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1
Kahn, Saima. "Neurochemical studies on substance P and substance P fragments in rat striatum." Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298358.
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Garrett, Neil Edward. "Substance P and experimental joint inflammation." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244679.
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McGregor, Gerard Patrick. "Radioimmunological studies of the physiology of substance P." Thesis, Imperial College London, 1985. http://hdl.handle.net/10044/1/37781.
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Abdullah, L. H. "A radioimmunoassay for substance P : Biochemical and pathological studies." Thesis, Queen's University Belfast, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373527.
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Sandweiss, Alexander Jordan, and Alexander Jordan Sandweiss. "The Role of Substance P in Opioid Induced Reward." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/621568.
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Chronic pain affects approximately 100 million Americans. Opioids are the mainstay therapy for the treatment of chronic pain. While physicians and patients alike are apprehensive about using opioids due to their side effects including respiratory depression and addiction, 259 million opioid prescriptions were written in 2012. Although opioids are the most efficacious available analgesics, they increase both positive and negative reinforcement, ultimately leading to addiction. The pro-nociceptive neurotransmitter, Substance P (SP) and its corresponding receptor (NK₁R), are not only found on pain pathways to promote pain but also found in the ventral tegmental area associated with dopamine neurons. Studies have shown that Substance P can potentiate positive reinforcement of opiates and may play a role in opioid reward. Here using in vivo microdialysis, we show that systemic morphine significantly increases SP release in the VTA, an effect mediated by ventral midbrain GABAergic neurons. Substance P administered to the VTA results in a significant increase in dopamine release in the nucleus accumbens (NAc). Using CRISPR-Cas9 knockdown of NK₁R in the VTA we prevent the induction of opiate reward as tested using a conditioned place preference paradigm (CPP). Finally, we developed a novel opioid agonist/NK₁R antagonist bifunctional compound, TY032, which inhibits acute and chronic pain in male rats. Importantly, TY032 microinjection into the VTA did not increase extracellular dopamine release in the NAc and did not produce a positive CPP score. These data indicate dual targeting of the dopamine reward circuitry and pain pathways with multifunctional opioid-NK₁R compounds may be an effective strategy in developing future analgesics that lack the potential for abuse.
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Wang, Linhong. "Differential processing of circulating substance P and neurokinin A /." The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487862972134708.
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Berthault, Béatrice. "Etude d'un systeme enzymatique membranaire degradant la substance p dans la substance noire chez le rat." Paris 6, 1988. http://www.theses.fr/1988PA066077.
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Berthault, Béatrice. "Etude d'un système enzymatique membranaire dégradant la substance P dans la substance noire chez le rat." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37611893v.
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Chui, Jeanie Jin Yee Medical Sciences Faculty of Medicine UNSW. "The role of substance P in the pathogenesis of pterygia." Publisher:University of New South Wales. Medical Sciences, 2007. http://handle.unsw.edu.au/1959.4/41503.
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Pterygium is an ocular surface disorder characterised by centripetal invasion of the cornea by altered limbal cells, accompanied by fibrosis and neovascularisation. One of the enigmatic features of pterygium is its wing-like shape and the mechanism(s) supporting its centripetal growth remain to be elucidated. As the growth pattern of pterygia mirrors the radial arrangement of corneal nerves, we hypothesised that neuropeptides may facilitate its directional growth. In this thesis, we investigated the roles that the sensory neuropeptide substance P (SP) may play in the pathogenesis of pterygia given its known functions in corneal cell migration, proliferation, wound healing and neurogenic inflammation. Using a modified Boyden chamber method, SP was shown to act as a chemoattractant to pterygium fibroblasts and vascular endothelial cells, and this activity was diminish by blockade of its receptor (NK1). 3H-thymidine incorporation assays confirmed that our cell migration results were unrelated to SP-stimulated proliferation. A bead-based multiplex cytokine array detected secretion of pro-inflammatory cytokines (IL-6, IL-8 and CCL2) from SP stimulated pterygium and limbal epithelial cells. Using real-time RT-PCR and immunoblotting, we show that UVB stimulated transcription of the TAC1 gene followed by secretion of SP in ocular surface epithelial cell cultures. Finally, SP and NK1receptor immunoreactivity was identified in pterygium tissue, where overall, NK1receptors were up-regulated in pterygia. Furthermore, we identified a population of NK1 receptor positive mononuclear cells in pterygia that did not express lineage markers for T or B-Iymphocytes, macrophages or mast cells, but may represent immature haemopoietic cells that may have migrated in from the blood since these cells were also present in autologous conjunctival tissue. In summary, SP may contribute to the shape of pterygia by facilitating migration of fibroblasts and vascular endothelial cells into the normally avascular cornea. Additionally, UVB stimulates SP production in epithelial cells and the presence of SP contributes to inflammation in pterygia by inducing pro-inflammatory cytokine release. Finally, we identified a population of relatively immature, NK1 receptor positive cells in pterygia that may have been attracted by the presence of SP. Collectively, these results imply that SP may contribute to the pathogenesis of pterygia.
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Vetsika, Eleni-Kyriaki. "Actions of substance p on cellular responses during neurogenic inflammation." Thesis, Queen Mary, University of London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445300.
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DARMAN, PAUL STEWART. "THE SYNTHESIS AND BIOLOGICAL EVALUATION OF ALPHA-MELANOTROPIN AND SUBSTANCE P PEPTIDE ANALOGUES (STRUCTURE, FUNCTION)." Diss., The University of Arizona, 1985. http://hdl.handle.net/10150/187929.
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To investigate the underlying structural features of the neuropeptides α-melanotropin (α-MSH) and substance P (SP), which are responsible for their biological actions, the following study was undertaken. By means of side-chain, fragment and conformational restriction analysis, several α-MSH peptides were prepared by solid-phase synthesis and evaluated by the frog and lizard skin bioassays. Using conformational restriction and fragment methods, several SP peptides were synthesized and examined for biological activity on the guinea-pig isolated ileum, rat brain binding and intrathecal injection assay systems. The results with the new α-MSH analogues show that the histidine-6 side-chain is not needed for signal transduction, but is very important for full potency. The tryptophan-9 side-chain is similarly not needed for signal transduction, but is critically important for full potency. The data also indicate that the positions 6 and 9 side-chains are important for full potency because they likely interact with the melanophore receptor, rather than playing a role in conformationally folding the MSH peptide into a pseudocyclic structure. The results also show that the arginine side-chain at position 8 is not particularly important for signal transduction or full potency, but on the lizard skin bioassay this side-chain is implicated in the previously reported prolongation of Nle⁴, D-Phe⁷-α-MSH. The data provided by the SP peptides suggest that the previously postulated pseudocyclic structure of the 5-11 sequence may not be as fundamental to SP activity as heretofore believed. The data suggest that this type of turn conformation may be important for signal transduction, but is apparently not the only requirement for receptor recognition. Finally, the data show that part of the signal transduction message of SP is contained within the 5-8 region of the peptide, but that most of the receptor recognition elements are probably located outside this sequence.
