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)

The excitability of spinal neurons that transmit pain is modulated by glutamate and substance P (SP). Glutamate is an excitatory neurotransmitter in the dorsal horn, and its effects are enhanced by SP acting on neurokinin 1 receptors (NK1Rs). We assessed activation of NK1Rs by studying their internalization in spinal cord slices. NK1Rs were localized in sections from the slices by using immunohistochemistry combined with fluorescence and confocal microscopy. Incubating the slices with SP induced internalization in most NK1R-positive neurons in laminae I, IIo, and X and in half of NK1R-positive neurons in laminae III-V. SP-induced internalization was abolished by the specific NK1R antagonist L-703,606 (1 microM). Stimulating the dorsal root with long-duration (0.4 msec) pulses evoked EPSPs in dorsal horn neurons with latencies consistent with the conduction speed of A partial differential- and C-fibers. High-frequency (100 Hz) stimulation of the dorsal root with these pulses induced NK1R internalization in neurons in laminae I-IIo of the stimulated side of the slice but not in the contralateral side or in other laminae. Stimulation at lower frequencies (1 and 10 Hz) failed to elicit significant internalization, suggesting that the release of SP is frequency-dependent. Internalization produced by the 100 Hz tetanus was mimicked by NMDA and blocked by an NMDA antagonist, 2-amino-5-phosphonopentanoic acid, but not by the AMPA and kainate antagonist CNQX. The NK1R antagonist L-703,606 abolished the internalization produced by 100 Hz stimulation or NMDA. Therefore, the release of SP in the dorsal horn appears to be controlled by NMDA receptors.
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PMID:Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. 933 88

Activation of GABA(B) receptors produces analgesia in acute and chronic pain models. Data indicate that a possible mechanism for this effect is a GABA(B) receptor-induced blockade of neurokinin-1 (NK-1) receptor gene expression in the spinal cord. While much more potent GABA(B) receptor agonists (CGP 44532) have been developed, there is no information on their antinociceptive properties or their ability to influence NK-1 receptors. To address these issues, rats were treated with baclofen or CGP 44532 and tested for sedation, ataxia, and pain-related behaviors in a chronic pain model (formalin hindpaw injection). In a separate group of experiments the analgesic response to a single dose of CGP 44532 was tested prior, and subsequent to, its chronic administration. The results indicate that CGP 44532 is a substantially more potent analgesic than baclofen. In addition, after chronic administration baclofen was no longer capable of inducing analgesia or of inhibiting the increased expression of NK-1R mRNA and CGP 44532 was still fully effective in both regards. The results suggest that GABA(B) agonists could be clinically useful analgesics.
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PMID:Regulation of neurokinin-1 receptor expression by GABA(B) receptor agonists. 958 30

Substance P plays an important role in the transmission of pain-related information in the dorsal horn of the spinal cord. Recent immunocytochemical studies have shown a mismatch between the distribution of substance P and its receptor in the superficial laminae of the dorsal horn. Because such a mismatch was not observed by using classical radioligand binding studies, we decided to investigate further the issue of the relationship between substance P and its receptor by using an antibody raised against a portion of the carboxyl terminal of the neurokinin 1 receptor and a bispecific monoclonal antibodies against substance P and horseradish peroxidase. Light microscopy revealed a good correlation between the distributions of substance P and the neurokinin 1 receptor, both being localized with highest densities in lamina I and outer lamina II of the spinal dorsal horn. An ultrastructural double-labeling study, combining preembedding immunogold with enzyme-based immunocytochemistry, showed that most neurokinin 1 receptor immunoreactive dendrites were apposed by substance P containing boutons. A detailed quantitative analysis revealed that neurokinin 1 receptor immunoreactive dendrites received more appositions and synapses from substance P immunoreactive terminals than those not expressing the neurokinin 1 receptor. Such preferential innervation by substance P occurred in all superficial dorsal horn laminae even though neurokinin 1 receptor immunoreactive dendrites were a minority of the total number of dendritic profiles in the above laminae. These results suggest that, contrary to the belief that neuropeptides act in a diffuse manner at a considerable distance from their sites of release, substance P should act on profiles expressing the neurokinin 1 receptor at a short distance from its site of release.
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PMID:Preferential synaptic relationships between substance P-immunoreactive boutons and neurokinin 1 receptor sites in the rat spinal cord. 986 Oct 46

