Experimental neurology
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Experimental neurology · May 2012
ReviewTreatments to restore respiratory function after spinal cord injury and their implications for regeneration, plasticity and adaptation.
Spinal cord injury (SCI) often leads to impaired breathing. In most cases, such severe respiratory complications lead to morbidity and death. ⋯ This review article will highlight experimental SCI resulting in compromised breathing, the various methods of restoring function after such injury, and some recent findings from our own laboratory. Additionally, it will discuss findings about motor and CNS respiratory plasticity and adaptation with potential clinical and translational implications.
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Experimental neurology · May 2012
P2X3-mediated peripheral sensitization of neuropathic pain in resiniferatoxin-induced neuropathy.
Patients suffering from sensory neuropathy due to skin denervation frequently have paradoxical manifestations of reduced nociception and neuropathic pain. However, there is a lack of satisfactory animal models to investigate these phenomena and underlying mechanisms. We developed a mouse system of neuropathy induced by resiniferatoxin (RTX), a capsaicin analog, and examined the functional significance of P2X3 receptor in neuropathic pain. ⋯ The number of P2X3(+)/ATF3(+) neurons was linearly correlated with mechanical thresholds (p=0.0017). The peripheral expression of P2X3 receptor in dermal nerves was accordingly increased (p=0.016), and an intraplantar injection of the P2X3 antagonists, A-317491 and TNP-ATP, relieved mechanical allodynia in a dose-dependent manner. In conclusion, RTX-induced sensory neuropathy with upregulation of P2X3 receptor for peripheral sensitization of mechanical allodynia, which provides a new therapeutic target for neuropathic pain after skin denervation.
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Experimental neurology · Apr 2012
ReviewATP receptors gate microglia signaling in neuropathic pain.
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 were topics 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. ⋯ 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 microglia-neuron 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.
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This special issue of Experimental Neurology is devoted to the role of Microglia and Chronic Pain. Chronic pain affects 116 million people per year in the United States, which is more than heart disease, cancer, and diabetes combined. Nervous system trauma and disease are principal contributors to the establishment of chronic pain in people and in animal models. ⋯ Once considered to function solely as the phagocytotic cells of the CNS, more recent work has demonstrated that persistent activation of the microglial population may contribute to continued dysfunction including chronic pain. In the invited articles for this special issue on Microglia and Chronic Pain, we present evidence for the role of persistent microglial activation in chronic pain after peripheral and central nervous system injury, as well as in diabetic pain, post-herpetic neuralgia pain and related diseases. Collectively, the body of work indicates the importance of understanding the roles of microglial cells in chronic pain which will lead to targeted treatment to attenuate or alleviate chronic neuropathic pain syndromes.
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Experimental neurology · Apr 2012
ReviewThe mechanisms of microgliosis and pain following peripheral nerve injury.
Microglia are the resident macrophages in the central nervous system (CNS). Any insult to the CNS homeostasis will induce a rapid change in microglia morphology, gene expression profile and functional behaviour. These responses of microglia have been collectively known as 'microgliosis'. ⋯ It should also be noted that in certain contexts microglia may have a role in the resolution of neuro-inflammation. Although there is still no direct evidence demonstrating that spinal microglia have a role in neuropathic pain in humans, these patients present a pro-inflammatory cytokine profile and it is a reasonable hypothesis that these cells may contribute to this inflammatory response. Modulating microglial functions offers a novel therapeutic opportunity following nerve injury which ideally would involve reducing the pro-inflammatory nature of these cells whilst retaining their potential beneficial functions.