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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

More than 8,000 researchers, clinicians and exhibitors from around the world gathered in San Francisco for the American Academy of Neurology 56th Annual Meeting, April 24 to May 1, 2004. Of the 1,300 studies at the conference, researchers presented more than 200 abstracts each on multiple sclerosis, stroke and dementia, 145 on epilepsy, 159 on Parkinson's disease, 132 on pain and about 50 each on tremor and dystonia. The use of brain imaging technology also figured strongly in the program, with 300 abstracts that mentioned magnetic resonance imaging and 50 that included positron emission tomography. Highlights included promising Parkinson's disease studies involving gene therapy and treatments using glial-cell-derived neurotrophic factor, but also new evidence of cardiac valve regurgitation associated with pergolide. Other highlights included studies on neural repair, new guidelines for the treatment of epilepsy and important studies comparing the thrombin inhibitor ximelagatran to warfarin for the prevention of stroke.
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PMID:New developments in the treatment of neurological diseases. 1533 92

Acute noxious stimuli activate a specialized neuronal detection system that generates sensations of pain and, generally, adaptive behavioral responses. More persistent noxious stimuli notably those associated with some chronic injuries and disease states not only activate the pain-signaling system but also dramatically alter its properties so that weak stimuli produce pain. These hyperalgesic states arise from at least two distinct broad classes of mechanisms. These are peripheral and central sensitization associated with increased responsiveness of peripheral nociceptor terminals and dorsal horn neurons, respectively. Here we review the key features of these sensitized states and discuss the role of one neurotrophic factor, nerve growth factor, as a peripheral mediator of sensitization and of another factor, brain-derived neurotrophic factor, as a mediator of central sensitization. We use as a specific example the pain induced by acid stimuli. We review the neurobiology of such pain states, and discuss how acid stimuli both initiate sensitization and how the neuronal processing of acid stimuli is subject to sensitization.
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PMID:Plasticity of pain signaling: role of neurotrophic factors exemplified by acid-induced pain. 1536 54

Neuropathic pain, a chronic pain state caused by injury to the nervous system, usually responds poorly to standard pain treatment. Antidepressants have been used to treat neuropathic pain, and animal and clinical studies have showed beneficial effects. However, the mechanisms underlying antidepressant antinociceptive effect in neuropathic pain are still unknown. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent animal and human studies have demonstrated that antidepressants can increase central as well as plasma BDNF levels. In addition: (1) BDNF is produced by a subset of primary sensory neurons that are located in the dorsal root ganglion; (2) BDNF levels change in animal models of neuropathic pain; (3) BDNF can indirectly depress sensory neuron transmission in the dorsal horn. From these findings, it is proposed that BDNF may play an important role in the antidepressant antinociceptive effect in neuropathic pain. The notion of BDNF mediating the therapeutic mechanisms of antidepressant in neuropathic pain may help to select the specific type and the optimal dose of antidepressants for the treatment of neuropathic pain. Exploration of this hypothesis could provide a new direction in the treatment of neuropathic pain, as well as other pain disorders.
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PMID:Possible involvement of brain-derived neurotrophic factor in the antinociceptive effect of antidepressants in neuropathic pain. 1590 42

Transplantation of neural stem cells (NSCs) in the injured spinal cord has been shown to improve functional outcome; however, recent evidence has demonstrated forelimb allodynia following transplantation of embryonic NSCs. The aim of this study was to investigate whether transplantation of murine C17.2 NSCs alone or transfected with glial-derived neurotrophic factor (C17.2/GDNF) would induce allodynia in transplanted spinal cord-injured animals. One week after a T8-level spinal cord injury (SCI), C17.2, C17.2/GDNF or normal saline was injected at the injury site. Locomotor function and sensory recovery to thermal and mechanical stimuli were then measured. Spinal cords were processed immunohistochemically at the injury/transplantation site for characterization of NSC survival and differentiation; and at the cervicothoracic level for calcitonin gene-related peptide (CGRP), a neuropeptide expressed in dorsal horn nocioceptive neurons, and growth-associated protein-43 (GAP43), a marker of neuronal sprouting. Locomotor function was not significantly improved following NSC transplantation at any time (P >0.05). Significant forelimb thermal and mechanical allodynia were observed following transplantation with both NSC populations (P <0.05). The C17.2 and C17.2/GDNF NSCs survived and differentiated into a predominately astrocytic population. Calcitonin gene-related peptide and GAP43 immunoreactivity significantly increased and co-localized in cervicothoracic dorsal horn laminae I-III following C17.2 and C17.2/GDNF transplantation. This study demonstrated that murine C17.2 NSCs differentiated primarily into astrocytes when transplanted into the injured spinal cord, and resulted in thermal and mechanical forelimb allodynia. Sprouting of nocioceptive afferents occurred rostral to the injury/transplantation site only in allodynic animals, suggesting a principal role in this aberrant pain state. Further, a difference in the degree of allodynia was noted between C17.2- and C17.2/GDNF transplant-treated groups; this difference correlated with the level of CGRP/GAP43 immunoreactivity and sprouting observed in the cervicothoracic dorsal horns. Both allodynia- and CGRP/GAP43-positive afferent sprouting were less in the C17.2/GDNF group compared to the C17.2 group, suggesting a possible protective or analgesic effect of GDNF on post-injury neuropathic pain.
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PMID:Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. 1683 48

