Disease relevance of Nts

• In addition, NT stimulates growth of certain colon cancers; the mechanism for this effect is not known [1].
• Neurotensin (NT), a tridecapeptide, is a neurotransmitter that elicits potent effects including hypothermia and antinociception in mice and rats [2].
• These findings show that the new NT peptide analogues are robust and can deliver imaging agents to NTR-positive tumors such as pancreatic cancer [3].
• In vivo biodistribution of a representative (111)In-DTPA-NT peptide analogue in SCID mice bearing NTR-positive human adenocarcinoma (HT29) xenograft shows that the compound was primarily retained in tumor tissue (2.2% ID/g) and the kidneys (4.8% ID/g) at 4 h postinjection [3].
• Colitis-induced body weight loss, colonic myeloperoxidase activity, and histological damage were significantly enhanced by SR-48642 administration, a nonpeptide NTR1 antagonist, whereas continuous NT infusion ameliorated colitis outcome [4].

Psychiatry related information on Nts

• Targeted inactivation of the neurotensin type 1 receptor reveals its role in body temperature control and feeding behavior but not in analgesia [5].
• In order to investigate whether "endogenous" NT may act as a natural occurring antipsychotic or may mediate antipsychotic drug activity, the effects of the selective NT receptor antagonists SR 48692 and SR 142948A were analyzed in different behavioural tests of locomotor activity using vehicle, amphetamine, or haloperidol in mice [6].
• These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse [7].

High impact information on Nts

• The longitudinal smooth muscle layer of the guinea pig ileum, where neurotensin has both a direct relaxant and an indirect contractile action, has been used extensively as a biological assay system for neurotensin [8].
• The calcium-dependent potassium channel blocker apamin inhibits both the neurotensin- and nerve stimulation-induced muscle relaxation [8].
• Incubation of the circular smooth muscle preparation with a neurotensin antiserum substantially inhibited the nerve stimulation-induced relaxation, indicating a direct relationship between the effects of neurotensin and of nerve stimulation [8].
• Hypothermia and intolerance to cold induced by intracisternal administration of the hypothalamic peptide neurotensin [9].
• These findings suggest that CRH induces skin vascular permeability through NT acting on mast cells and that both peptides should be considered in the pathogenesis of skin disorders exacerbated by stress [10].

Chemical compound and disease context of Nts

• Our results support the notion that colon cancer growth may be dependent on blood-borne neurotensin and suggest that non-peptide neurotensin antagonists, such as SR 48692, may be useful for the development of novel therapeutic strategies of colon cancer [11].
• Blockade of neurotensin receptors affects differently hypo-locomotion and catalepsy induced by haloperidol in mice [6].
• NT was also required for acetic acid-induced hyperalgesia [12].
• Neither levocabastine nor mepyramine modified the colonic temperature or reversed the neurotensin-induced hypothermia [13].
• Indeed, ethanol doses that are hypnotic in control mice (2.8 g/kg) were not effective in abolishing locomotor activity following chronic NT administration [14].

Biological context of Nts

• The pharmacological properties of this receptor correspond to those of the low-affinity, levocabastine-sensitive NT binding site described initially in membranes prepared from rat and mouse brain [15].
• Murine neuroblastoma clone N1E-115 possesses receptors that specifically bind the tridecapeptide neurotensin, mediate the formation of intracellular cyclic GMP, and stimulate inositol phospholipid hydrolysis [16].
• This decrease in Bmax is more likely to be a result of intracellular sequestration of recyclable NT receptors than of true down-regulation due to the rapid resensitization seen for the NT-mediated biological response [16].
• In this study, we examined the effect of neurotensin on DARPP-32 Thr75 phosphorylation using mouse neostriatal slices [17].
• A dose of 18 nmol of NT or NT27 caused a body temperature lowering of 1.8 and 1.2 degrees C, respectively [2].