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Maduka, Uche Patrick. "Elucidating mechanisms by which substance P in the RVM contributes to the maintenance of pain following inflammatory injury." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/5019.
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Chronic pain is a major healthcare concern that directly affects over one hundred million people in the United States alone. While current treatment options like opioids and NSAIDs are effective, they are with significant drawbacks that prevent long term use. It is important to identify and understand new druggable targets for the treatment of pain. Recent findings have demonstrated substance P functions in the RVM to maintain hypersensitivity to noxious heat stimuli in models of persistent peripheral inflammatory injury in a manner dependent on presynaptic NMDA receptors. What remains unclear is how substance P assumes this pronociceptive role following peripheral inflammatory injury. The experiments detailed in this thesis investigated whether the levels and or release of substance P in the RVM was altered following peripheral inflammatory injury.
The effect of peripheral inflammatory injury on levels of substance P in the RVM was tested at several time points. The data show that there were no changes in substance P levels in the ipsilateral or contralateral RVM of CFA injected rats compared to their saline controls at any of the time points tested. To assess whether changes in substance P levels occurred in a subset of neurons within the RVM, computer aided densitometry analysis was used to measure substance P immunoreactivity in sections from the RVM of rats treated with CFA or saline. Substance P immunoreactivity was increased in the ipsilateral RVM of the CFA group compared to the corresponding saline sections at the 4 day, but not the 2 week time point. No other changes were observed.
Electron microscopy was used to demonstrate the presence of the NMDA receptor and substance P on the same axon terminals within the RVMs of rats treated with either CFA or saline. This colocalization is significant because it identifies NMDA receptors in position to regulate the release of substance P from axon terminals in the RVM. There were no obvious differences in the degree of colocalization between CFA and saline groups. Functional experiments were devised that tested whether substance P release (basal and evoked) in the RVM was increased following peripheral inflammatory injury, and whether said release was regulated by NMDA receptors. The data show that neither basal nor evoked (potassium or veratridine) release was increased following peripheral inflammatory injury. NMDA was able to facilitate the release of substance P in both the CFA and saline treatment groups, but the facilitation was not different between groups. In the absence of any depolarization stimulus, NMDA was unable to elicit any release of substance P beyond basal values.
All told, the data show substance P levels in the RVM are not altered by peripheral inflammatory injury. Additionally, neither basal nor evoked release of substance P is altered by peripheral inflammatory injury. The data provide functional and anatomical evidence for modulation of substance P release by glutamate acting at presynaptic NMDA receptors, but do not support the idea of differential modulation of substance P release following peripheral inflammatory injury.
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Wong, Chui Mae. "Substance P and neurokinin A as markers of pain in neonates." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/25329.
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Both substance P (SP) and neurokinin A (NKA) have been postulated to be involved in persistent pain in adult studies, but never previously researched in newborn infants. Methods of sample handling and analysis were developed to accommodate neonatal microsamples. Sample extraction was found to be essential, as were speed of sample collection and the use of polypropylene materials during sample handing. The clinical study enrolled 174 infants of different gestational ages, who had serial measurements of SP, NKA, and cortisol performed in plasma and saliva samples. Plasma SP concentrations in neonates ranged from 0.0-11.2 pmol/L (median 1.7 pmol/L) and NKA concentrations from 1.8-74.6 pmol/L (median 6.0 pmol/L). Gestation and birth weight had no significant correlation with peptide concentrations. Postnatally, there was a gradual rise in median plasma SP and NKA during the first three days which decreased again by days 7 to 14. Perinatal factors such as labour, the mode of delivery, and epidural analgesia affected NKA but not SP concentrations. With regard to either pain or assisted ventilation, plasma SP concentrations did not appear to be a useful marker of persistent pain or distress. Conversely, plasma NKA concentrations showed significant changes with ventilation, which were further modulated by the use of analgesia. Cortisol responses in the same group of infants demonstrated significant changes with ventilation, but not with the administration of analgesia. This suggests that although cortisol is a useful indicator of overall stress, NKA might be more specific for pain. There was a weak correlation between plasma SP and NKA. Plasma SP did not correlate with plasma cortisol or other physiological measures of pain used in this study.
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Backman, Ludvig J., Gloria Fong, Gustav Andersson, Alexander Scott, and Patrik Danielson. "Substance P is a mechanoresponsive, autocrine regulator of human tenocyte proliferation." Umeå universitet, Anatomi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-50694.
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It has been hypothesised that substance P (SP) may be produced by primary fibroblastic tendon cells (tenocytes), and that this production, together with the widespread distribution of the neurokinin-1 receptor (NK-1 R) in tendon tissue, could play an important role in the development of tendinopathy, a condition of chronic tendon pain and thickening. The aim of this study was to examine the possibility of endogenous SP production and the expression of NK-1 R by human tenocytes. Because tendinopathy is related to overload, and because the predominant tissue pathology (tendinosis) underlying early tendinopathy is characterized by tenocyte hypercellularity, the production of SP in response to loading/strain and the effects of exogenously administered SP on tenocyte proliferation were also studied. A cell culture model of primary human tendon cells was used. The vast majority of tendon cells were immunopositive for the tenocyte/fibroblast markers tenomodulin and vimentin, and immunocytochemical counterstaining revealed that positive immunoreactions for SP and NK-1 R were seen in a majority of these cells. Gene expression analyses showed that mechanical loading (strain) of tendon cell cultures using the FlexCell (R) technique significantly increased the mRNA levels of SP, whereas the expression of NK-1 R mRNA decreased in loaded as compared to unloaded tendon cells. Reduced NK-1 R protein was also observed, using Western blot, after exogenously administered SP at a concentration of 10(-7) M. SP exposure furthermore resulted in increased cell metabolism, increased cell viability, and increased cell proliferation, all of which were found to be specifically mediated via the NK-1 R; this in turn involving a common mitogenic cell signalling pathway, namely phosphorylation of ERK1/2. This study indicates that SP, produced by tenocytes in response to mechanical loading, may regulate proliferation through an autocrine loop involving the NK-1 R.
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和子, 水谷, and Kazuko Mizutani. "Substance P affects exclusively on prototypic neurons in mouse globus pallidus." Thesis, https://doors.doshisha.ac.jp/opac/opac_link/bibid/BB13059544/?lang=0, 2017. https://doors.doshisha.ac.jp/opac/opac_link/bibid/BB13059544/?lang=0.
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本研究は、先行研究で示唆されていた淡蒼球外節（GP）におけるニューロキニン１型受容体（NK-1R）の局在を、免疫染色と投射パターン、電気生理学の観点から示した。形態学的には、NK-1Rを持つ細胞がLhx6やPVを共発現し、線条体と視床下核の両方に投射するものの、FoxP2を発現する細胞とは共存しなかった。さらに、パッチクランプを用いてGP細胞の電気的性質を調べた後、NK-1Rアゴニストへの応答を観察した結果を合わせたところ、NK-1R細胞がPrototypicタイプに含まれる特定の集団であることが明らかになった。博士(理学)
Doctor of Philosophy in Science
同志社大学
Doshisha University
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Ploux, Olivier. "Synthèse d'analogues cycliques de la substance P : études biochimiques et structurales." Paris 6, 1986. http://www.theses.fr/1986PA066076.
