Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat

Liu, L.; ̈rnqvist, E. To; Mattsson, Per; Eriksson, N. P.; Persson, Jonas; Morgan, B. Paul; Aldskogius, Håkan; Svensson, Mikael

doi:10.1016/0306-4522(95)00103-p

Cited by 80 publications

(48 citation statements)

References 35 publications

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“…Microglia respond with a stereotypical 'activation'-their numbers swell through proliferation and infiltration and they change their morphology from the characteristic ramified 'resting' state to the more amoeboid 'activated' state, a process also associated with considerable change in gene expression (Perry, 1994;Kreutzberg, 1996;Stoll and Jander, 1999;Nakajima and Kohsaka, 2001). This 'activation' response has been reported in all experimental models of neuropathic pain involving peripheral nerve injury (Liu et al, 1995;Coyle, 1998;Colburn et al, 1999;Herzberg and Sagen, 2001;Tsuda et al, 2003;Zhang and De Koninck, 2006). In all cases the response is typified by a marked increase in the number of microglia in the ipsilateral dorsal horn of the spinal cord.…”

Section: Introductionmentioning

confidence: 60%

“…Other proteins indicative of activation include members of the complement cascade; complement receptor 3 (CR3), Toll-like receptor 4 (TLR4), CD14, CD4 and major histocompatibility complex (MHC) class I and II. A correlation between an upregulation of many of these markers in the spinal cord and peripheral nerve injury has long been reported (Gehrmann et al, 1991;Streit et al, 1988;Eriksson et al, 1993;Liu et al, 1995). The coincident onset of pain behavior with increases in microglial activity has also been well documented (Colburn et al, 1997;Coyle, 1998;Colburn et al, 1999), but it is only recently that a causal role of microglial activation in nerve injury-induced pain behaviors has been established (Tsuda et al, 2003;Jin et al, 2003) and the key mediator released by microglia identified as BDNF (Coull et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

Beggs

Salter

2007

Brain, Behavior, and Immunity

131

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The involvement of glia, and glia-neuronal signalling in enhancing nociceptive transmission has become an area of intense scientific interest. In particular, a role has emerged for activated microglia in the development and maintenance of neuropathic pain following peripheral nerve injury. Following activation, spinal microglia proliferate and release many substances which are capable of modulating neuronal excitability within the spinal cord. Here, we the investigated the response of spinal microglia to a unilateral spared nerve injury (SNI) in terms of the quantitative increase in cell number and the spatial distribution of the increase. Design-based stereological techniques were combined with iba-1 immunohistochemistry to estimate the total number of microglia in the spinal dorsal horn in naïve and peripheral nerve-injured adult rats. In addition, by mapping the central terminals of hindlimb nerves, the somatotopic distribution of the microglial response was mapped. Following SNI there was a marked increase in the number of spinal microglia: The total number of microglia (mean ± SD) in the dorsal horn sciatic territory of the naïve rat was estimated to be 28,591 ± 2715. Following SNI the number of microglia was 82,034 ± 8828. While the pattern of microglial activation generally followed somatotopic boundaries, with the majority of microglia within the territory occupied by peripherally axotomised primary afferents, some spread was seen into regions occupied by intact, 'spared' central projections of the sural nerve. This study provides a reproducible method of assaying spinal microglial dynamics following peripheral nerve injury both quantitatively and spatially.

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Section: Introductionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

Beggs

Salter

2007

Brain, Behavior, and Immunity

131

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“…A progressive series of morphological changes in spinal microglia has been reported in rodent models of nerve injury caused by compression, ligation, or transection (Liu et al, 1995;Tsuda et al, 2003;Zhang and De, 2006). After peripheral nerve injury, microglia withdraw their thin processes and adopt an amoeboid-like structure (Eriksson et al, 1993).…”

Section: Cihr Author Manuscript Cihr Author Manuscriptmentioning

confidence: 99%

“…These morphological changes are often followed by an increase in the number and density of microglia in the ipsilateral spinal dorsal horn Echeverry et al, 2008;Gehrmann and Banati, 1995;Perry, 1994;Stoll and Jander, 1999). The stereotypical microglial response also entails the upregulation of a number of surface marker proteins belonging to the complement cascade: complement receptor 3 (CR3), Toll-like receptor 4 (TLR4), CD14, CD4, and major histocompatibility complex (MHC) class I and II (Coyle, 1998;Liu et al, 1995;Sweitzer et al, 2002b;Tanga et al, 2004;Tsuda et al, 2003). In addition, spinal microglia produce and secrete cytokines, chemokines, and neurotrophic factors that signal to neurons in the spinal cord to alter neuronal excitability.…”

