spinal dorsal horn neurons and facilitating nociceptive transmission in the spinal dorsal horn. The cellular and molecular mechanisms by which CCL2 enhances spinal pain transmission and causes hyperalgesia remain unknown. The substantia gelatinosa (lamina II) of the spinal dorsal horn plays a critical role in nociceptive transmission. An activated spinal microglia, which is believed to release pro-inflammatory cytokines including TNF-α, plays an important role in the development of neuropathic pain, and CCL2 is a key mediator for spinal microglia activation. In the present study, we tested the hypothesis that spinal CCL2 causes the central sensitization of substantia gelatinosa neurons and enhances spinal nociceptive transmission by activating the spinal microglia and augmenting glutamatergic transmission in lamina II neurons.
CCL2 was intrathecally administered to 2-month-old male rats. An intrathecal injection of CCL2 induced heat hyperalgesia, which was assessed using the hot plate test. Whole-cell voltage-clamp recordings substantia gelatinosa neurons in spinal cord slices were performed to record glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs).
The hot plate test showed that 1 day after the intrathecal injection of CCL2 (1 μg), the latency of hind-paw withdrawal caused by a heat stimulus was significantly reduced in rats. One day after the intrathecal administration of CCL2, the amplitude of the evoked glutamatergic EPSCs and the frequency of spontaneous glutamatergic miniature EPSCs (mEPSCs) were significantly increased in outer lamina II neurons. Intrathecal co-injection of minocycline, a specific inhibitor of microglial activation, and CCL2 blocked the CCL2-induced reduction in the latency of hind-paw withdrawal and thermal hyperalgesia. Following intrathecal co-administration of CCL2 and minocycline, CCL2 failed to increase the frequency of glutamatergic mEPSCs and failed to promote glutamine release in lamina II neurons. Intrathecal co-injection of WP9QY, a selective TNF-α antagonist, and CCL2 completely inhibited CCL2-induced heat hyperalgesia and inhibited the increase in the frequency of glutamatergic mEPSCs in substantia gelatinosa neurons.
In summary, our results suggest that an intrathecal injection of CCL2 causes thermal hyperalgesia by augmenting the excitatory glutamatergic transmission in substantia gelatinosa neurons through a presynaptic mechanism and facilitating nociceptive transmission in the spinal dorsal horn. Further studies show that intrathecal co-administration of minocycline, a specific inhibitor of microglial activation, or WP9QY, a selective TNF-α antagonist, completely inhibited CCL2 potentiation of glutamatergic transmission in substantia gelatinosa neurons and CCL2-induced heat hyperalgesia. The results of the present study suggest that peripheral nerve injury-induced upregulation of the spinal CCL2 level causes the central sensitization of substantia gelatinosa neurons by activating spinal microglia and that TNF-α mediates CCL2-induced thermal hyperalgesia and augmentation of glutamatergic transmission in lamina II neurons.
CC chemokine ligand 2; Heat hyperalgesia; Substantia gelatinosa neurons; Glutamatergic transmission; Microglia; Tumor necrosis factor-α
Related Articles
T-Cell Infiltration and Signaling in the Adult Dorsal Spinal Cord Is a Major Contributor to Neuropathic Pain-Like Hypersensitivity
Costigan, Michael
Moss, Andrew
Latremoliere, Alban
Johnston, Caroline
Verma-Gandhu, Monica
Herbert, Teri A.
Barrett, Lee
Brenner, Gary J.
Vardeh, Daniel
Woolf, Clifford J.
