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M O Urban - One of the best experts on this subject based on the ideXlab platform.
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biphasic modulation of visceral nociception by Neurotensin in rat rostral ventromedial medulla
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: M O Urban, S V Coutinho, Gerald F. GebhartAbstract:A potential role for Neurotensin in the rostral ventromedial medulla (RVM) in modulation of visceral nociceptive transmission was examined in this study. Microinjection of Neurotensin (3–3000 pmol) into the RVM of awake rats produced a dose-dependent inhibition of the visceromotor response (VMR) to noxious colorectal distension (CRD) that lasted 30 to 120 min. Additionally, intra-RVM injection of Neurotensin (300 pmol) significantly reduced the slope of the stimulus-response function to graded CRD (20–80 mm Hg), whereas the greatest dose of Neurotensin (3000 pmol) completely inhibited the VMR at all intensities of CRD. General motor function was unaffected after intra-RVM injection of Neurotensin (3000 pmol). Intra-RVM injection of lesser doses of Neurotensin (0.03–0.30 pmol) resulted an enhancement of the VMR to noxious CRD that had a short duration (18–30 min), and produced a leftward shift of the stimulus-response function to graded CRD without a change in the slope of the function. Additionally, intra-RVM injection of the Neurotensin-receptor antagonist SR48692 (0.3–300 fmol) in naive animals produced dose-dependent inhibition of VMR to noxious CRD, whereas a lesser dose (0.03 fmol) enhanced the VMR. These data support a role for Neurotensin in the RVM in biphasic modulation of visceral nociception. The results obtained with SR48692 suggest that endogenous Neurotensin in the RVM modulates VMR to noxious CRD via a prominent interaction with Neurotensin receptors that mediate facilitatory influences and a lesser interaction with Neurotensin receptors that mediate masked inhibitory influences.
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characterization of biphasic modulation of spinal nociceptive transmission by Neurotensin in the rat rostral ventromedial medulla
Journal of Neurophysiology, 1997Co-Authors: M O Urban, Gerald F. GebhartAbstract:Urban, M. O. and G. F. Gebhart. Characterization of biphasic modulation of spinal nociceptive transmission by Neurotensin in the rat rostral ventromedial medulla. J. Neurophysiol. 78: 1550–1562, 1997. Modulation of spinal nociceptive transmission by Neurotensin microinjected in the rostral ventromedial medulla (RVM) was examined in anesthetized, paralyzed rats. Forty-three spinal dorsal horn neurons in the L3–L5 spinal segments responding to mechanical and noxious thermal stimulation (50°C) of the plantar surface of the ipsilateral hind foot were studied. Spinal units were classified as either wide dynamic range or nociceptive specific and were located in spinal laminae I–V. Microinjection of Neurotensin (0.03 pmol/0.2 μl) into the RVM produced a significant facilitation (135% of control) of spinal unit responses to noxious thermal stimulation (50°C) that lasted ∼12 min. In contrast, injection of greater doses of Neurotensin (300 or 3,000 pmol) produced an inhibition of spinal unit responses to noxious he...
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involvement of spinal cholecystokininb receptors in mediating Neurotensin hyperalgesia from the medullary nucleus raphe magnus in the rat
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: M O Urban, D J Smith, G F GebhartAbstract:Neurotensin microinjection into the medullary nucleus raphe magnus (RMg) has been shown to both inhibit and facilitate the spinal nociceptive tail-flick reflex in a dose-dependent manner. Our study was designed to determine a potential involvement of spinal cholecystokinin octapeptide (CCK) in mediating Neurotensin hyperalgesia from the RMg. Microinjection of Neurotensin (50 ng) into the RMg of awake rats produced a facilitation of the tail-flick reflex that was completely inhibited by intrathecal (i.t.) administration of the nonselective CCK receptor antagonist proglumide (100 ng). Conversely, injection of a greater dose of Neurotensin (5 micrograms) into the RMg produced an inhibition of the tail-flick reflex that was enhanced by i.t. proglumide. Intrathecal administration of the selective CCKB receptor antagonist L-365260 dose-dependently inhibited Neurotensin hyperalgesia from the RMg (ID50 = 0.42 ng) at doses approximately 1000-fold less than that observed with the selective CCKA receptor antagonist devazepide (ID50 = 646 ng). Injection of CCK alone i.t. produced a biphasic response on the tail-flick reflex as lesser doses (0.1-0.3 ng) inhibited the reflex although greater doses (30-100 ng) facilitated it. Similar to supraspinal Neurotensin hyperalgesia, the hyperalgesia observed with i.t. CCK (30 ng) was inhibited by i.t. L-365260 (ID50 = 0.59 ng) at doses approximately 1000-fold less than that observed with i.t. devazepide (ID50 = 630 ng). These data indicate that spinal CCK can both inhibit and facilitate spinal nociceptive responses. The facilitation of nociception observed with spinal CCK appears to involve CCKB receptors, which is consistent with the data in our study suggesting that spinal CCKB receptors mediate Neurotensin hyperalgesia from the RMg via descending neuronal projections.