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Waters, Catherine M. "The mechanisms underlying the anti-cancer activity of substance-P analogues." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23248.
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This study explores the range of tumour types, which are sensitive to substance P analogues. It was found that a wider range of tumour types than had been previously demonstrated were sensitive to growth inhibition by the substance P analogue, [Arg6,D-Trp7,9,NmePhe8]- Substance P(6-11) (antagonist G). Sensitive tumour types included SCLC, NSCLC, colo-rectal and ovarian tumour cell lines with a mean IC50 value of 33mM for 11 tumour cell lines of various origin. The mechanism of action of the growth inhibitory effects of substance P analogues is unclear. Using RT-PCR this study shows that sensitivity of tumour cells to antagonist G is dependent upon the expression of neuropeptide receptors, in particular the bombesin/gastrin releasing peptide (GRP) receptor, and not dependent on tumour type. This is confirmed by the demonstration of increased sensitivity of rat-1 fibroblasts transfected with the bombesin receptor when compared to the parent cell line. Substance P analogues have previously been thought to act as neuropeptide receptor antagonists but more recently they have been shown to have some agonist effects including the activation of c-Jun N-terminal kinase (JNK). Further studies using fibroblast cells transfected with the bombesin receptor show that substance P analogues are potent activators of MAPK and that this occurs via activation of the bombesin receptor. It was found that the substance P analogue, [Arg, D-Phe, D-Trp, Leu11]-Substance P (antagonist D), activates MAPK and inhibits bombesin stimulated calcium flux by the activation of Gi stimulated down stream effectors in preference to the bombesin stimulated Gq downstream effectors. It is demonstrated that MAPK activation by antagonist D is integral in the pro-apoptotic effects of this compound. Thus, the combined effects of substance P analogue stimulated, discordant MAPK and JNK activation, together with the inhibition of neuropeptide stimulated calcium flux, results in growth inhibition and apoptosis in cell types which express neuropeptide receptors.
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Lindsay, Gregory W. "Enhanced Renal Sympathetic and Cardiovascular Responses to Substance P in Hypertension." Digital Commons @ East Tennessee State University, 1993. https://dc.etsu.edu/etd/2718.
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Blood pressure, heart rate, and renal sympathetic nerve responses were measured in 9-13 week old male spontaneously hypertensive rats (SHR) and compared to those in age and sex-matched Wistar-Kyoto (WKY) rats following intravenous injection of the neuropeptide substance P (SP), the nicotinic stimulant 1,1-dimethyl-4-phenylpiperazinium (DMPP), and the adrenoceptor stimulant norepinephrine (NE). Charles River Sprague-Dawley (CD) rats were used in some studies to develop methodologies. Measurements were made in control rats and also following sinoaortic denervation, pithing, ganglion blockade, or adrenoceptor blockade. Responses were evaluated in order to determine if ganglion stimulation by SP was enhanced in SHR compared to WKY rats and if this enhancement was selective for SP or would also be exhibited to DMPP. NE was used to evaluate adrenergic sensitivity and to confirm the success of baroreceptor denervations. SHR exhibited greater intrinsic sympathetic tone than WKY rats before and following ganglion blockade. Ganglion stimulation by SP and DMPP was only fully revealed following elimination of baroreceptor input. Results indicated that SP stimulates sympathetic ganglia to increase renal sympathetic nerve activity, heart rate and blood pressure in CD, SHR and WKY rats. This increase was enhanced in SHR compared to WKY rats in the absence of a similar enhancement of responses to DMPP. The action of SP to cause vasodilation was attenuated in SHR versus WKY rats which may augment its action as a pressor agent in SHR. In conclusion, increases in blood pressure, heart rate and renal sympathetic nerve activity were selectively increased to SP in SHR versus WKY rats. This enhanced action of SP may contribute to the elevation of basal and/or evoked sympathetic discharge observed in this model of hypertension.
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Haga, Jamie L. "The effect of substance P on ovariectomy-induced memory deficits in rats." Huntington, WV : [Marshall University Libraries], 2006. http://www.marshall.edu/etd/descript.asp?ref=670.
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Meadows, Rena. "Substance P receptor activation and desensitization as monitored by M current inhibition /." Connect to resource online, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1219192543.
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TOETSCH, PIERRE PAUL. "Interventions possibles de la substance p au cours de syndromes inflammatoires coliques." Strasbourg 1, 1992. http://www.theses.fr/1992STR15044.
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Ward, R. A. "The interaction of substance P and 5-hydroxytryptamine in the spinal cord." Thesis, Bucks New University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376427.
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Mee, Ann Marie. "Receptors for substance P and calcitonin gene-related peptide in the dog." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250278.
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Smith, Derek David. "Use of phosphorus-based reagents in the synthesis of substance P analogues." Thesis, University of Edinburgh, 1986. http://hdl.handle.net/1842/11405.
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Ragsdale, John. "The role of substance p in bovine pneumonia caused by Mannheimia haemolytica." Diss., Kansas State University, 2010. http://hdl.handle.net/2097/4634.
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Doctor of PhilosophyDepartment of Diagnostic Medicine/Pathobiology
Derek A. Mosier
The bovine respiratory disease complex (BRDC) is a major concern for cattle producers in the United States and worldwide. One of the most costly and deadly components of BRDC is bovine pneumonic pasteurellosis (BPP) caused by Mannheimia haemolytica. The initial pulmonary inflammation associated with BPP is a characteristic serofibrinous exudation into the lung, which is believed to be induced by M. haemolytica virulence factors such as lipopolysaccharide (LPS) and leukotoxin (LKT) and host cytokines and chemokines such as tumor necrosis factor – α, interleukin – 1β, and interleukin – 8. However, these pulmonary changes often occur before virulence factors or cytokines are substantial components of the pulmonary microenvironment. Other proinflammatory molecules such as substance P (SP) may be involved in the pathogenesis of the peracute serofibrinous exudation of BPP. SP is an 11 amino acid long neuropeptide that is a neurotransmitter of pain that can be released from sensory nerves into tissues to cause neurogenic inflammation. Neurogenic inflammation is characterized by serofibrinous exudation and leukocyte activation. SP-like immunoreactivity was present in the airways, alveolar septa, macrophages, endothelium, and peribronchial nerves in both pneumonic and normal bovine lung; however, SP-like immunoreactivity was increased in pneumonic compared to normal bovine lung due to increased immunoreactivity in macrophages. SP and the combination of SP with histamine and LPS increased the permeability of a calf pulmonary arterial endothelial cell line to Evans blue dye labeled albumin by 12.34%, 13.57%, and 22.03%, respectively compared to a cell control. Similarly, SP and the combination of SP and histamine increased the monolayer permeability of a bovine adrenal gland capillary endothelium by 8.27% and 16.69% compared to a cell control. The increase in permeability was due to endothelial cell shape change and the formation of intercellular gaps rather than cell death. However, SP does not increase the surface expression of the β2 integrin CD18 (the M. haemolytica LKT receptor) on bovine neutrophils nor does it increase LKT-induced leukocytotoxicity of bovine peripheral blood leukocytes. These findings indicate that SP may be a contributor to BPP in association with other cytokines.