Fitzgerald, Maria
The Journal of neuroscience : the official journal of the Society for Neuroscience
Partial peripheral nerve injury in adult rats results in neuropathic pain-like hypersensitivity, while that in neonatal rats does not, a phenomenon also observed in humans. We therefore compared gene expression profiles in the dorsal horn of adult and neonatal rats in response to the spared nerve injury (SNI) model of peripheral neuropathic pain. The 148 differentially regulated genes in adult, but not young, rat spinal cords indicate a greater microglial and T-cell response in adult than in young animals. T-cells show a large infiltration in the adult dorsal horn but not in the neonate after SNI. T-cell-deficient Rag1-null adult mice develop less neuropathic mechanical allodynia than controls, and central expression of cytokines involved in T-cell signaling exhibits large relative differences between young and adult animals after SNI. One such cytokine, interferon-γ (IFNγ), is upregulated in the dorsal horn after nerve injury in the adult but not neonate, and we show that IFNγ signaling is required for full expression of adult neuropathic hypersensitivity. These data reveal that T-cell infiltration and activation in the dorsal horn of the spinal cord following peripheral nerve injury contribute to the evolution of neuropathic pain-like hypersensitivity. The neuroimmune interaction following peripheral nerve injury has therefore a substantial adaptive immune component, which is absent or suppressed in the young CNS.
Related Articles
Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats
Scholz, Joachim
Abele, Andrea
Marian, Claudiu
Häussler, Annett
Herbert, Teri A.
Woolf, Clifford J.
Tegeder, Irmgard
Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker CD11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionized calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrate that suppression of this cellular immune response is a promising approach for preventing neuropathic pain.
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xabix: User Profile
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Skip to comments.WHY WE ARE IGNORING ARMSTRONG
Posted on 08/28/2012 6:20:39 AM PDT by shortstop
As long as mankind is a species of sentience and technology, as long as history is kept and read, the name of Neil A. Armstrong will be known.
It will be Columbus and Magellan and Armstrong, each leapfrogging the other in the innate human impulse to explore, remembered as long as man remembers.
Whether man walked out of Africa or was kicked out of Eden, he went where hed never been, and his descendants did the same until the earth was peopled and the heavens were challenged.
Some walked across the Bering Strait, others rowed through the nothingness of the south Pacific, or hiked over mountains and swamps and deserts. We conquered this earth and Neil A. Armstrong was the first to conquer beyond.
And history will wonder at the way we ignored his passing.
When the names Romney and Obama have moldered into meaninglessness, school children will still learn the name of Armstrong and be inspired by what he did. His will be one of the greatest names of our era, one of the greatest men to ever live.
This man should have a state funeral.
This man should lie in state in the Capitol.
This man should have been afforded something other than the slightest of half-staff honors.
Yesterday, the president ordered the America flags at federal properties to be flown at half- staff on Friday, the day Neil A. Armstrong is buried.
That seems like a nice gesture, but it is such a slight gesture as to be insulting.
When Obama himself dies, for example, the flag will be lowered for 30 days. The Chief Justice of the United States, or the Speaker of the House, would get 10 days, and if a member of the presidents cabinet were to die, the period of respect would be from the day of their death until the day of their burial.
If a member of Congress dies, the flags are lowered the day they die and the day that follows.
And the first man to walk on the moon gets half that.
It is an honor, but not really.
And it is emblematic of the disrespect being shown this hero in his death. He chose to live humbly, we have chosen to bury him ignobly.
Part of it could be that the one time he spoke up in criticism of a federal policy in all the years since he walked on the moon was just recently, when he harshly criticized the current president for essentially ending Americas manned space flight program.
Obama gets his revenge, but history will have the last say.
And history will understand what we cannot.
Six hundred million people around the world watched this man climb down a ladder on black-and-white television because they understood the significance of what he was doing. They knew they were witnessing history, and they wanted to be a part of it.
Today, we want no part of it.
We have lost the spine and the stones necessary to go new places, to solve hard problems and reach great heights. We are more concerned about not interrupting the welfare cheese than we are about being men and truly exploring.
We have been castrated by a new way of thinking and doing. Neil A. Armstrong rode a rocket of American might, but todays NASA has specifically denounced any more all-American flights.
It would be arrogant for America to go to Mars or the Moon alone, NASA has said, so we would only go as part of a coalition.
Neil A. Armstrongs coalition was him and Buzz and an army of crew-cut engineers.
While todays space exploration consists of landing our seventh rover on the surface of Mars, and politely ignoring the fact that the Spanish weather equipment doesnt work, the exploration of Armstrongs era involved creating whole new technologies to go to a whole new place.
Perhaps we have ignored the passing of Neil A. Armstrong because we cannot live up to the legacy of Neil A. Armstrong. Perhaps looking back at him and his era makes us look weak and useless by comparison.