Developmentally, semaphorin 3A (sema3A) is an important chemorepellent that guides centrally projecting axons of dorsal root ganglion (DRG) neurons. Sema3A-mediated growth cone collapse can be prevented by cyclic GMP (cGMP) and nerve growth factor (NGF) in embryonic neurons. Sema3A may also play a role in directing regrowth of injured axons in adults, and interactions with neurotrophic factors near the injury site may determine the extent and targeting of both regenerative and aberrant growth. The aim of this study was to determine whether NGF, glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) modulate sema3A-mediated growth cone collapse in cultured adult rat DRG neurons. Sema3A caused a significant increase in growth cone collapse, which was completely prevented by prior treatment with NGF, GDNF or NTN. Immunocytochemical experiments showed that sema3A-sensitive neurons were heterogeneous in their expression of neurotrophic factor receptors and responses to neurotrophic factors, raising the possibility of novel, convergent signaling mechanisms between these substances. Increasing cGMP levels caused growth cone collapse, whereas sema3A-mediated collapse was prevented by inhibition of guanylate cyclase or by increasing cyclic AMP levels. In conclusion, sema3A signaling pathways in adult neurons differ to those described in embryonic neurons. Three different neurotrophic factors each completely prevent sema3A-mediated collapse, raising the possibility of novel converging signaling pathways. These studies also show that there is considerable potential for neurotrophic factors to regulate sema3A actions in the adult nervous system. This may provide insights into the mechanisms underling misdirected growth and targeting of sensory fibers within the spinal cord after injury, that is thought to contribute to development of autonomic dysreflexia and neuropathic pain.
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PMID:Nerve growth factor, glial cell line-derived neurotrophic factor and neurturin prevent semaphorin 3A-mediated growth cone collapse in adult sensory neurons. 1687 31

We are still far from reaching a complete understanding of the molecular mechanisms that control neuronal diversification during nervous system development. In this issue of Neuron, Luo et al. bring that goal a step closer by revealing how a hierarchical interaction between two neurotrophic factor systems drives the differentiation, maturation, and extension of peripheral projections in a subclass of sensory neurons that mediate pain perception.
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PMID:Hierarchical control of sensory neuron development by neurotrophic factors. 1755 23

The World Health Organization (WHO) predicts there will be 300 million people world-wide with diabetes mellitus by 2025. Currently it is estimated that there are 20 and 60 million people suffering from diabetes mellitus in North America and Europe, respectively. Within this huge population of diabetic persons approximately 50% will develop some form of sensory polyneuropathy, which involves the dying back of distal axons and a failure of axons to regenerate. This leads to incapacitating pain, sensory loss and poor wound healing. The end result is lower extremity amputation with approximately 90,000 diabetes-related amputations occurring each year in North America and the expectation of a 5-fold increase over the next 10 years due to increased incidence of type 2 diabetes. Abnormal neuronal Ca(2+) homeostasis and impaired mitochondrial function have been implicated in numerous CNS and PNS diseases including diabetic sensory neuropathy. The endoplasmic reticulum (ER), in part, regulates cellular Ca(2+) homeostasis and this process is linked to regulation of mitochondrial function and activity of anti-apoptotic signal transduction pathways. Here we review the current state of research regarding role of Ca(2+) dyshomeostasis and mitochondrial physiology in neuronal dysfunction in diabetes. The central impact of diabetes-induced alteration of Ca(2+) handling on sensory neurone function is discussed and related to abnormal ER performance. New results are presented showing suboptimal Ca(2+) concentration in the ER lumen in association with reduced SERCA2 expression in sensory neurones from type 1 diabetic rats. We hypothesize that deficits in neurotrophic factor support, specifically linked to diabetes-induced lowered expression of insulin and neurotrophin-3, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca(2+) homeostasis and associated mitochondrial dysfunction. The role of hyperglycaemia in diabetes is also discussed and we propose that high glucose concentration may impact at other sites to contribute to the heterogeneous aetiology of nerve damage in diabetes.
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PMID:Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes. 1819 Nov 98