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Dubois, Dave. "Rôle de la substance P dans la régulation du récepteur opioïdergique delta." Mémoire, Université de Sherbrooke, 2010. http://savoirs.usherbrooke.ca/handle/11143/4076.
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À ce jour, les analgésiques de choix dans le traitement de la douleur sont toujours les composés opioïdergiques agissant sur le récepteur mu (MOPR), comme par exemple la morphine. Étant donné les effets secondaires indésirables observés avec ces agonistes, des alternatives ont été envisagées pour traiter la douleur adéquatement tout en réduisant les effets indésirables. Un rôle pour le récepteur opioïdergique delta (DOPR) a été proposé, car son activation engendre moins d'effets secondaires que MOPR. Cependant, la faible efficacité analgésique de ses agonistes limite son utilisation clinique. Les études menées dans le laboratoire du Pr Louis Gendron ont pour but principal d'étudier les rôles de DOPR, sa régulation et ses mécanismes d'action pour contrer la douleur. Chez les rongeurs, il est entre autre [i.e. autres] possible d'augmenter l'analgésie induite par les agonistes DOPR dans certaines conditions, comme suite à un traitement chronique avec un agoniste MOPR ou lors d'une douleur de type inflammatoire ou neuropathique. En conditions normales, DOPR semble séquestré au niveau intracellulaire, ce qui pourrait expliquer sa faible efficacité analgésique. Cependant, une augmentation de la disponibilité membranaire de DOPR semble corrélée à l'augmentation de ses effets analgésiques. Différentes hypothèses ont été proposées pour expliquer ce phénomène et ce mémoire présente un survol des différents mécanismes de régulation proposés pour DOPR en s'attardant principalement sur le rôle possible de la substance P. Ce neuropeptide a en effet été décrit comme étant essentiel pour permettre l'expression membranaire de DOPR et ainsi permettre l'analgésie via ce récepteur. Cependant, des différences dans la localisation de la substance P et de DOPR ont été soulevées. Mon étude évalue donc le rôle de la substance P dans l'analgésie produite par des agonistes DOPR dans un modèle de douleur inflammatoire. Les résultats obtenus ici démontrent que la substance P ne semblent [i.e. semble] pas essentielle pour permettre la compétence fonctionnelle de DOPR. Cela suggère donc l'existence de mécanismes de régulation de DOPR indépendants de la substance P. Il ne semble donc pas y avoir un seul et unique mécanisme responsable de la régulation de DOPR, différentes hypothèses sont explorées dans ce mémoire.
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Tufail-Hanif, Uzma. "Modulation of neuropeptide growth factor signalling by anti-cancer substance P analogues." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/30862.
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Model cell systems consisting of CHO-K1 cell-lines stably expressing GRP or V1A receptors were established and the effect of SP-D and SP-G tested. Expression of GRP and V1A receptors led to the development of a transformed phenotype as cells showed increased cloning efficiency and survival in soft-agar and suspension growth respectively. GRP and V1A receptor expressing cells were less adherent, more migratory and not contact inhibited. Neuropeptide receptor stimulation provided some protection from the cytotoxic effects of etoposide suggesting a role in chemoresistance. Substance-P analogues inhibited normal and anchorage-independent growth of receptor expressing cells. In receptor binding studies on GRP and V1A receptor expressing cells, analogue inhibited radioligand binding non-competitively. Transfected GRP and V1A receptors effectively coupled to Gαq to increase intercellular calcium and the analogues were effective antagonists of this response. Neuropeptide and analogues stimulated ERK activity in GRP and V1A receptor expressing cells. Activation of ERK by neuropeptide was rapid and transient while analogue induced activation was delayed and sustained. Analogue-stimulated ERK activity was pertussis toxin sensitive whereas neuropeptide-stimulated ERK activation was not. In addition, analogue induced ERK activity was blocked by inhibition of EGF receptor kinase. This indicates that SP-D and SP-G facilitate receptor coupling to G-protein Gi/Go subunits for subsequent calcium-independent ERK activation via EGFR transactivation. Stable cell-lines expressing different levels of V1A receptor were used to examine the effect of altering the ratio of receptor to G-protein on the ability of the analogues to direct receptor signalling. Chimeric V1A receptors containing the second (V1i2) on third intracellular (V1i3) loop of the V2 receptor were used to investigate the influence of substance-P analogues on G-protein selectivity. Both receptors were still capable of binding AVP and Sp-G but had altered ability to activate PLC and ERK. The second intracellular loop of V1AR was essential for AVP-stimulated PLC and ERK activation but not for SP-G-induced ERK activation. This confirms that the effects of the agents cause an alteration in the receptor-G-protein coupling domains of receptors. These findings demonstrate that substance-P analogues are biased agonists of receptors other than GRP receptors, activating downstream signals which differ fro those stimulated by the natural agonist through promoting an alternative agonist state of the receptor. This pathway selectivity combined with the receptor specificity of different substance-P analogues offers great potential for the tailored treatment of neuropeptide-dependent tumours.
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Meadows, Rena Marie. "Substance P Receptor Activation and Desensitization as Monitored By M Current Inhibition." Youngstown State University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1219192543.
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Uzubalis, Ranate Ingrid. "A study of the metabolism, pharmacological properties and disposition of substance P /." Title page, table of contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09PH/09phu99.pdf.
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Parnet, Patricia. "Role de la substance p et de la b-endorphine dans le controle de la fonction gonadotrope cyclique. Etude particuliere des recepteurs hypophysaires et lymphocytaires de la substance p." Paris 6, 1990. http://www.theses.fr/1990PA066263.