You dont know how puny you are until you stand next to a giant, and Neil A. Armstrong was a giant. For what he did, and for what he represented.
And now he is gone.
And perhaps he took our soul with him.
Perhaps its been downhill since 1969.
He will inspire future generations, but mostly he is shaming ours.
By reminding us of who we used to be.
When the names Romney and Obama have moldered into meaninglessness, school children will still learn the name of Armstrong and be inspired by what he did. His will be one of the greatest names of our era, one of the greatest men to ever live.
Neal or Lance?.........
I would include Lewis & Clark in that pantheon as well.
Why doesn't the Republicans have a memorial service for the guy. They have the microphone for the next three days. Use it for some good. There are two stories hogging up the airwaves....the storm and the GOP. Nothing else is going on.
Yesterday, the president ordered the America flags at federal properties to be flown at half- staff on Friday, the day Neil A. Armstrong is buried.
I told everyone that Armstrong would get his flag day at 1/2 staff. Nobody believed me but I knew it 100 percent. Right again. Someday you guys will at least believe 1/2 what I say.
I disagree with this article. I've done google searches on his death and followed twitter. I was amazed at even the young celebrities who chimed in on his death.
Even the BBC had shows talking about him and all over the world. Armstrong wouldn't want any fanfare at all.He would not want a state funeral. He truly felt he was doing his job, doing what he loved and was just fortunate to be at the right place at the right time.
Just because CBS NBC or ABC doesn't do a big story doesn't mean anything. They are irrelevant.
Funny thing about Armstrong...He'd probably look at all this fuss and say "nahhhhhhh"...
But he'd say it in a way that could be written down for the ages to learn from...
There was economy of effort in the things he said and did in his lifetime, and that is a lesson in and of itself...
IIRC, you could go back and look at the medical telemetry and when the 1200 series of alerts came from HOUSTON to the Eagle about those concerns...
I believe his heartrate stayed normal...I stand to be corrected,but that is what I remember of a little side story years ago...
But hey...He was not alone in that effort either...There was another guy there in that lander...And he lost a pretty good friend there...
Good question.
The death of Neil Armstrong wasn't ignored. The second he died, and for some time thereafter, this was the lead story on every newsbreak, on every tv screen news crawler, etc. I heard it, I saw it, it was dominant.
What happened is that people have gone on from there in a somewhat understated way, not like Kennedy, King, etc being assassinated. The circumstances of Armstrong's death at 82, from heart disease, wasn't shocking. He had lived as long as his body was able, so he passed from this life, and his enormous achievement was noted.
Beyond that, where would you go? Neil Armstrong was very understated and hated personal publicity. The man would not want anything more than what he received. He was PAINFULLy against anything more than that in life, and no doubt, in death.
In point of fact, I have always been astounded by how very little homage was given to the Mercury and Apollo astronauts. I would guess that 99% of Americans could have run into Alan Shepard or Neil Armstrong at the grocery store, and never recognized them. 50% of Americans alive today probably couldn't even tell you who they were, if provided the name.
He hates white boys and their achievements.
I am not being facetious.
Nothing is allowed now unless it includes females and minorities.
Greatness is done, and will be eradicated from history; look at Columbus for object lesson #1.
Just like the arch-bureaucrats want it.
Lewis and Clark were American heroes but they are scarcely known anywhere else.
Actually Armstrong was probably the only legitimate first. The Vikings, at a minimum, preceded Columbus and Magellan died prior to circling the globe.
Other than another excuse to put his ugly face in a picture, the kenyan usurper has yet to figure out how to capitalize on a True American Hero who was humble. Therefore, ignoring him so that Hussein remains the center of attention, is the strategy.
"Neal or Lance?........."
...haf mast for losing his Tour de France trophies? In an Obama world, it makes sense.
He was a humble man.
He did not crave the limelights or the fortune and fame.
He is remembered by those he inspired and will always do so...........
In our celeb-ri-world it sure would...........
He also was openly critical of the White Hut's (non-)space policy. I'm sure that went a long way to putting him on Zero's sh*tlist.