Protein kinase C (PKC) is thought to have a role in sensitization of dorsal horn neurons in certain pain states, and a recent study has reported that mice which lack the gamma isoform (PKCgamma) show reduced neuropathic pain after peripheral nerve injury. Although PKCgamma is present at high levels in the ventral part of lamina II we have limited information concerning the types of neuron in which it is located. In this study we have used immunocytochemistry to characterise the neurons which contain PKCgamma. Immunoreactive neurons were concentrated in ventral lamina II, but were also present in lamina III. Some weakly-immunoreactive neurons were located in the dorsal part of lamina II and in lamina I. The great majority (92%) of cells with PKCgamma were not GABA-immunoreactive, and these cells are likely to be excitatory interneurons. Dual-immunofluorescence labelling showed that PKCgamma was not randomly distributed amongst non-GABAergic neurons, since it was present in 76% of cells with neurotensin and 45% of those with somatostatin, but only 5% of those with the mu-opioid receptor (MOR-1). Cells with the neurokinin 1 receptor are found in lamina I and lamina III, and PKCgamma was present in 22% and 37% of these populations, respectively. These results suggest that excitatory interneurons in laminae II and III which lack the micro-opioid receptor may have a significant role in generating neuropathic pain.
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PMID:The types of neuron which contain protein kinase C gamma in rat spinal cord. 1037 78

Large neurons in laminae III and IV of the spinal cord which express the neurokinin 1 receptor and have dendrites that enter the superficial laminae are a major target for substance P (SP)-containing (nociceptive) primary afferents. Although some of these neurons project to the thalamus, we know little about other possible projection targets. The main aim of this study was to determine whether all cells of this type are projection neurons and to provide information about brainstem sites to which they project. Injections of cholera toxin B subunit were made into four brainstem areas that receive input from the spinal cord, and the proportion of cells of this type in the L4 spinal segment that were retrogradely labelled was determined in each case. The results suggest that most of these cells (>90%) project to the contralateral lateral reticular nucleus (or to a nearby region), while many (>60%) send axons to the lateral parabrachial area and some to the dorsal part of the caudal medulla. However, few of these cells project to the periaqueductal grey matter. As lamina I neurons with the neurokinin 1 receptor appear to be important in the generation of hyperalgesia, we also examined projection neurons in this lamina and found that for each injection site the great majority possessed the receptor. These results demonstrate that dorsal horn neurons which express the neurokinin 1 receptor contribute to several ascending pathways that are thought to be important in pain mechanisms.
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PMID:Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. 1071 49

The morphology of neurons in lamina I of the dorsal horn of the lumbar spinal cord which express neurokinin 1 receptors in the rat has been investigated. On the basis of soma and dendritic measurements, these neurons form two populations. One group consists of large neurons that stain intensely for the neurokinin 1 receptor with the immunochemical methods employed. They have a large soma, typically giving rise to between three and five thick principal dendrites. The dendritic tree, however, is relatively sparse, with the principal dendrites giving rise to small numbers of second- and third-order branches. All these dendrites are almost spine free. The dendritic tree spreads extensively in the rostrocaudal (approximately 550microm) and mediolateral (approximately 30microm) orientations, with few ventrally directed branches. These cells give rise to a single axon from their soma or a principal dendrite that generates a few local branches and also ramifies sparsely in deeper laminae (II-IV). The details of axonal morphology were established from intracellularly labelled material. Ultrastructural analysis of the synaptic input to these neurons reveals that they receive synapses with both clear round, flattened and dense-core vesicles; however, they do not form components of glomerular synapses. The second neuron type stains less intensely and typically has a small fusiform soma, giving rise to dendrites at its rostral and caudal poles. The dendritic tree is long in the rostrocaudal orientation (approximately 350microm), but restricted mediolaterally (approximately 40microm). The primary dendrites of these neurons bifurcate and soon give rise to third-order branches that are spiny. No pattern of organization could be detected for the distribution of either neuron type. These observations are discussed in the light of other recent studies indicating a central role for lamina I neurons expressing neurokinin 1 in the perception of severe pain.
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PMID:Spinal lamina I neurons that express neurokinin 1 receptors: morphological analysis. 1079 65

Recent theories of pathogenesis of pain in chronic pancreatitis (CP) are neuroimmune interactions of intrapancreatic nerves and inflammatory cells and increase in levels of pain neurotransmitters such as substance P (SP). This study analyzed the expression and localization of neurokinin 1 receptor (NK-1R), which binds SP, and its association with pain and inflammation in CP. Pancreatic tissues from 31 patients (22 males, nine females; mean age 45.9+/-9.4 years) with CP were evaluated. Nine normal pancreases (five males, four females; mean age 42.9+/-9.5 years) served as controls. Quantitative PCR was used to determine the NK-1R mRNA expression levels and in situ hybridization and immunohistochemistry were used to localize expression sites of NK-1R mRNA and protein, respectively. We also analyzed whether an association exists between NK-1R mRNA expression and pain and inflammation. In CP samples, in situ hybridization and immunohistochemistry localized NK-1R mRNA expression and protein mainly in the nerves, ganglia, blood vessels, inflammatory cells and occasionally in fibroblasts. In patients with mild to moderate and strong intensity of pain, NK-1R mRNA levels were increased 14- and 30-fold over controls, respectively. There was a significant relationship between NK-1R mRNA levels and intensity of pain (r=0.46, P=0.03), NK-1R mRNA and the frequency of pain (r=0.51, P=0.04), and NK-1 mRNA and duration of pain (r=0.46, P=0.01) in CP patients, but not with the degree of tissue inflammation. NK-1R signaling may be involved in the pain syndrome of CP. The expression of NK-1R in inflammatory cells and blood vessels also points to an interaction of immunoreactive substance P nerves, inflammatory cells and blood vessels, and further supports the existence of a neuroimmune interaction that probably influences the pain syndrome and chronic inflammatory changes so characteristic of CP.
Pain 2001 Apr
PMID:NK-1 receptor gene expression is related to pain in chronic pancreatitis. 1127 76