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role of Neurotensin in the nucleus raphe magnus in opioid induced antinociception from the periaqueductal gray
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: M O Urban, D J SmithAbstract:These studies examined the role of the Neurotensinergic projections extending from the periaqueductal gray (PAG) to the nucleus raphe magnus (NRM) on the inhibition of the tail-flick reflex produced by microinjection of morphine or beta-endorphin in the PAG. Neurotensin (3-30 nmol) or the partial agonist [D-Trp11] Neurotensin (100 and 300 pmol) microinjected into the NRM of awake rats produced a dose-dependent inhibition of the tail-flick response lasting 90 to 150 min. Lower doses of Neurotensin (0.03-0.3 nmol) produced a hyperreflexive tail-flick response 10 min after injection, which correlated with a decreased hot plate latency. Additionally, a dose of [D-Trp11]Neurotensin (3 pmol) that had no intrinsic activity antagonized both the antinociceptive as well as hyperreflexive responses of Neurotensin. Morphine (6 nmol) injected into the PAG produced an inhibition of the tail-flick response that was enhanced by injection of [D-Trp11]Neurotensin (3 pmol) into the NRM. In contrast, injection of [D-Trp11]Neurotensin (3 pmol) into the NRM had no effect on the inhibition of the tail-flick produced by beta-endorphin (10 nmol) in the PAG. AntiNeurotensin antiserum yielded results similar to those obtained with [D-Trp11]Neurotensin. Although Neurotensin was found to produce changes in tail skin temperature, it was possible to dissociate these effects from changes in tail-flick latency. These data suggest that Neurotensin produces both antinociceptive and hyperalgesic responses when injected into the NRM.(ABSTRACT TRUNCATED AT 250 WORDS)
Gerald F. Gebhart - One of the best experts on this subject based on the ideXlab platform.
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biphasic modulation of visceral nociception by Neurotensin in rat rostral ventromedial medulla
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: M O Urban, S V Coutinho, Gerald F. GebhartAbstract:A potential role for Neurotensin in the rostral ventromedial medulla (RVM) in modulation of visceral nociceptive transmission was examined in this study. Microinjection of Neurotensin (3–3000 pmol) into the RVM of awake rats produced a dose-dependent inhibition of the visceromotor response (VMR) to noxious colorectal distension (CRD) that lasted 30 to 120 min. Additionally, intra-RVM injection of Neurotensin (300 pmol) significantly reduced the slope of the stimulus-response function to graded CRD (20–80 mm Hg), whereas the greatest dose of Neurotensin (3000 pmol) completely inhibited the VMR at all intensities of CRD. General motor function was unaffected after intra-RVM injection of Neurotensin (3000 pmol). Intra-RVM injection of lesser doses of Neurotensin (0.03–0.30 pmol) resulted an enhancement of the VMR to noxious CRD that had a short duration (18–30 min), and produced a leftward shift of the stimulus-response function to graded CRD without a change in the slope of the function. Additionally, intra-RVM injection of the Neurotensin-receptor antagonist SR48692 (0.3–300 fmol) in naive animals produced dose-dependent inhibition of VMR to noxious CRD, whereas a lesser dose (0.03 fmol) enhanced the VMR. These data support a role for Neurotensin in the RVM in biphasic modulation of visceral nociception. The results obtained with SR48692 suggest that endogenous Neurotensin in the RVM modulates VMR to noxious CRD via a prominent interaction with Neurotensin receptors that mediate facilitatory influences and a lesser interaction with Neurotensin receptors that mediate masked inhibitory influences.