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Des etudes anterieures du laboratoire ont montre que, la sp est localisee chez la ratte par immunohistochimie dans les noyaux hypothalamiques impliques dans la fonction gonadotrope et au niveau de l'antehypophyse ou elle agit via un recepteur specifique. L'injection d'un immunserum anti-sp, le matin du proestrus provoque prematurement un pic preovulatoire de lh. L'administration intracerebroventriculaire de sp reduit la liberation de lh. Par perifusion d'antehypophyse, il est montre que la sp agit directement en inhibant la liberation de lh induite par le gnrh. Le dosage radioimmunologique de la sp et du gnrh au niveau du noyau arque, du noyau preoptique median et de l'eminence mediane met en evidence une evolution de la concentration des neuropeptides au cours du cycle strien. L'activite du systeme spergique est egalement mesuree par l'evolution du nombre de recepteurs hypophysaires de la sp. Lorsque l'stradiol plasmatique s'eleve, on observe: une augmentation de la liaison hypophysaire du gnrh et une augmentation de la liberation du gnrh de l'eminence mediane vers l'hypophyse, permettant la mise en place du pic preovulatoire de lh. Lorsque la progesterone s'eleve, on observe: une augmentation de la liaison hypophysaire de la sp et une augmentation de la liberation de la sp, de l'eminence mediane vers l'hypophyse permettant l'induction de fin du pic preovulatoire. De plus, nous montrons que la testosterone modifie le nombre et l'affinite des recepteurs lymphocytaires de la sp. En utilisant pour antigene des peptides correspondant a des parties du recepteur de la sk nous avons obtenu des anticorps specifiques du recepteur de la sp et avons ainsi pu demontrer l'homologie des structures entre les deux recepteurs
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Le, Gall-Ianotto Christelle. "Régulation neuro-endocrine de l'hématopoïèse : rôle de la Substance P et de son dérivé, la Substance P(1-4), dans la régulation négative de l'érythropoïèse dans la polyglobulie de Vaquez." Brest, 2007. http://www.theses.fr/2007BRES3203.
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Il existe une communication bidirectionnelle entre les systèmes nerveux et hématopoïétique, médiée par des mécanismes complexes impliquant la libération de facteurs solubles et la présence de récepteurs spécifiques. La substance P (SP), tachykinine de li acides aminés, est un exemple type de neuropeptide synthétisé et libéré dans la moelle osseuse, capable d’agir sur l’hématopoïèse. Des métabolites comme la SP(l-4), issus de la dégradation de la SP par des peptidases présentes dans la moelle, sont également présents et actifs. Le but de ce travail a été de déterminer l’action de la SP et de la SP(l-4) dans un contexte d’érythropoïèse pathologique comme celle caractérisant la polyglobulie de Vaquez (PV). La PV est un syndrome myéloprolifératif chronique, secondaire à l’expansion clonale de cellules souches, qui peut être mise e évidence in vitro par une pousse spontanée, c’est-à-dire sans addition de facteurs de croissance, des progéniteurs érythroblastiques issus de moelle ou de sang. Les résultats montrent que ces deux molécules sont capables d’inhiber efficacement et à des concentrations physiologiques, la pousse spontanée, en agissant directement sur les progéniteurs érythroïdes par une voie dépendante d’un récepteur de type NK-1R pour la SP, et l’implication d’un autre récepteur couplé à des protéines G (RCPG) pour la SP(l-4). L’expression majoritaire de la forme tronquée du NK-lR sur les progéniteurs érythroïdes de PV suggère le rôle préférentiel de ce récepteur dans l’action de la SP. Ces différences de voies membranaires entre les deux molécules sont sans doute à l’origine de l’action différentielle sur la PKCɛ et sur les mouvements calciques intracellulaires. Pour la SP comme pour la SP( l-4), cette inhibition se traduit par une diminution de la différenciation érythroïde terminale et une augmentation de la mort cellulaire. L’implication du monoxyde d’azote ou NO (« nitric oxide ») dans la transduction du signal inhibiteur de la SP et de la SPU -4) constitue une étape importante dans l’analyse des mécanismes intracellulaires impliqués dans ces deux processus. L’adhésion cellulaire est un processus physiologique indispensable à la survie et à la prolifération des cellules in vitro et in vivo. Nous montrons que l’inhibition exercée par la SP et la SP(l-4) sur les cellules de PV, n’est pas la conséquence d’une rupture de cette adhésion. Outre, cette action in vitro, la SP est présente en quantité plus importante dans le sérum de patients atteints de PV, et n’ est pas corrélée avec la présence de fibrose. Nous pensons que ces données reflètent un mécanisme mis en place par l’organisme pour maintenir l’homéostasie chez ces patients. Ce travail s’inscrit dans l’optique d’identifier les molécules capables d’inhiber la pousse spontanée des progéniteurs érythroïdes de PV et de comprendre les mécanismes impliqués dans cet effet inhibiteur ainsi que ceux impliqués dans la pousse spontanée en généralThe hematopoietic and nervous systems communicate bidirectionally through the release of soluble factors and specific receptors. Substance P (SP), an undecapeptide belonging to the tachykinin family, is an example 0f a neurotransmitter that could be synthetized and released in the bone marrow (BM). SP could act as a hematopoietic modulator and can be further digested by peptidases ubiquitously expressed in BM. SP fragments as SP(1 -4) could exert hematopoietic regulation too. The aim of this study was to determine effect of SP and its derivate, SP( 1-4), on pathologie erythropoiesis. Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by the abnormal proliferation of multipotent hematopoietic progenitor. Endogenous erythroid colonies (EEC) formation is the biological hallmark of the PV. Resuits obtained show that SP and SP(1-4), at physiological concentration, are potent inhibitors of EEC formation by direct action on erythroid progenitors. SP-induced inhibition is mediated by a NK-1R-type dependent mechanism and another G coupled-protein receptor (GPCR) for SP( 1-4) effect. High expression of the truncated form of NK-1 R on PV erythroid progenitor suggests preferential implication in the SP effect, Difference in membranar signaling pathway for SP and SP(l-4) could explain the differential implication of PKCɛ and intracellular calcium rise, However, for both molecules, inhibitory effect is characterized by inhibition of terminal erythroid differentiation and increase cell death. Nitric oxide (NO) implication in signal transduction constitutes an important information to explain these mechanisms. Furthermore, inhibitory effect of SP and SP(1-4) is independent of action on adhesion molecules and rupture of cell adhesion of PV progenitors. In addition to its role in vitro, high concentrations of SP were detected in PV patients sera and was not correlated with fibrosis. We propose that this phenomenon reflect a mechanism induces by the organism to maintain homeostasis in PV patients. This work participates to the identification of new molecules able to inhibit spontaneous growth of PV erythroid progenitor and in the understanding of mechanisms implicated in the EEC formation and inhibition of this phenomenon
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Placenza, Franca M. "The involvement of substance P in relapse to cocaine-seeking behaviour in rats." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58709.pdf.
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Ma, Weiya. "Substance P sensory fiber innervation of CNS target tissues in two experimental models." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40185.