An understanding of the mechanisms that regulate signaling by the substance P (SP) or neurokinin 1 receptor (NK1-R) is of interest because of their role in inflammation and pain. By using activators and inhibitors of protein kinase C (PKC) and NK1-R mutations of potential PKC phosphorylation sites, we determined the role of PKC in desensitization of responses to SP. Activation of PKC abolished SP-induced Ca(2+) mobilization in cells that express wild-type NK1-R. This did not occur in cells expressing a COOH-terminally truncated NK1-R (NK1-Rdelta324), which may correspond to a naturally occurring variant, or a point mutant lacking eight potential PKC phosphorylation sites within the COOH tail (NK1-R Ser-338, Thr-339, Ser-352, Ser-387, Ser-388, Ser-390, Ser-392, Ser-394/Ala, NK1-RKC4). Compared with wild-type NK1-R, the t(1/2) of SP-induced Ca(2+) mobilization was seven- and twofold greater in cells expressing NK1-Rdelta324 and NK1-RKC4, respectively. In cells expressing wild-type NK1-R, inhibition of PKC caused a 35% increase in the t(1/2) of SP-induced Ca(2+) mobilization. Neither inhibition of PKC nor receptor mutation affected desensitization of Ca(2+) mobilization to repeated challenge with SP or SP-induced endocytosis of the NK1-R. Thus PKC regulates SP-induced Ca(2+) mobilization by full-length NK1-R and does not regulate a naturally occurring truncated variant. PKC does not mediate desensitization to repeated stimulation or endocytosis of the NK1-R.
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PMID:Protein kinase C-mediated desensitization of the neurokinin 1 receptor. 1128 22

Understanding the molecular mechanisms of agonist-induced trafficking of G-protein-coupled receptors is important because of the essential role of trafficking in signal transduction. We examined the role of the GTPases dynamin 1 and Rab5a in substance P (SP)-induced trafficking and signaling of the neurokinin 1 receptor (NK1R), an important mediator of pain, depression, and inflammation, by studying transfected cells and enteric neurons that naturally express the NK1R. In unstimulated cells, the NK1R colocalized with dynamin at the plasma membrane, and Rab5a was detected in endosomes. SP induced translocation of the receptor into endosomes containing Rab5a immediately beneath the plasma membrane and then in a perinuclear location. Expression of the dominant negative mutants dynamin 1 K44E and Rab5aS34N inhibited endocytosis of SP by 45 and 32%, respectively. Dynamin K44E caused membrane retention of the NK1R, whereas Rab5aS34N also impeded the translocation of the receptor from superficially located to perinuclear endosomes. Both dynamin K44E and Rab5aS34N strongly inhibited resensitization of SP-induced Ca(2+) mobilization by 60 and 85%, respectively, but had no effect on NK1R desensitization. Dynamin K44E but not Rab5aS34N markedly reduced SP-induced phosphorylation of extracellular signal regulated kinases 1 and 2. Thus, dynamin mediates the formation of endosomes containing the NK1R, and Rab5a mediates both endosomal formation and their translocation from a superficial to a perinuclear location. Dynamin and Rab5a-dependent trafficking is essential for NK1R resensitization but is not necessary for desensitization of signaling. Dynamin-dependent but not Rab5a-dependent trafficking is required for coupling of the NK1R to the mitogen-activated protein kinase cascade. These processes may regulate the nociceptive, depressive, and proinflammatory effects of SP.
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PMID:Dynamin and Rab5a-dependent trafficking and signaling of the neurokinin 1 receptor. 1130 80

Substance P (SP) is a neuropeptide which is abundant in the periphery and the central nervous system, where it is colocalized with other neurotransmitters such as serotonin or dopamine. SP has been proposed to play a role in the regulation of pain including migraine and fibromyalgia, asthma, inflammatory bowel disease, emesis, psoriasis as well as in central nervous system disorders. This review summarizes our current knowledge of the role of SP in the pathogenesis of neuropsychiatric disorders with special emphasis on affective disorders including bipolar disorders. It also reviews current treatment approaches with neurokinin 1 receptor antagonists which appear to be promising drugs for the future treatment of affective disorders.
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PMID:Substance P and affective disorders: new treatment opportunities by neurokinin 1 receptor antagonists? 1189 70


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