Neurotrophic factors comprise a broad family of secreted proteins that have growth promoting, survival promoting and differentiation inducing activities. Disruption of neurotrophic factor signalling is a characteristic of many central and peripheral nervous system disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and peripheral neuropathy and pain. It follows that treating patients with neurotrophic factors might be beneficial in a range of neurological diseases. However, the promising results seen in animal models of disease have not translated well into clinical trials due to the poor pharmacokinetics associated with the intact proteins, in particular, their short in vivo half-life, low blood brain barrier permeability, limited diffusion, and undesirable effects through multiple receptor interactions. This has been the main motivation for the design of small molecule modulators of the neurotrophic factor pathways. The review gives a brief survey of the various strategies to design mimetics that have been reported in the literature with special emphasis on the tandem repeat peptide agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.
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PMID:Tandem repeat peptide strategy for the design of neurotrophic factor mimetics. 1828 37

Neurotrophic factors and cytokines are involved in the regulation of neuronal survival, axonal myelination, and synaptic plasticity in both central nervous system (CNS) and peripheral nervous system (PNS). The members of the neurotrophic factor family include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). These molecules bind to two types of receptors: (1) tyrosine kinase receptors (TrkA, TrkB, TrkC) and 2) common neurotrophin receptor (p 75 NTR). The internalization and retrograde axonal transport of neurotrophin receptors are important for their signal transduction supporting neuronal survival, synaptic plasticity, and axonal myelination. In addition, a growing body of data suggests that neurotrophins are involved in the pathophysiologicl courses of inflammatory pain, neurodegenerative disease, and psychiatric diseases. Cytokines, including IL-1, IL-2, IL-6, and TNF-alpha,are important mediators of the immune response and play a key role in the diseases by acting on inflammatory immune cells, neuronal cells, muscle cells, and vessel cells. Interestingly, some cytokines (e.g. TNF-alpha, IL-2, TGF-beta) are also able to regulate synaptic plasticity and affect CNS functions. The neurotrophins and cytokines release in response to various stimuli, such as electronic stimulation, or inflammation. This crosstalk from PNS to CNS is involved in the pathophysiology of many human diseases and may contribute to the effects of acupuncture. Based on our knowledge to neurotrophins and cytokines, we proposed the neurotrophin/cytokine hypothesis for the mechanism of acupuncture. This hypothesis may initiate the discussion on the possible roles of neurotrophins/cytokines in the therapeutic effects of acupuncture and shed light to the discovery of mechanism of acupuncture in the treatment of devastating diseases.
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PMID:[The messengers from peripheral nervous system to central nervous system: involvement of neurotrophins and cytokines in the mechanisms of acupuncture]. 1838 43

Central nervous system (CNS) insults elevate endogenous toxins and alter levels of indicators of metabolic disorder. These contribute to neurotrauma, neurodegenerative diseases and chronic pain and are possible targets for pharmaceutical treatment. Microdialysis samples substances in the extracellular space for chemical analysis. It has demonstrated that toxic levels of glutamate are released and that toxic levels of the reactive species O(2)(-), H(2)O(2), HO. NO and HOONO are generated upon CNS injury. Agent administration by microdialysis can also help elucidate mechanisms of damage and protection, and to identify targets for clinical application. Microdialysis sampling indicates that circuits descending from the brain to the spinal cord transmit and modulate pain signals by releasing neurotransmitter amines and amino acids. Efforts are under way to develop microdialysis into a technique for intensive care monitoring and predicting outcomes of brain insults. Finally, microdialysis sampling has demonstrated in vivo elevation of glial cell line-derived neurotrophic factor following grafting of primed fetal human neural stem cells into brain-injured rats, the first in vivo demonstration of the release of a neurotrophic factor by grafted stem cells. This increased release correlated with significantly improved spatial learning and memory.
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PMID:Microdialysis in central nervous system disorders and their treatment. 1843 92


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