Shout out for Astronaut Michael Collins, the third member of the Apollo 11 crew.
Because the current President was only "Made In America?"
He does not have a clue how to speak of nor honor anyone of greatness?
And of course the minions surrounding him could care less of anything that might acknowledge "American Exceptionalism"
Whitney Houston got nearly a week of having the flag at half staff. How does she rate above Neil Armstrong? Neil has accomplished more than she has in an endeavor that MEANT something. Singing and acting are fluff compared to going to the moon and doing what Neil and the rest of those guys did back then. The shooting at that temple a few weeks ago garnered a few days of having the flag lowered. And Neil gets ONE DAY!
Does he deserve a state funeral? Probably because of who is was, that being the first to set foot on another world. But he was a private man and will get a private service. He may have wanted things that way. He may have been embarassed by a full blown state funeral.
Brings back memories of the early space program.
I can still name all 7 Mercury astronauts. Alan Shepherd, Gus Grissom, John Glenn, Scott Carpenter, Wally Schirra, Gordon Cooper, and Deke Slayton. Back in the day, they were all heroes.
They all paved the way for the Appolo moon landings, and all other space activity since.
they will be remembered, as long as history is taught. Do they teach school kids about things such as the moon landings?
I got in an argument the other day with somebody, about California's new law that requires teaching homosexual, trans-whatever history. I said that with limited school time, that teaching homosexual history would crowd out other things. And I am convinced that history such as our space program could indeed be squeezed out in favor of politically correct history.
Along with the American Flag, Armstrong and Aldrin left this little item on the surface of the moon.
The Apollo One Mission patch designed by the three astronauts themselves.
A memorial to their three comrades who died in the command module fire during a test on the launch pad. Apollo One, the flight that never was.
The investigation of the fire uncovered severe deficiencies and lapses in the NASA mind set, design flaws, and dereliction in monitoring contract work, not to mention the cover-up efforts after the fact.
The Wikipedia piece is worth the read.
Unnoticed, by intent...a male, and a white guy as well...
Or to paraphrase what one of high school teachers once said about Neil Armstrong, "A thousand years from now when students pick up their history books and the entire 20th century is reduced to one or two pages, Neil Armstrong being the first man on the moon will be what they read learn our time."
I assume this is a rhetorical question.
78 missions over Korea for a total of 121 hours in the air. He received the Air Medal for 20 combat missions, a Gold Star for the next 20, and the Korean Service Medal and Engagement Star.
Master of science degree in aeronautical engineering.
Professor of aeronautical engineering Purdue University.
Presidential Medal of Freedom.
The Congressional Space Medal of Honor.
Robert H. Goddard Memorial Trophy
The Sylvanus Thayer Award
The Collier Trophy from the National Aeronautics Association
Congressional Gold Medal.
The lunar crater Armstrong, 31 mi (50 km) from the Apollo 11 landing site, and asteroid 6469 Armstrong[133] are named in his honor.
Treating his death as a sidebar, as a trivial foot note, absolutely disgusts me to the point of vomiting in my throat.
Any leader of our nation who had an once of character and respect would go on national television and pay tribute to the greatest American to ever live and declare a national day of mourning, propose a plan to send man to Mars with in the next decade and remind us all that it is not what the nation can do for you, it's about what you can do for your nation.
I am so enraged, disappointed, and designedly disgusted with today's culture of irresponsible, underachieving and mentally disabled gurly-men who are shaping and controlling the minds of our future generations.
I mourn for Neil Armstrong.
I mourn for our nation.
I mourn for our children.
I mourn for our greatness. I mourn for our freedom and our Republic.
I've heard two lunar astronauts (Collins and Cernan) speak in person. Both of them went out of their way to emphasize that they got the PR because their skiils and training enabled them to sit at the sharp end of the rocket, but that there were thousands of others who contributed every bit as much as the astronauts did.
That's true. And their may have been other Europeans before them. But they weren't robust enough to project themselves onto the New World. We are the cultural descendents of Columbus, not Ericson.