Anatomical context of Nts

• When the receptor is expressed in Xenopus laevis oocytes, the H1 antihistaminic drug levocabastine, like NT and neuromedin N, triggers an inward current [15].
• Neurotensin/N mRNA transcripts were identified in all four of the HCC cell lines and in one of nine HCC in nude mice [1].
• Neurotensin expression was found in two of six freshly resected HCC and in none of the six corresponding samples of normal mucosa [1].
• In vitro, NT and NT-2 at 30 nM caused predominantly contraction and relaxation in isolated distal colon and proximal ileum, respectively, from +/+ mice, but no responses were observed with tissues from -/- mice [18].
• We have identified a NT analog of the NT(8-13) fragment, NT27, that selectively causes only the hypothermic response in vivo, when microinjected into the periaqueductal gray (PAG) of rats [2].

Associations of Nts with chemical compounds

• Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain [15].
• We have recently reported that neurotensin stimulates the phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (PKA-site) by activating dopamine D1-type receptors in neostriatal neurons [17].
• The time course of this desensitization was very rapid; the maximal effect on cyclic GMP production (reduction to 10-30% of control values) occurred within 5 min of exposure of intact cells to neurotensin [16].
• This desensitization was homologous, as cells desensitized by neurotensin demonstrated no decrease in their cyclic GMP response to angiotensin II (1 microM) or bradykinin (10 nM) [16].
• Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: involvement of glutamate signalling [17].

Physical interactions of Nts

• Biochemical analysis and confocal microscopic imaging clearly indicate that NT is efficiently internalized after binding to NTR3, and that despite this internalization, the amount of receptor present on the cell surface is maintained [19].
• Native neurotensin (NT) is a tridecapeptide that binds to NTR and induces tumor growth [3].
• Radiolabeled ligands specific for the G protein-coupled state of neurotensin receptors [20].

Regulatory relationships of Nts

• Leptin-induced NT regulation was attenuated by dominant-negative STAT3 protein expression [21].
• We previously found that genetic or pharmacological manipulations that disrupt endogenous NT signaling attenuate antipsychotic drug-induced Fos expression in the dorsolateral and central striatum but not other striatal regions [22].
• Inhibition of neurotensin-induced pancreatic carcinoma growth by a nonpeptide neurotensin receptor antagonist, SR48692 [23].
• Finally a high expression of NTRL was evident in brainstem structures implicated in descending antinociceptive influences (e.g., the periaqueductal gray, nucleus raphe magnus, gigantocellular reticular nucleus, pars alpha, and lateral paragigantocellular nucleus) consistent with the proposed mediation of NT-induced analgesia by the NTRL [24].
• Neurotensin (10 microM) exhibited no influence on adenylate cyclase activity, 45Ca uptake, or 32Pi incorporation into phosphatidylinositol fractions of NG108-15 cells [25].

Other interactions of Nts

• Structure-activity studies revealed a close correlation between the analgesic potency of NT analogs and their affinity for the NTR2 and disclosed potent and selective agonists of this receptor [26].
• Pharmacological properties of the mouse neurotensin receptor 3. Maintenance of cell surface receptor during internalization of neurotensin [19].
• In addition, histochemical analyses of both Ntsr1 and Ntsr2 mRNAs were performed in the mouse brain regions involved in NT-related nociception [27].
• Leptin-mediated induction of NT gene expression was biphasic at 10(-11) and 10(-7) M [21].
• Neurotensin receptor-mediated cyclic GMP formation in neuroblastoma clone N1E-115 was decreased following prolonged exposure of intact cells to nondegraded neurotensin [16].

Analytical, diagnostic and therapeutic context of Nts

• The recent cloning of a second NT receptor (NTR2) prompted us to evaluate its role in NT-induced analgesia [26].
• Neurotensin and a non-peptide neurotensin receptor antagonist control human colon cancer cell growth in cell culture and in cells xenografted into nude mice [11].
• Subcutaneous delivery of neurotensin (0.54 micromol/kg every 24 hr) by osmotic pumps to nude mice that have been xenografted with SW480 cells results in a significant increase of tumor volume, i.e., up to 255% of control at day 20 of treatment [11].
• Using semiquantitative reverse-transcriptase (RT) PCR, we demonstrate that neurotensin induces gene expression of several cytokines/chemokines including macrophage inflammatory protein (MIP)-2, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha [28].
• METHODS: (125)I-NT binding and Northern blot analyses were performed for evaluation of the NT receptor in MIA PaCa-2 cells [23].

References