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

Neurotensin (NT) is a brain-gut tridecapeptide that fulfils a dual function, as a neurotransmitter/neuromodulator in the nervous system, and as a paracrine and circulating hormone in the periphery. Three NT receptors, NTS1, NTS2 and NTS3, have been cloned to date. NTS1 and NTS2 belong to the family of G protein-coupled receptors with seven transmembrane domains, whereas NTS3 is a single transmembrane domain protein that belongs to a recently identified family of sorting receptors. Most of the known peripheral and central effects of NT are mediated through NTS1. NTS2 might take part in the analgesic response elicited by central administration of NT; the biological roles of NTS3 are yet to be discovered. Most NT agonists and non-peptide antagonists developed to date have been studied for their NTS1-targeting abilities. Here, we will discuss the potential diagnostic and therapeutic uses of these compounds in cancer, schizophrenia, obesity and pain suppression.
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PMID:Targeting neurotensin receptors with agonists and antagonists for therapeutic purposes. 1263 Feb 97

The present article provides a concise overview of progress in our understanding of neuropeptides, their receptors and the current and potential ways in which they may be targeted for clinical use. Neuropeptide systems offer certain characteristics that distinguish them from those utilizing classic neurotransmitters and thus make them increasingly attractive for drug targeting. A key example of the highly successful use of neuropeptide receptor ligands is that of opioid receptor agonists for the treatment of pain. More recently, classically identified neuropeptide receptors, including those for substance P, cholecystokinin and neurotensin, have been singled out for development of antagonists by several pharmaceutical companies, for various therapeutic indications. These examples can be categorized as having been identified using classic methods; that is, the neuropeptide(s) and/or their function(s) were established prior to molecular identification of their receptor(s). Modern methodologies being widely applied in the industry today have somewhat reversed the need for this ordering in drug discovery. Technologies based upon bioinformatics, molecular, proteomic and transgenic approaches have accelerated the identification of putative receptor targets and the generation of information on their involvement in physiological and pathophysiological processes. Now research and development teams are in a position to best select targets from this rapidly expanding catalogue. This article seeks to outline aspects of these procedures and additionally summarize recent data which have important implications for drug development in this field. Consideration has been given to potential targets and how these may ultimately lead to clinical benefit.
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PMID:From basic research on neuropeptide receptors to clinical benefit. 1287 24

G protein-coupled receptors (GPCRs) mediate the perception of smell, light, taste, and pain. They are involved in signal recognition and cell communication and are some of the most important targets for drug development. Because currently no direct structural information on high-affinity ligands bound to GPCRs is available, rational drug design is limited to computational prediction combined with mutagenesis experiments. Here, we present the conformation of a high-affinity peptide agonist (neurotensin, NT) bound to its GPCR NTS-1, determined by direct structural methods. Functional receptors were expressed in Escherichia coli, purified in milligram amounts by using optimized procedures, and subsequently reconstituted into lipid vesicles. Solid-state NMR experiments were tailored to allow for the unequivocal detection of microgram quantities of 13C,15N-labeled NT(8-13) in complex with functional NTS-1. The NMR data are consistent with a disordered state of the ligand in the absence of receptor. Upon receptor binding, the peptide undergoes a linear rearrangement, adopting a beta-strand conformation. Our results provide a viable structural template for further pharmacological investigations.
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PMID:The conformation of neurotensin bound to its G protein-coupled receptor. 1296 Mar 62

Cone snails have evolved a vast array of peptide toxins for prey capture and defence. These peptides are directed against a wide variety of pharmacological targets, making them an invaluable source of ligands for studying the properties of these targets in normal and diseased states. A number of these peptides have shown efficacy in vivo, including inhibitors of calcium channels, the norepinephrine transporter, nicotinic acetylcholine receptors, NMDA receptors and neurotensin receptors, with several having undergone pre-clinical or clinical development for the treatment of pain.
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PMID:Conotoxins as selective inhibitors of neuronal ion channels, receptors and transporters. 1508 32