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characterization of biphasic modulation of spinal nociceptive transmission by Neurotensin in the rat rostral ventromedial medulla
Journal of Neurophysiology, 1997Co-Authors: M O Urban, Gerald F. GebhartAbstract:Urban, M. O. and G. F. Gebhart. Characterization of biphasic modulation of spinal nociceptive transmission by Neurotensin in the rat rostral ventromedial medulla. J. Neurophysiol. 78: 1550–1562, 1997. Modulation of spinal nociceptive transmission by Neurotensin microinjected in the rostral ventromedial medulla (RVM) was examined in anesthetized, paralyzed rats. Forty-three spinal dorsal horn neurons in the L3–L5 spinal segments responding to mechanical and noxious thermal stimulation (50°C) of the plantar surface of the ipsilateral hind foot were studied. Spinal units were classified as either wide dynamic range or nociceptive specific and were located in spinal laminae I–V. Microinjection of Neurotensin (0.03 pmol/0.2 μl) into the RVM produced a significant facilitation (135% of control) of spinal unit responses to noxious thermal stimulation (50°C) that lasted ∼12 min. In contrast, injection of greater doses of Neurotensin (300 or 3,000 pmol) produced an inhibition of spinal unit responses to noxious he...
Philippe Soubrie - One of the best experts on this subject based on the ideXlab platform.
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specific involvement of Neurotensin type 1 receptor in the Neurotensin mediated in vivo dopamine efflux using knock out mice
Journal of Neurochemistry, 2004Co-Authors: Maud Leonetti, Philippe Brun, Regis Steinberg, Philippe Soubrie, Bernard Renaud, Magali Clerget, Mariefrancoise SuaudchagnyAbstract:Neurotensin is a tridecapeptide neurotransmitter known to be involved in psychiatric disorders, various physiological processes and several different neurobiological mechanisms, including modulation of accumbal dopamine release. Two Neurotensin extracellular binding sites, namely NT1- and NT2-receptor (NT1R and NT2R), have been cloned from the rat brain. These receptors are distinguishable by their different in vitro pharmacological properties but the available pharmacological tools have weak in vivo potency and specificity. The use of genetically engineered knock-out mice has provided a powerful alternative to the classical pharmacological approach to investigate their respective roles. In this study, using in vivo differential pulse amperometry, we show that, in wild-type mice, Neurotensin application into the ventral tegmental area dose-dependently evokes dopamine efflux in the nucleus accumbens. This Neurotensin-mediated efflux is dramatically decreased in mice lacking NT1R while it is unaffected in NT2R-deleted mice. This finding indicates that a large part of the dopamine efflux evoked by Neurotensin in the nucleus accumbens of wild-type mice is mediated via NT1R present in the ventral tegmental area.
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comparative effects of Neurotensin Neurotensin 8 13 and d tyr11 Neurotensin applied into the ventral tegmental area on extracellular dopamine in the rat prefrontal cortex and nucleus accumbens
Neuroscience, 2000Co-Authors: Florence Sotty, Philippe Brun, Maud Leonetti, Regis Steinberg, Philippe Soubrie, Bernard Renaud, Mariefrancoise SuaudchagnyAbstract:Abstract Ejections of 10 −5 –10 −3 M Neurotensin into the ventral tegmental area increased dopamine efflux measured by electrochemical approaches in the prefrontal cortex of anaesthetized rats. In the same conditions, the effects evoked on dopamine efflux by 10 −5 M Neurotensin(8-13) and [D-Tyr 11 ]Neurotensin were different from each other and depended on the explored area: the prefrontal cortex and the caudal and rostral nucleus accumbens. In the prefrontal cortex, Neurotensin(8-13) was as potent as Neurotensin, whereas [D-Tyr 11 ]Neurotensin was ineffective. In the caudal nucleus accumbens, when considering the initial intensity of the effect, Neurotensin(8-13) and Neurotensin appeared more potent than [D-Tyr 11 ]Neurotensin. In contrast, in the rostral nucleus accumbens, Neurotensin(8-13) was less potent than [D-Tyr 11 ]Neurotensin and Neurotensin. These results support the differential involvement of two pharmacologically distinct Neurotensin receptor entities on ventral tegmental area neurons in the modulation of mesolimbic and mesocortical dopaminergic activity.
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sr 48692 a non peptide Neurotensin receptor antagonist differentially affects Neurotensin induced behaviour and changes in dopaminergic transmission
Neuroscience, 1994Co-Authors: Regis Steinberg, Philippe Brun, M Fournier, J Souilhac, D Rodier, G Mons, J P Terranova, Le G Fur, Philippe SoubrieAbstract:Abstract Unilateral microinjection of Neurotensin in the ventral tegmental area of the rat (2.5 μg/0.5 μ1) produced behavioural excitation illustrated by contralateral circling. Given orally, SR 48692, a selective and potent non-peptide Neurotensin receptor antagonist, significantly reduced these rotations with a triphasic dose-effect relationship. Inhibition occurred at 0.12 mg/kg; further increases in dose up to 2.5 mg/kg produced no significant antagonism, then at doses ⩾ 5 mg/kg, a second phase of antagonism was observed. Bilateral injection of Neurotensin (0.5 μg each side) into the nucleus accumbens antagonized the increase in locomotor activity following intraperitoneal injection of amphetamine. Given orally, SR 48692 reduced dose-dependently (0.1–1 mg/kg) these intra-accumbens Neurotensin effects. Using high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of Neurotensin injected into the ventral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of Neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1–10 mg/kg). These results indicate complex interactions between Neurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR 48692 to affect Neurotensin-evoked behavioural versus biochemical changes supports the concept of Neurotensin receptor heterogeneity.