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confidence: 99%

ATP receptors gate microglia signaling in neuropathic pain

Trang

Beggs

Salter

2012

Experimental Neurology

138

104

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Microglia were described by Pio del Rio-Hortega (1932) as being the 'third element' distinct from neurons and astrocytes. Decades after this observation, the function and even the very existence of microglia as a distinct cell type was a topic of intense debate and conjecture. However, considerable advances have been made towards understanding the neurobiology of microglia resulting in a radical shift in our view of them as being passive bystanders that have solely immune and supportive roles, to being active principal players that contribute to central nervous system pathologies caused by disease or following injury. Converging lines of evidence implicate microglia as being essential in the pathogenesis of neuropathic pain, a debilitating chronic pain condition that can occur after peripheral nerve damage caused by disease, infection, or physical injury. A key molecule that modulates microglial activity is ATP, an endogenous ligand of the P2-purinoceptor family consisting of P2X ionotropic and P2Y metabotropic receptors. Microglia express several P2 receptor subtypes, and of these the P2X4, P2X7, and P2Y12 receptor subtypes have been implicated in neuropathic pain. The P2X4 receptor has emerged as the core microglianeuron signaling pathway: activation of this receptor causes release of brain-derived neurotrophic factor (BDNF) which causes disinhibition of pain-transmission neurons in spinal lamina I. The present review highlights recent advances in understanding the signaling and regulation of P2 receptors expressed in microglia and the implications for microglia-neuron interactions for the management of neuropathic pain. KeywordsMicroglia; P2 purinoceptors; Neuropathic pain; Nerve injury; ATP; BDNF; spinal cord Pain is a double-edged sword that can be protective or cause considerable suffering. Acute nociceptive pain warns against imminent or existing tissue damage, whereas chronic pain has no known defensive or beneficial function and is unremitting for those who suffer from this condition. Acute pain is produced by physiological functioning of the normal peripheral and central nervous systems. However, the processes initiated during acute pain can sometimes progress to chronic pain that is characterized as persisting long after the initiating event has healed. This transition to chronicity is highly variable between individuals and the degree of injury is not necessarily predictive of the severity or chronicity of the pain. There is mounting evidence that the transition from acute to chronic pain involves discrete CIHR Author ManuscriptCIHR Author Manuscript CIHR Author Manuscript pathophysiological steps that alter the cellular, molecular, and anatomical organization of nociceptive neural networks in the spinal dorsal horn (Latremoliere and Woolf, 2009;Scholz and Woolf, 2002;Voscopoulos and Lema, 2010;Woolf and Salter, 2000). In this pathologically altered system, the balance of inhibitory and excitatory control is shifted such that inhibitory mechanisms are weakened while excitatory mechanisms ar...

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“…Microglia become activated by various stimuli. Microglia activation is also described in various ways , such as changes in morphology from ramified to amoeboid (Eriksson et al, 1993), increase in the expression of microglial markers [e.g., MHC II, CD 11b (Coyle, 1998;Eriksson et al, 1993;Liu et al, 1995)], and increase in the number of microglia (proliferation). These slow changes often take hours to days to manifest.…”

Section: Microglia Activation and Proliferation In The Spinal Cord Inmentioning

confidence: 99%

Do glial cells control pain?

Wen²,

et al. 2007

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Management of chronic pain is a real challenge, and current treatments focusing on blocking neurotransmission in the pain pathway have only resulted in limited success. Activation of glia cells has been widely implicated in neuroinflammation in the central nervous system, leading to neruodegeneration in many disease conditions such as Alzheimer's and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-α and interleukin-1β can not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as BDNF and bFGF that are produced by glia to protect neurons. Thus, glia cells can powerfully control pain when they are activated to produce various pain mediators. We will review accumulating evidence supporting an important role of microglia cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We will also discuss possible signaling mechanisms in particular MAP kinase pathways that are critical for glia control of pain. Investigating signaling mechanisms in microglia may lead to more effective management of devastating chronic pain.

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Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat

Cited by 80 publications

References 35 publications

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

ATP receptors gate microglia signaling in neuropathic pain

Do glial cells control pain?

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