Unfortunately I think that's a lot of it. Armstrong wasn't a minority, a women or gay. He wasn't an outspoken liberal, he didn't push a "cause" such as global warming or gay rights and by all accounts he was publicly apolitical and refused to endorse a candidate from any party. In other words, he just didn't fit the narrative of the modern "hero" as defined by the media.
Crackers on the moon rank right up there.
I wonder if stomping around on the moon was an especially heinous blasphemy for the moongod worshipers. After all, twelve crackers have walked on the moon, all Americans.
Neil Armstrong needed a billion dollar rocket to get as high as the moon...Whitney Houston only need a few grams of crack.
It would be interesting to compare and contrast with the media's treatment of Sally Ride's recent passing.
The US had "won" the space race and in the process had developed a lot of the technology we take for granted today. It was a time when crew-cut, pocket-protector wearing engineers and square-jawed test pilots ruled the earth.
Most of the Mercury, Gemini, and Apollo astronauts went about their post flight careers without the need to seek publicity. Armstrong was no exception. His was the ultimate accomplishment, but he chose to shun the limelight and live out his years as an academian.
If you've ever had the opportunity to visit the Armstrong museum in his hometown of Wapakoneta, Ohio you'll find it is as he was; simple, purposeful, but not self-serving.
I did not know Neil Armstrong personally, but I've known many men like him. I doubt he would want the fanfare of a state funeral. Nor would he care if the flags were lowered to half-staff for 1 day or 30. It was never about him. He was one of many who just happened to draw the flight assignment that ended up on the moon.
The President can publish a picture of himself standing in silhouette. He can stare at the moon and the stars and offer up some prose (written by another) that attempts to show some link between a man of little accomplishment and one whose accomplishment will never be equaled.
But at the end of the day, when the President is no longer in office and largely forgotten, the lunar lander, the American flag, (tattered by solar winds) and the footprints of a true American hero will still be embedded in the lunar surface.
Rest in Peace Neil A. Armstrong. YOU will always be remembered.
I have enjoyed and own that excellent movie, "The Right Stuff", that is as good a movie on this topic and history as can be found. It is hard to believe that the Mercury Program Astronauts were named in 1959 and the last Mercury flight was Gordo Cooper's in 1965.
When you hear about rockets failing, even today, 50 years after the Mercury Program, it becomes more clear how dangerous these missions were. Yes, they were test pilots and knew the risks, but nevertheless, they are genuine HEROES!
And yes, Dilbert San Diego, I too can name them from memory and even their military affiliations as well. As a young Army Brat, I resented the fact that there were no Army Astronauts at that time. Somehow rotary wing test pilots didn't make the cut. Ah well!
As long as there is written history of mankind, Armstrong will be remembered regardless of what is taught to Americans during the 21st century. Armstrong setting foot on the moon is an immutable fact. His footprints are still there.
Well, you got me there. I didn't know the military affiliations of the Mercury 7!!
They were all heroes. It was a different time back then. There was a lot of excitement back then about us going into space. Can't think of anything going on nowadays which excites people that way.
I don't...
FTA..."He will inspire future generations, but mostly he is shaming ours.
"By reminding us of who we used to be.
Many in this generation don't want to be reminded of American exceptionalism. It's not so much about those who know of and admire Armstrong, it's what he and his generation REPRESENT. American ingenuity, individuality, exceptionalism, accomplishment, drive, desire, motivation, etc.
Armstrong represents many of the same characteristics that made America great. The same characteristics that many in today's society want swept under the rug as they destroy America.
Spot on Bob Lonsberry!
Who remembers the name of the brave sailor in Columbus' crew who first stepped ashore in the New World?
Are we sure that people 1,000 years from now won't learn instead about Harvey Milk, "Chazz" Bono, and their ilk????
Of course at the rate our education system is going, this will be the typical American in the future
I hope you are right that Armstrong will be remembered.
I am concerned too, that the space program doesn't seem to generate interest among many people anymore. So, I was also thinking that people in the future may not care that we had sent astronauts to the moon.
The Right Stuff....