The periaqueductal gray matter and the rostral ventromedial medulla (RVM), with its projections to the spinal dorsal horn, constitute the efferent channel of the 'descending pain-control system'. Noxious stimulation of a peripheral tissue causes more pain if this tissue is inflamed (primary hyperalgesia). In such cases, stimulation of neighboring but uninflamed tissues also becomes more painful (secondary hyperalgesia). In animal models of inflammation, the descending pain-control system sends down, simultaneously, inhibitory and facilitatory influences, but inhibition predominates for primary hyperalgesia while facilitation predominates for secondary hyperalgesia. Descending inhibition and facilitation during peripheral inflammation are due not only to previously existing descending modulation, but also to inflammation-induced changes in RVM which involve receptors for NMDA, AMPA, cholecystokinin and neurotensin, as well as synthesis of enkephalins and nitric oxide.
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PMID:To the descending pain-control system in rats, inflammation-induced primary and secondary hyperalgesia are two different things. 1513 34

In this article we show some recent findings that constitute a great progress in the molecular knowledge of synaptic dynamics. To communicate, neurons use a code that includes electrical (action potentials) and chemical signals (neurotransmitters, neuromodulators). At the moment a great variety of molecules are known, whose neurotransmitter function in brain and the peripheral nervous system are out of question. Monoamines like acetylcholine, dopamine, noradrenaline, adrenaline, histamine, serotonin, glutamate, aspartate, glycine, ATP and GABA are good examples. Opioid neuropeptides, vasoactive intestinal peptide (VIP), neurokinines (substance P), somatostatin, neurotensin, neuropeptide Y, cholecystokinine, vasopressin or oxitocin have been related to the control of the stress response, sexual behaviour, food intake, pain, learning and memory, qualities that are also related to nitric oxide (NO). A great part of the molecular structure of the secretory machinery is known to be responsible for fast neurotransmitter release at the synapse, in response to action potentials. Proteins like sinaptobrevin (located in the membrane of the synaptic vesicle), sintaxin and SNAP-25 (both located at the presynaptic plasma membrane) constitute a trimeric complex which is responsible of the vesicular docking at the active sites for exocytosis. From this strategic location, vesicles release their neurotransmitter within few milliseconds, when the action potential invades the nerve terminal and activates the opening of the different subtypes of voltage-dependent Ca2+ channels. The asymmetric geographical distribution of each type of channel, in different neurons, rose the hypothesis that Ca2+ that enters through each subtype of channel is compartmentalised, thus favouring the generation of Ca2+ microdomains, in the cytosol and the nucleus, involved in different cellular functions. This great biochemical synaptic heterogeneity is facilitating the selection of many biological targets to develop drugs with potential therapeutic applications in neuropsychiatric diseases i.e. Alzheimer's, Parkinson, epilepsies, stroke, vascular dementia, depression, schizophrenia, anxiety and so on.
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PMID:[Neurotransmitters, calcium signalling and neuronal communication]. 1515 88

Many neuropeptides have been shown to be up-regulated in response to pain. The purpose of this study was to identify pain-related peptides in a rat model of neuropathic pain induced by sciatic nerve cuff implantation. Rats were tested for touch sensitivity prior to and 7 days following cuff implantation or sham surgeries. The lumbar spinal cord was removed on the 8th day post-surgery and the lumbar enlargement was processed for the detection of selected peptides using time-of-flight mass spectrometry. Only substance P (MW 1346.74) and neurotensin (MW 1673.0) were detected in the lumbar spinal cord of animals with mechanical allodynia (P < 0.01) following innocuous tactile stimulation of the affected hind paw. Therefore, substance P and neurotensin may be target candidates for the understanding and treatment of neuropathic pain.
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PMID:Substance P and neurotensin are up-regulated in the lumbar spinal cord of animals with neuropathic pain. 1518 51