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The aim of this thesis study was to investigate the substance P (SP)-immunoreactive (IR) sensory fiber innervation of CNS target tissues in two experimental models. In the first model, we examined the SP-IR boutons apposed to three functional types of dorsal horn neurons and their morphological interaction with calcitonin gene-related peptide (CGRP) and enkephalin (ENK) in the cat spinal cord, using a combination of intracellular electrophysiological recording and horseradish peroxidase injection with ultrastructural immunocytochemistry. In addition to SP-IR only boutons, we detected boutons co-localizing SP plus CGRP and SP plus ENK immunoreactivities presynaptic to nociceptive neurons. Quantitatively, significantly higher numbers of SP-IR, SP+CGRP-IR and SP+ENK-IR boutons were apposed to nociceptive neurons. Non-nociceptive neurons were rarely innervated by boutons which were SP-IR, SP+CGRP-IR and SP+ENK-IR. In contrast, ENK-IR only boutons innervated non-nociceptive neurons considerably. Boutons co-localizing SP and CGRP were considered as originating from primary sensory afferents. Most nociceptive neurons contained ENK immunoreactivity, but non-nociceptive neurons were never ENK-IR. The interaction of SP and $ gamma$-aminobutyric acid (GABA) in the superficial dorsal horn of the cat and rat spiral cord was also investigated. The co-localization of SP and GABA in axonal terminals was detected for the first time in the superficial layers of the dorsal horn of the cat, but not rat, spinal cord.In the second model, we used immunocytochemistry to study the SP-IR fiber innervation of the white matter of transgenic mice expressing NGF in myelinating oligodendrocytes driven by a MBP promoter. SP-IR fibers were observed in the white matter of the CNS of both transgenic and control mice from postnatal day 0 to day 2. From day 5 on, however, these SP-IR fibers increased markedly to become ectopic fibers in transgenic mice, but decreased dramatically, and finally disappeared, in control mice. The ectopic SP-IR fibers of transgenic mice persisted throughout adulthood. Capsaicin treatment abolished all ectopic SP-IR fibers, indicating their primary sensory origin.
In conclusion, SP-IR fibers specifically innervated nociceptive neurons and co-localized with CGRP, ENK and GABA in the cat dorsal horn. The finding provides anatomical substrates for roles of SP in nociception and for functional interactions of SP with ENK and GABA. Ectopic SP-IR fibers innervated the white matter of the CNS of transgenic mice where NGF was abnormally-produced.
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BENMBAREK, ABDELLAH. "Etude conformationnelle de molecules peptidiques a interet pharmacologique enkephalines, substance p et cholecystokinines." Université Louis Pasteur (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR13037.
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Cette etude presente un large echantillonnage de l'espace conformationnel de trois series de neuropeptides: les tachykinines, les enkephalines et les cholecystokinines. Les methodes utilisees pour cela sont, la dynamique moleculaire a haute temperature et la methode de metropolis. Un algorithme de classification utilisant la matrice de superposition structurale a ete developpe afin d'analyser les echantillons obtenus. Les classes de similitude ont ete associees a certains aspects de l'activite pharmacologique. De nouvelles hypotheses ont ete formulees dans le sens de la comprehension ou de l'amelioration des dites activites biologiques
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Wymore, Troy. "Molecular dynamics simulations of substance P and ACTH peptides in membrane mimetic environments /." free to MU campus, to others for purchase, 1999. http://wwwlib.umi.com/cr/mo/fullcit?p9951137.
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MEHBOOB, RIFFAT MEHBOOB. "EXPRESSION OF SUBSTANCE P IN BRAINSTEMS OF VICTIMS OF SUDDEN UNEXPLAINED PERINATAL DEATH." Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/150185.
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Sudden perinatal death including SIDS is a rare but lethal syndrome and there is no symptom of this disorder until the fatal outcome has occurred. Epidemiological, genetic, molecular and pathological studies conducted so far give us some possible explanations about it but are inadequate to explain it completely. Brainstem etiology is a mostly accepted hypothesis to induce sudden perinatal death. We investigated the immunohistochemical expression of substance P (SP) in the brainstems of 56 subjects aged from 17 gestational weeks to 10 postnatal months, died of unknown (sudden unexplained perinatal deaths and SIDS) and known causes (controls). The goals of this study were to obtain basic information about the expression of the SP during the first phases of human nervous system development; to evaluate whether there are altered manifestations of this neuromodulator in victims of sudden death; to verify the correlation with maternal cigarette smoking and to see the evolutionary aspects of SP gene (TAC1) through computational analysis.
Immunohistochemistry demonstrated SP-immunoreactivity in correspondence of the caudal trigeminal nucleus area, with progressive increase in density of positive fibers of the corresponding tract from fetal life to first postnatal months. So, we first delineated the structure of the human trigeminal nucleus, so far little investigated, and provided essential data on its morphologic and functional development. Nevertheless, a negativity or low SP-positivity of the tract fibres was detectable in a wide subset of SIDS and, conversely, high SP-expression in a wide subset of sudden fetal deaths. Therefore we postulate, on the basis of these results, the functional importance of the SP in the early phases of central nervous system development and in the regulation of autonomic functions.
Besides, the observation of a significant correlation between sudden unexplained death, altered SP staining and maternal smoking, prompted us to suppose a close relation between smoking absorption in utero and decrease of the functional activity of the trigeminal nucleus, leading to sudden death during pregnancy and in the first months of life. Computational analysis suggests that SP encoding gene (TAC1) is a singleton, appeared in vertebrates and is more prone to induce neuropathologies along with its interactors, if mutated or functionally altered, as it is located mostly in brain.
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Murris-Espin, Marlène. "Interactions macrophages alveolaires - substance p dans les voies aeriennes : revue de la litterature ; approche experimentale." Toulouse 3, 1992. http://www.theses.fr/1992TOU31545.
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Philippe, Lionel. "Rôle de la substance P dans la régulation de l'anabolisme du cartilage : application aux antagonistes du recepteur NK1." Nancy 1, 1998. http://www.theses.fr/1998NAN10360.
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Wong, Brett James. "Histamine receptors and substance P in cutaneous active vasodilation and thermal hyperemia in humans." view abstract or download file of text, 2005. http://www.oregonpdf.org.
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Thesis (Ph. D.)--University of Oregon, 2005.Includes bibliographical references (leaves 195-207). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.
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Yu, Long-Chuan. "Role of calcitonin gene-related peptide in nociception : interactions with substance P and opioids /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2853-3.
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Macdonald, Susan G. "G Protein Interactions with the Substance P Receptor in Rat Submaxillary Gland: a Dissertation." eScholarship@UMMS, 1991. http://escholarship.umassmed.edu/gsbs_diss/268.
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Substance P (SP) is an undecapeptide whose functions are as varied as its locations. In the nervous system, it is thought to act as a neurotransmitter. In the peripheral vasculature, it has hypotensive effects and it causes contraction in the smooth muscle of the gut. In salivary gland, it is a potent secretagogue and it is how this effect is transduced that is the subject of this dissertation. Activation of the SP receptor in rat submaxillary gland by SP results in the hydrolysis of inositol phospholipids and the mobilization of intracellular Ca2+. These second messengers are then able to activate a pathway(s) which results in the secretion of electrolytes, water and macromolecules. The production of these second messengers, however, is thought to require the participation of a guanine nucleotide binding protein (G protein). The G protein that couples to the SP receptor (Gp), has not yet been identified. Although several investigators have recently reported the purification of G protein α subunits that are capable of activating phospholipase C, it is not known if they couple to receptors in order to activate phospholipase C. In an effort to learn more about the mechanisms of signal transduction by SP in salivary gland, the interactions of the SP receptor with G proteins were studied.