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IT WAS inevitable that, given her place in Jewish apologetic literature and the Graeco-Roman ethical and rhetorical tradition', Sparta should occasionally attract the attention of the Fathers of the Church. During the great age of debate, when some Christians, in self-defence, were ready to assimilate a part of pagan culture, we find Tertullian describing Christian heroism as outdoing all precedents, including the Lacedaemonian endurance of flagellatio, and urging on the martyrs with the same examples. Here the famous and then still existing festival at Lacedaemon forms his climax: how slight such torments must be to those who will gain a divine reward, if they are so bravely home for the sake of mere human glory!1
The Christian writers of Alexandria, that centre of Greek scholarship and hellenizing Judaism, show their double ancestry clearly. St. Clement, accepting what is as we saw a Jewish thesis, like many others after him, not only supposes that Plato was following Moses in blaming Minos' and Lycurgus' concentration on physical courage, but also assumes that Moses was himself the archetype of all the Greek lawgivers. Clement regarded exempla as vital (for which reason he even approves of the Lacedaemonian way of teaching their children temperance by making their helots drunk). His works are full of classical learning. They remind his readers of how the Spartans excelled in simplicity and endurance,, banished myrrh and purple dye, refused to allow respectable women to wear gold or flowered dresses (though in other passages he complains that their skirts were too short), and how it was not only Sparta that, as the oracle prophesied, love of riches would ruin. He contrasts the Spartan law, 'inscribed on the scytalae of the ephors', with the true, royal, living law, identical with reason.2____________________


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Thursday, Mar 06, 2014 9:00 PM CST (8:00 PM Doors)
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|Key Info
Studio apartment, with beautiful sea views and a sunny terrace. Double glazed patio doors,air conditioning and a modern, fully equipped kitchen means you don't have to go out every night. Should you decide not to. Garden City is surrounded by restaurants, pubs, clubs and bars. Beaches are a short stroll away, with Siam Park and Aqualand within a 10 minute walk. The local shopping centre with large supermarket is no more than 4 minutes away.
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Bids for Worlds 2015
Submitted by Colm Flynn on 19 December 2012
At the moment there are two bidders for the right to host Worlds in 2015. With just over a week left to Worlds I think we can be fairly sure there are no others out there so this is a good point to remind people of the two bidders.
The University of Auckland in New Zealand are bidding for Worlds. To see details of their bid visit: http://www.aucklandworlds.com/
UT Mara in Malaysia are bidding for Worlds 2015. To see details of their bid visit: http://malaysiaworlds2015.com/
Best of luck to both bidders.
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Hi! your work is awesome. In July I'll get married and I'd love to wear this beautiful art. I'd like to purchase these how can I make it?
Hey sweetie, do you still have these? I'd like to purchase them if you still do!
How did you make them?
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can you teach me how to do that? my art teacher had me make a metel person out of one line of wire but I sucked at bending and wrapping.
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United Parcel Service, Inc.
) saw a disappointing end to its $6.8 billion proposed
acquisition of Dutch shipping company, TNT Express. Challenged by
the European regulators' dejection with the proposed acquisition,
the company finally dropped its plans to acquire TNT.
This set back remains a big jolt for the company's aspirations
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Prohibition remains a big disappointment for the company, as
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UPS retains a Zacks Rank #3 (Hold) rating. For the long term,
we have a Neutral recommendation on the stock.
The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.
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The Grossest Criminal Ever Punks Cops
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Two EmbracesDos Abrazos
Mexico, 2007, 86 Minute Running Time
Topic: Drama
Programs: Best of Fest, New Voices/New VisionsLanguage: Spanish English Sub-Titles
Four people forced to fend for themselves in life – a burdened twelve-year-old boy, the cashier he has a crush on, an angry taxi driver and the estranged daughter of one of his passengers – come together in two embraces. An auspicious film debut and poignant tale of lonely people who find a glimmer of hope in each other in today's Mexico City.
DIRECTOR: Enrique Begne
Producer: Enrique Begne, Monica Lozano, Ricardo ZiehlEditor: Samuel LarsonScreenwriter: Enrique Begne, Paula MarkovichCinematographer: Federico BarbabosaMusic: Antonio Fernández RosPrincipal Cast: Maya Zapata, Jorge Zárate, Giovanni Florido, Ximena SariñanaFilmography: Debut Feature Film