Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal aggregates involved in conscious awareness are not evenly distributed throughout the CNS but comprise key components referred to as the neural network correlates of consciousness (NNCC). A critical node in this network is the posterior cingulate, precuneal, and retrosplenial cortices. The cytological and neurochemical composition of this region is reviewed in relation to the Brodmann map. This region has the highest level of cortical glucose metabolism and cytochrome c oxidase activity. Monkey studies suggest that the anterior thalamic projection likely drives retrosplenial and posterior cingulate cortex metabolism and that the midbrain projection to the anteroventral thalamic nucleus is a key coupling site between the brainstem system for arousal and cortical systems for cognitive processing and awareness. The pivotal role of the posterior cingulate, precuneal, and retrosplenial cortices in consciousness is demonstrated with posterior cingulate epilepsy cases, midcingulate lesions that de-afferent this region and are associated with unilateral sensory neglect, observations from stroke and vegetative state patients, alterations in blood flow during sleep, and the actions of general anesthetics. Since this region is critically involved in self reflection, it is not surprising that it is similarly a site for the NNCC. Interestingly, information processing during complex cognitive tasks and during aversive sensations such as pain induces efforts to terminate self reflection and result in decreased processing in posterior cingulate and precuneal cortices.
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PMID:Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness. 1618 25

Peripheral nerve injury can induce spinal microglial/astrocyte activation. Substances released by activated glial cells excite spinal nociceptive neurons. Pharmacological disruption of glial activation or antagonism of substances released by activated glia prevent or reverse pain hypersensitivity. It is not known, however, what causes spinal cord glia to shift from a resting to an activated state. In an attempt to understand the potential role of monocyte chemoattractant protein-1 (MCP-1) in triggering spinal glial activation and its contribution to the development of neuropathic pain, we investigated the effect of peripheral nerve injury on MCP-1 expression in dorsal root ganglia (DRG) and the spinal cord, and established its temporal relationship with activation of spinal microglia and astrocytes. We observed that MCP-1 was induced by chronic constriction of the sciatic nerve in DRG sensory neurons, spinal cord motor neurons and in the superficial dorsal horn, ipsilateral to the injury. Neuronal MCP-1 induction was followed by surrounding microglial activation. After peaking at day 7 after injury, MCP-1 levels began to decline rapidly and had returned to baseline by day 150. In contrast, microglial activation peaked by day 14 and declined afterwards to reach a lower, yet significantly raised level beyond day 22 and remained increased until the end of the test period. Astrocyte activation became detectable later, progressed more slowly and also remained increased until the end of the test period, in parallel with a decreased nociceptive threshold. Our results suggest that neuronal MCP-1 may serve as a trigger for spinal microglial activation, which participates in the initiation of neuropathic pain. Delayed, sustained astrocyte activation may participate with microglia in the persistent phase of pain hypersensitivity.
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PMID:Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. 1652 71

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found throughout the central and peripheral nervous systems. They are crucial to normal physiology and have been clearly implicated in nicotine addiction. In addition, they are possible therapeutic targets in a wide range of pathological conditions, including cognitive disorders, Parkinson's disease, and neuropathic pain. Nicotinic ligands are usually classified as agonists (or partial agonists), competitive antagonists, or noncompetitive antagonists. Sazetidine-A is a new nicotinic ligand that shows a different pharmacological profile from any of these known classes of ligands. Sazetidine-A competes with very high binding affinity (Ki approximately 0.5 nM) and selectivity for the alpha4beta2 nAChR subtype (Ki ratio alpha3beta4/alpha4beta2 approximately 24,000). Despite its high affinity, sazetidine-A neither activates nAChR channel function nor prevents channel activation when it is applied simultaneously with nicotine. However, when it is pre-incubated for 10 min with the receptors, it potently blocks nicotine-stimulated alpha4beta2 nAChR function (IC50 approximately 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the alpha4beta2 nAChRs, and its very high affinity for the desensitized state of the receptor. We propose that sazetidine-A is a "silent desensitizer" of nAChRs, meaning that it desensitizes the receptor without first activating it. Furthermore, comparison of the effects of sazetidine-A and nicotine at alpha4beta2 nAChRs suggests that the predominant effects of nicotine and other nicotinic agonists are related to desensitization of the receptors and that sazetidine-A potently mimics these effects.
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PMID:Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them. 1685 41

Mammalian CLC proteins function as Cl(-) channels or as electrogenic Cl(-)/H(+) exchangers and are present in the plasma membrane and intracellular vesicles. We now show that the ClC-6 protein is almost exclusively expressed in neurons of the central and peripheral nervous systems, with a particularly high expression in dorsal root ganglia. ClC-6 colocalized with markers for late endosomes in neuronal cell bodies. The disruption of ClC-6 in mice reduced their pain sensitivity and caused moderate behavioral abnormalities. Neuronal tissues showed autofluorescence at initial axon segments. At these sites, electron microscopy revealed electron-dense storage material that caused a pathological enlargement of proximal axons. These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. However, the lysosomal pH of Clcn6(-/-) neurons appeared normal. CLCN6 is a candidate gene for mild forms of human NCL. Analysis of 75 NCL patients identified ClC-6 amino acid exchanges in two patients but failed to prove a causative role of CLCN6 in that disease.
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PMID:Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6. 1695 Aug 70

This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.
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PMID:Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. 1701 91