In the first study, the question of whether the SP receptor functionally couples to a G protein was investigated. Alkaline treatment was used to deplete membranes containing SP receptors of endogenous G proteins. These membranes were not capable of binding SP with high affinity. High affinity binding capability was restored in those membranes, however, by reconstituting them with exogenous G proteins. Thus, it was concluded that that SP receptor agonist affinity is regulated by a G protein. It was also determined that the G proteins (a Go/Gi mixture) used to reconstitute the membranes may not be those that couple to the SP receptor in vivo, since the reconstituted Go/Gi mixture was inactivated by treatment with pertussis toxin, while Gp was not.
The next study was undertaken in an effort to identify other G proteins that are able to interact with the SP receptor. G proteins were chromatographically purified from horse submaxillary gland membranes, and assayed for characteristics that could identify one or more G proteins as potential physiological couplers to the SP receptor. G proteins were identified in fractions by the ability to bind [35S]GTPγS. These GTP-binding proteins were further characterized by testing their susceptibility to ADP- ribosylation catalyzed by pertussis toxin and their ability to restore high affinity agonist binding in membranes containing the SP receptor, but no endogenous G proteins. In addition to identifying G proteins that are substrates for pertussis toxin-catalyzed ADP-ribosylation (e.g. Go and/or Gi), a GTP-binding protein was identified which possesses characteristics that are unlike those of the well-known G proteins, Go, Gi and Gs. This protein elutes from anion exchange resins at a high salt concentration, is not susceptible to ADP- ribosylation catalyzed by pertussis toxin, is able to reconstitute high affinity binding in G protein depleted rat submaxillary gland membranes and is not recognized by antibodies to Go, Gi, Gs or Gz.
Finally, a direct characterization of the G protein coupled to the SP receptor in rat submaxillary gland was undertaken. Using photo-affinity labelling techniques in conjunction with chemical crosslinking techniques, a covalent 96 kDa SP receptor complex was identified. The generation of this 96 kDa complex was inhibited by a nonhydrolyzable analog of GTP, but not a nonhydrolyzable analog of ATP. Furthermore, the complex could not be produced in membranes that had been depleted of G proteins by alkaline treatment. Reversal of the chemical crosslink yielded only the 53 kDa SP receptor, showing that the protein crosslinking to the SP receptor possesses a molecular weight of about 43 kDa. This molecular weight is typical of G protein α subunits. It was concluded that the 96 kDa crosslinked receptor complex consisted of the SP receptor, the radioiodinated SP derivative and the α subunit of Gp.
The studies show that the SP receptor may be coupled to a novel G protein, whose purification characteristics differ from those of the known G proteins. Although Gp has yet to be identified, comparisons of the results of these investigations with those of several recent articles in which the purification of G protein α subunits that are capable of stimulating phospholipase C is reported, suggests that Gp is similar, if not identical to those proteins. Furthermore, this dissertation describes a unique reconstitution system and crosslinking techniques which should prove useful in the identification of Gp, as well as in the study of other receptor-G protein interactions and perhaps, the reconstitution of the receptor-G protein-phospholipase C signal transduction pathway.
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Michalek, R. "Mechanism of potentiation in substance P-stimulated amylase secretion in isolated rat parotid slices." Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233214.
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Liu, Xinhuai. "Effets de la substance p et du glutamate au niveau du complexe vagal dorsal." Aix-Marseille 2, 1998. http://www.theses.fr/1998AIX22041.
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Le complexe vagal dorsal est un centre majeur d'integration du systeme nerveux vegetatif. La substance p, qui est tres representee dans cette structure vagale, est connue pour son role modulateur de nombreuses fonctions de l'organisme. Le glutamate intervient egalement dans cette region comme neurotransmetteur principal dans plusieurs reflexes visceraux. Nous avons etudie les effets modulateurs de la substance p par deux approches experimentales : dans la premiere, les effets centraux de la substance p sur des parametres cardio-vasculaires sont etudies in situ chez le lapin ; dans la deuxieme, les actions de la substance p et du glutamate sont etudiees a l'aide de techniques electrophysiologiques sur une preparation in vitro de neurones vagaux de rat. Cette these comprend quatre parties : rappels bibliographiques sur le glutamate et la substance p, resultats, discussion generale et conclusion, et bibliographie. La premiere partie des resultats montre que la substance p, injectee dans le iv#e#m#e ventricule, supprime instantanement les dysrythmies cardiaques et retablit un rythme cardiaque normal et regulier, cet effet est bloque par un antagoniste des recepteurs nk1 (sr 14033). La stimulation des fibres baroceptives des nerfs aortiques a le meme effet que la substance p. Ces resultats indiquent que la sp regularise le rythme cardiaque en agissant sur la voie du reflexe baroceptif au niveau central. Plus precisement, la sp pourrait activer selectivement les neurones dromotropes du noyau dorsal du nerf vague. La deuxieme partie des resultats, obtenus sur des tranches de bulbe rachidien, montre que tous les neurones preganglionnaires vagaux ont des recepteurs nmda et non-nmda. Les recepteurs nk1, nmda et non-nmda coexistent sur environ 30% des neurones. Les recepteurs nk1 et nmda interagissent entre eux : la sp augmente l'activite du recepteur nmda via l'activation des recepteurs nk1. Ces resultats sont des arguments supplementaires pour appuyer l'hypothese, discutee a la fin de la these, qui attribue a la sp un role dans la regulation homeostasique de grandes fonctions physiologiques.
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Karlsson, Krister. "Substance P endopeptidase : purification and characterization of enzyme activity and evaluation of its function during stressful condition /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4130.
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Frick, Andreas. "Imaging Anxiety : Neurochemistry in Anxiety Disorders Assessed by Positron Emission Tomography." Doctoral thesis, Uppsala universitet, Institutionen för psykologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-261983.
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Anxiety disorders, including social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD) are common and disabling conditions. Largely based on animal and pharmacological studies, both the serotonergic and substance P/neurokinin-1 (SP/NK1) systems have been implicated in their underlying pathology. However, only few neuroimaging studies have directly assessed these neurotransmitter systems in human sufferers of anxiety disorders, and none have addressed possible between-systems relationships. The overall aim of this thesis was to study possible neurochemical alterations associated with anxiety disorders. To this end, three studies using positron emission tomography (PET) for in-vivo imaging of the brain serotonergic and SP/NK1 systems in patients with SAD and PTSD were conducted. The radiotracers [11C]5-HTP, [11C]DASB, and [11C]GR205171 were used to index serotonin synthesis rate, serotonin transporter (SERT) availability, and NK1 receptor availability respectively. In Study I, patients with SAD relative to controls exhibited enhanced serotonin synthesis rate and serotonin transporter availability. Serotonin synthesis rate in the amygdala was positively related to social anxiety symptom scores. Study II demonstrated increased NK1 receptor availability in the amygdala in patients with SAD relative to controls. In Study III, patients with PTSD showed elevated NK1 receptor availability in the amygdala as compared to controls. SERT availability in the amygdala was negatively related to PTSD symptom severity, a relationship that was moderated by NK1 receptor levels. The regional overlap between SERT and NK1 receptor expression was altered in patients with PTSD, with reduced overlap linked to more severe symptoms. Collectively, the findings are consistent with the view that serotonin in the amygdala induces rather than reduces anxiety and links exaggerated anxiety to an overactive presynaptic serotonin system. In addition, the involvement of the SP/NK1 system in stress and anxiety, as suggested by animal studies, was demonstrated in two common human anxiety disorders. Finally, PTSD symptomatology is better accounted for by interactions between the serotonergic and SP/NK1 systems in the amygdala than by each system separately. In conclusion, this thesis supports that both the serotonergic and SP/NK1 systems in and of themselves, but also interactively, may be important contributors to anxiety symptomatology.