Central neurotensin (NT) administration can both facilitate and inhibit somatic and visceral nociception, depending on the dose and administration site. NT microinjection in the rostroventral medulla facilitates nociception at low doses, while NT antagonist microinjection can markedly attenuate nociception, supporting the hypothesis that endogenous NT facilitates nociception. However, higher doses of NT produce a mu-opioid receptor-independent analgesia, similar to that resulting from various intense stressors. Furthermore, intense stress results in increased NT expression in several hypothalamic nuclei that have been implicated in stress-induced antinociception (SIAN); however, there is little direct evidence that endogenous NT is required for SIAN. We have investigated the role of endogenous NT in both basal visceral nociception and SIAN using both NT knockout mice and pharmacological approaches in rats. Visceral nociception was monitored by measuring visceromotor responses during colorectal distension both prior to and following water avoidance stress. Visceral nociception was significantly attenuated in both NT knockout mice and rats pre-treated with the NT antagonist SR 48692. Disruption of NT signaling also blocked SIAN, revealing a novel stress-induced hyperalgesic response that was significantly greater in female than in male rats. NT was also required for acetic acid-induced hyperalgesia. These results indicate that endogenous NT normally facilitates visceral pain responses, is required for irritant-induced hyperalgesia, and plays a critical role in SIAN.
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PMID:Endogenous neurotensin facilitates visceral nociception and is required for stress-induced antinociception in mice and rats. 1520 35

The role of the periaqueductal gray-rostral ventromedial medulla (RVM) system in descending inhibition of nociception has been studied for over 30 years. The neural basis for this antinociceptive action is reasonably well understood, with strong evidence that activation of a class of RVM neurons termed 'off-cells' exerts a net inhibitory effect on nociception. However, it has recently become clear that this system can facilitate, as well as inhibit pain. Although the mechanisms underlying the facilitation of nociception have not been conclusively identified, indirect evidence points to activation of a class of neurons termed 'on-cells' as mediating descending facilitation. Here we used focal infusion of the tridecapeptide neurotensin within the RVM in lightly anesthetized rats to activate on-cells selectively. Neurotensin has been shown in awake animals to produce a dose-related, bi-directional effect on nociception when applied within the RVM, with hyperalgesia at low doses, and analgesia at higher doses. Using a combination of single cell recording and behavioral testing, we now show that on-cells are activated selectively by low-dose neurotensin, and that the activation of on-cells by neurotensin results in enhanced nociceptive responding, as measured by the paw withdrawal reflex. Furthermore, higher neurotensin doses recruit off-cells in addition to on-cells, producing behavioral antinociception. Selective activation of on-cells is thus sufficient to produce hyperalgesia, confirming the role of these neurons in facilitating nociception. Activation of on-cells likely contributes to enhanced sensitivity to noxious stimulation or reduced sensitivity to analgesic drugs in a variety of conditions.
Pain 2004 Jul
PMID:Nociceptive facilitating neurons in the rostral ventromedial medulla. 1527 63

Microinjection of neurotensin (NT) in the rostral ventromedial medulla (RVM) produces dose-dependent antinociception. The NTR1 (Neurotensin Receptor Subtype 1) may mediate part of this response, however definitive evidence is lacking, and the spinal mediators of NTR1-induced antinociception are unknown. In the present study, we used immunohistochemical techniques to show that the NTR1, but not the NTR2 is expressed by spinally projecting serotonergic neurons of the RVM. We also show that microinjection of NT or the NTR1-selective agonist PD149163 in the RVM both produce dose-dependent antinociception in the tail-flick test that is blocked by the NTR1-selective antagonist SR48692. The antinociception produced by NT or PD149163 is also blocked by intrathecal administration of the non-selective serotonergic receptor antagonist methysergide. The results of these experiments provide anatomical and behavioral evidence that activation of NTR1-expressing spinally projecting neurons in the RVM produces antinociception through release of serotonin in the spinal dorsal horn. These results support the conclusion that the NTR1 plays an important role in the central modulation of nociception.
Pain 2005 Mar
PMID:Neurotensin activation of the NTR1 on spinally-projecting serotonergic neurons in the rostral ventromedial medulla is antinociceptive. 1573 55


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