Jean Mazella - One of the best experts on this subject based on the ideXlab platform.
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Neurotensin receptor 3 sortilin mediates Neurotensin induced cytokine chemokine expression in a murine microglial cell line
Journal of Neuroscience Research, 2004Co-Authors: Eleni Dicou, Jeanpierre Vincent, Jean MazellaAbstract:We show that the type I Neurotensin receptor-3 (also called sortilin) is the only known Neurotensin receptor expressed in a murine microglial cell line and that its activation leads to phosphorylation of both extracellular signaling-regulated (Erk1/2) and Akt kinases. 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)-1β and tumor necrosis factor (TNF)-α. This induction is dependent on both phosphatidylinositol 3-kinase and mitogen-activated protein kinases pathways. We observe that the effect of Neurotensin on cytokine/chemokine expression is inhibited by the Neurotensin receptor-3 propeptide, a selective ligand of this receptor. These results demonstrate that the Neurotensin receptor-3 is functional in microglial cells where it mediates the induction of chemokines/cytokines expression by Neurotensin. © 2004 Wiley-Liss, Inc.
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involvement of the Neurotensin receptor 3 in the Neurotensin induced migration of human microglia
The Journal of Neuroscience, 2003Co-Authors: Stephane Martin, Jeanpierre Vincent, Jean MazellaAbstract:Microglia motility plays a crucial role in response to lesion or exocytotoxic damage of the cerebral tissue. We used two in vitro assays, a wound-healing model and a chemotaxis assay, to show that the neuropeptide Neurotensin elicited the migration of the human microglial cell line C13NJ by a mechanism dependent on both phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein (MAP) kinase pathways. The effect of Neurotensin on cell migration was blocked by the Neurotensin receptor-3 propeptide, a selective ligand of this receptor. We demonstrate, by using RT-PCR, photoaffinity labeling, and Western blot analysis, that the type I Neurotensin receptor-3 was the only known Neurotensin receptor expressed in these microglial cells and that its activation led to the phosphorylation of both extracellular signal-regulating kinases 1/2 and Akt. Furthermore, the effect of Neurotensin on cell migration was preceded by a profound modification of the F-actin cytoskeleton, particularly by the rapid formation of numerous cell filopodia. Both the motility and the filopodia appearance induced by Neurotensin were totally blocked by selective inhibitors of MAP kinases or PI 3-kinase pathways. This demonstrates that the Neurotensin receptor-3 is functional and mediates the migratory actions of Neurotensin.
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involvement of the Neurotensin receptor subtype ntr3 in the growth effect of Neurotensin on cancer cell lines
International Journal of Cancer, 2001Co-Authors: Claude Dal Farra, Jean Mazella, Jeanmarie Botto, Philippe Sarret, Valerie Navarro, Jeanpierre VincentAbstract:The expression of the 3 currently known Neurotensin receptors was studied in human cancer cells of prostatic, colonic or pancreatic origin by means of RT-PCR analysis and binding experiments. All the cells selected for this work have been shown to exhibit a growth response to Neurotensin. We found that the 7 transmembrane domain, levocabastine insensitive receptor (NTR1) is expressed in most but not all of the cells studied whereas the 7 transmembrane domain, levocabastine sensitive receptor (NTR2) is present in none of these cells. The 100 kDa-type I Neurotensin receptor (NTR3) is expressed in all the cells assayed. Moreover, we demonstrated that Neurotensin can stimulate the growth of CHO cells stably transfected with the NTR3. Taken together, our results strongly suggest that the NTR3 subtype could be involved in the growth response of human cancer cells to Neurotensin. © 2001 Wiley-Liss, Inc.