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André, Judith. "Etude des relations entre pathologies anxio-dépressives et douleurs : implication des systèmes substancépergiques et cholécystokininergiques." Paris 5, 2006. http://www.theses.fr/2006PA05P633.
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Afin d’étudier les interactions entre les troubles anxio-dépressifs et la douleur, nous avons élaboré un test comportemental associant, chez le rat, un stress social et un test nociceptif. Parallèlement, nous mesurons, par la technique de microdialyse, la libération spontanée de Substance P (SP) et de Cholecystokinine (CCK), deux peptides impliqués dans la dépression et la douleur. Nous avons observé une hyperalgésie induite par l’état « anxio-dépressif », insensible à la morphine mais réversée par les anxiolytiques. Cet « excès » de douleur s’accompagne d’une diminution de la libération de SP dans la Substance Grise Périaqueducale et d’une augmentation de CCK dans le cortex frontal, toutes deux prévenues par un traitement avec la morphine ou les benzodiazépines. L’association de la morphine et d’un antagoniste des récepteurs du CCK pourrait représenter une nouvelle approche thérapeutique pour réduire l’excès de douleur observé chez les patients dépressifsTo investigate in rats the consequences of an experimentally provoked state of anxiety/depression on pain behavior and on its underlying mechanisms, we used a model of social defeat associated to a formalin test. Rats showed an enhanced nociceptive behavior prevented by anxiolytic, suggested that this experimental procedure might be a suitable animal model of “anxiety-induced hyperalgesia”. Hyperalgesia was associated to a decrease of Substance P in Periaqueducal Gray matter (PAG) and a decrease of Cholecystokinin (CCK) in frontal cortex. These effects were not prevented by morphine but by anxiolytic treatments strongly supporting anxiolytic part of pain. Finally, combined treatments completely suppressed pain related behavior, supporting the idea that association of both compounds might represent new therapeutic approach to reduce the increase of pain complaints highly prevalent among anxious or depressive patients
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Hasenbein, Simone [Verfasser], Jürgen P. [Akademischer Betreuer] Geist, and Richard E. [Akademischer Betreuer] Connon. "Mixture toxicity - single-substance testing to ecosystem effect assessment / Simone Hasenbein. Gutachter: Jürgen P. Geist ; Richard E. Connon. Betreuer: Jürgen P. Geist." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1076125026/34.
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Svensson, Erik. "Modulatory effects and interactions of substance P, dopamine, and 5-HT in a neuronal network /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-524-7/.
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Jonsson, Anna. "The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain." Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-241637.
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There is an unmet medical need for the efficient treatment of neuropathic pain, a condition that affects approximately 10% of the population worldwide. Current therapies need to be improved due to the associated side effects and lack of response in many patients. Moreover, neuropathic pain causes great suffering to patients and puts an economical burden on society. The work presented in this thesis addresses SP1-7, (Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), a major metabolite of the pronociceptive neuropeptide Substance P (SP). SP is released in the spinal cord following a noxious stimulus and binds to the NK1 receptor. In contrast to SP, the degradation fragment SP1-7 is antinociceptive through binding to specific binding sites distinct from the NK1 receptor. The aim of this thesis was to investigate the impact of SP1-7 on neuropathic pain. To understand how SP1-7 exerts its effect, a series of N-truncated forms of the heptapeptide were biologically evaluated. A set of small high-affinity ligands was evaluated in animal models of neuropathic pain. To confirm a clinical relevance the levels of SP1-7 in human neuropathic pain were assessed incerebrospinal fluid (CSF) collected from neuropathic pain patients. The results showed that SP1-7 could alleviate thermal as well as mechanical hypersensitivity in three different animal models of neuropathic pain. C-terminal amidation was connected with increased efficacy. N-terminal truncation of SP1-7 indicated a necessity of five amino acids in order to retain biological effect. One small high-affinity ligand showed a significant anti-allodynic effect. CSF levels of SP1-7 in neuropathic pain patients were lower compared to controls. Taken together, these findings demonstrate that the formation of SP1-7 may be attenuated in neuropathic pain. C-terminal amidation and a majority of its amino acids are necessary for stability and permeability. Clearly, SP1-7 and SP1-7 mimetics with high affinity to the SP1-7 binding site ameliorate neuropathic pain-like behaviors in animal models of neuropathic pain. Overall, the findings presented in this thesis contribute to new knowledge regarding the role of SP1-7 and related analogues and fragments in neuropathic pain. In a future perspective, this could be essential for the development of efficient strategies for managing patients with neuropathic pain.
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Girault, Sophie. "Etude par photomarquage de l'interaction de la substance p avec le recepteur nk-1 humain." Paris 6, 1996. http://www.theses.fr/1996PA066163.
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L'acide amine la p-benzoyl-l-phenylalanine, (p-bz)phe, a ete incorporee dans la substance p (sp), arg-pro-lys-pro-gln-gln-phe-gly-leu-met-nh2 pour localiser son domaine de liaison dans le recepteur neurokinine-1 (nk-1) humain, surexprime dans une lignee cellulaire de mammiferes transfectee. L'agoniste specifique du recepteur nk-1, la pro9sp, a ete modifie en position 8 par (p-bz)phe et acyle a l'extremite n-terminale par une molecule de biotine sulfone via un bras 5-aminopentanoyl. Apres irradiation et fragmentation du recepteur lie covalemment au peptide biotinyle, le groupe biotine sulfone permet d'extraire les fragments biotinyles du milieu complexe d'incubation par des billes magnetiques de streptavidine. Une elution directe des billes par la matrice utilisee en spectrometrie de masse (desorption-ionisation par laser assistee par matrice, ou maldi-tof ms) et une analyse maldi permet l'identification des fragments du recepteur nk-1 marque. Une digestion par la trypsine combinee a une digestion par l'endoproteinase glu-c a etabli que le site d'attachement covalent de la sp photoactivable se trouvait dans la deuxieme boucle extracellulaire, thr173-arg177. Une fragmentation au bromure de cyanogene a montre que la sonde etait liee covalemment au groupe methyl d'un residu methionine. Ainsi, ces experiences ont montre que la methionine 174 etait le residu modifie