The voltage-gated calcium channels (VGCCs) are a large and functionally diverse group of ion channels found throughout the central nervous system (CNS) and the periphery. Neuronal functions include the control of neurotransmitter release and neuronal excitability in important pain pathways. In the current review we will give an overview of the data that has been generated in support of these channels performing a pivotal role in the pain pathway.
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PMID:The role of voltage-gated calcium channels in pain and nociception. 1714 38

Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels contribute to rhythmic spontaneous activity in the heart and CNS. Ectopic spontaneous neuronal activity has been implicated in the development and maintenance of acute and chronic hyperalgesia, allodynia and spontaneous pain. Previously, we documented that systemic administration of ZD7288, a specific blocker of pacemaker current (I(h)), decreased ectopic activity in dorsal root ganglion (DRG) and reversed tactile allodynia in spinal nerve ligated (SNL) rats [Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE (2003) Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J Neurosci 23:1169-1178]. Spontaneous pain is the chief clinical manifestation of peripheral nerve injury; however, a role for I(h) in spontaneous pain has not been described. Here, in further rat studies, we report that systemic administration of ZD7288 reversed spontaneous pain induced by mild thermal injury (MTI) and tactile allodynia induced by SNL and MTI. In contrast, ZD7288 did not reduce thermal hyperalgesia. An important locus of action appears to be in the skin since intraplantar (local) administration of ZD7288 completely suppressed tactile allodynia arising from MTI and SNL and reduced spontaneous pain due to MTI. Immunohistochemical staining of plantar skin sections detected HCN1-HCN4 expression in mechanosensory structures (e.g., Meissner's corpuscles and Merkel cells). Collectively, these data suggest that expression and modulation of I(h) in the peripheral nervous system, including specialized sensory structures, may play a significant role in sensory processing and contribute to spontaneous pain and tactile allodynia.
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PMID:Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. 1719 50

Peripheral nerve injury is often followed by the development of severe neuropathic pain. Nerve degeneration accompanied by inflammatory mediators is thought to play a role in generation of neuropathic pain. Neuronal cell death follows axonal degeneration, devastating a vast number of molecules in injured neurons and the neighboring cells. Because we have little understanding of the cellular and molecular mechanisms underlying neuronal cell death triggered by nerve injury, we conducted a proteomics study of rat 4th and 5th lumbar (L4 and L5) dorsal root ganglion (DRG) after L5 spinal nerve ligation. DRG proteins were displayed on two-dimensional gels and analyzed through quantitative densitometry, statistical validation of the quantitative data, and peptide mass fingerprinting for protein identification. Among approximately 1,300 protein spots detected on each gel, we discovered 67 proteins that were tightly regulated by nerve ligation. We find that the injury to primary sensory neurons turned on multiple cellular mechanisms critical for the structural and functional integrity of neurons and for the defense against oxidative damage. Our data indicate that the regulation of metabolic enzymes was carefully orchestrated to meet the altered energy requirement of the DRG cells. Our data also demonstrate that ligation of the L5 spinal nerve led to the upregulation in the L4 DRG of the proteins that are highly expressed in embryonic sensory neurons. To understand the molecular mechanisms underlying neuropathic pain, we need to comprehend such dynamic aspect of protein modulations that follow nerve injury.
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PMID:Proteomics study of neuropathic and nonneuropathic dorsal root ganglia: altered protein regulation following segmental spinal nerve ligation injury. 1721 66

Chronic opiate exposure produces tolerance and hypersensitivity to mechanical and thermal stimulation that involves increased pain facilitation from the rostral ventromedial medulla (RVM). The aim of the present study was to determine the effect of sustained systemic morphine exposure on RVM neurons. Three cell types in the RVM have been described: on-cells, off-cells and neutral cells. The activity of on-cells increases in response to noxious stimulation, whereas the activity of off-cells decreases following noxious stimulation. Neutral cells remain relatively unaffected. In lightly anesthetized rats, systematic exploration throughout the RVM using single-unit extracellular recordings was used to examine both the relative proportion and the neuronal properties of the different cell classes in chronic morphine and placebo treated animals. Seven days after implanting either morphine (150 mg, s.c.) or placebo pellets a total of four electrode penetrations through the RVM were made in each animal at identical coordinates along midline. Neuronal responses related to radiant heat-evoked paw withdrawals were recorded. When compared to placebo treated rats, chronic morphine increased the number of on-cells and decreased the number of neutral cells, while the number of off-cells remained unchanged. Chronic morphine exposure had no effect on the spontaneous or heat-evoked discharges in on-, off-, or neutral cells. These results indicate that chronic morphine may sensitize a subpopulation of RVM neurons to noxious stimulation, which would be expected to increase descending facilitation and promote tolerance and chronic morphine-induced paradoxical pain.
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PMID:Chronic morphine exposure increases the proportion of on-cells in the rostral ventromedial medulla in rats. 1740 Feb 54

SCS is an efficacious, reversible, and safe therapy that improves quality of life, increases exercise tolerance, and relieves angina pectoris, but clinical trials in North America are needed to confirm the data coming from Europe. Neuronal convergence onto STT cells underlies the referred pain associated with angina pectoris. With pain referred to the chest and upper arm, cardiac nociceptive information is transmitted via sympathetic afferent fibers to thoracic cells. With pain referred to the jaw and neck, cardiac nociceptive information is transmitted via vagal afferent fibers onto cervical cells. SCS can modulate the responses of thoracic STT cells to nociceptive input originating from the heart. SCS modulates cardiac function. It stabilizes neurons in the intrinsic cardiac nervous system, and can reduce infarct size via adrenoreceptors.
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PMID:Neurological mechanisms of chest pain and cardiac disease. 1745 40


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