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Neurotensin and Neurotensin receptors
Trends in Pharmacological Sciences, 1999Co-Authors: Jeanpierre Vincent, Jean Mazella, Patrick KitabgiAbstract:Neurotensin is a brain and gastrointestinal peptide that fulfils many central and peripheral functions through its interaction with specific receptors. Three subtypes of Neurotensin receptors have been cloned. Two of them belong to the family of G protein-coupled receptors, whereas the third one is an entirely new type of neuropeptide receptor and is identical to gp95/sortilin, a 100 kDa-protein with a single transmembrane domain. In this review, the present knowledge regarding the molecular and pharmacological properties of the three cloned Neurotensin receptors is summarized and the relationship between these receptors and the known pharmacological effects of Neurotensin is discussed.
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effects of sr 48692 on Neurotensin induced calcium activated chloride currents in the xenopus oocyte expression system agonist like activity on the levocabastine sensitive Neurotensin receptor and absence of antagonist effect on the levocabastine ins
Neuroscience Letters, 1997Co-Authors: Jeanmarie Botto, Jeanpierre Vincent, Eric Guillemare, Jean MazellaAbstract:Abstract The effect of the drug SR 48692 on the Ca 2+ -activated Cl − current induced by Neurotensin on Xenopus oocytes injected with cRNAs encoding rodent high and low affinity Neurotensin receptors, was examined. In this receptor expression system, SR 48692 failed to antagonize electrophysiological measurement of Neurotensin-evoked current via the rat high affinity Neurotensin receptor, whereas its application onto oocytes expressing the mouse low affinity Neurotensin receptor triggered an inward current, as well as Neurotensin itself. However, no current activation was observed after application of the drug on oocytes expressing the rat high affinity Neurotensin receptor. These observations in the oocyte expression system did not reflect typical antagonist properties of SR 48692 drug.
Mariefrancoise Suaudchagny - One of the best experts on this subject based on the ideXlab platform.
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specific involvement of Neurotensin type 1 receptor in the Neurotensin mediated in vivo dopamine efflux using knock out mice
Journal of Neurochemistry, 2004Co-Authors: Maud Leonetti, Philippe Brun, Regis Steinberg, Philippe Soubrie, Bernard Renaud, Magali Clerget, Mariefrancoise SuaudchagnyAbstract:Neurotensin is a tridecapeptide neurotransmitter known to be involved in psychiatric disorders, various physiological processes and several different neurobiological mechanisms, including modulation of accumbal dopamine release. Two Neurotensin extracellular binding sites, namely NT1- and NT2-receptor (NT1R and NT2R), have been cloned from the rat brain. These receptors are distinguishable by their different in vitro pharmacological properties but the available pharmacological tools have weak in vivo potency and specificity. The use of genetically engineered knock-out mice has provided a powerful alternative to the classical pharmacological approach to investigate their respective roles. In this study, using in vivo differential pulse amperometry, we show that, in wild-type mice, Neurotensin application into the ventral tegmental area dose-dependently evokes dopamine efflux in the nucleus accumbens. This Neurotensin-mediated efflux is dramatically decreased in mice lacking NT1R while it is unaffected in NT2R-deleted mice. This finding indicates that a large part of the dopamine efflux evoked by Neurotensin in the nucleus accumbens of wild-type mice is mediated via NT1R present in the ventral tegmental area.
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comparative effects of Neurotensin Neurotensin 8 13 and d tyr11 Neurotensin applied into the ventral tegmental area on extracellular dopamine in the rat prefrontal cortex and nucleus accumbens
Neuroscience, 2000Co-Authors: Florence Sotty, Philippe Brun, Maud Leonetti, Regis Steinberg, Philippe Soubrie, Bernard Renaud, Mariefrancoise SuaudchagnyAbstract:Abstract Ejections of 10 −5 –10 −3 M Neurotensin into the ventral tegmental area increased dopamine efflux measured by electrochemical approaches in the prefrontal cortex of anaesthetized rats. In the same conditions, the effects evoked on dopamine efflux by 10 −5 M Neurotensin(8-13) and [D-Tyr 11 ]Neurotensin were different from each other and depended on the explored area: the prefrontal cortex and the caudal and rostral nucleus accumbens. In the prefrontal cortex, Neurotensin(8-13) was as potent as Neurotensin, whereas [D-Tyr 11 ]Neurotensin was ineffective. In the caudal nucleus accumbens, when considering the initial intensity of the effect, Neurotensin(8-13) and Neurotensin appeared more potent than [D-Tyr 11 ]Neurotensin. In contrast, in the rostral nucleus accumbens, Neurotensin(8-13) was less potent than [D-Tyr 11 ]Neurotensin and Neurotensin. These results support the differential involvement of two pharmacologically distinct Neurotensin receptor entities on ventral tegmental area neurons in the modulation of mesolimbic and mesocortical dopaminergic activity.
