Thesis (M.S.)--University of Wyoming, 2009. / Title from PDF title page (viewed on July 22, 2010). Includes bibliographical references (p. 74-91).

Capsaicin (1.3 mumol/kg, i.v.) and resiniferatoxin (48 nmol/kg, i.v.) failed to induce plasma extravasation in Suncus murinus (P>0.05). But SP (20 nmol/kg, i.v.) was able to induce salivation, and plasma extravasation in the bladder and the trachea significantly (P<0.05). NK1 receptor antagonists CP-99,994, R116301 (ID50 = 1.2 mumol/kg), and R115614 (ID50 = 1.8 mumol/kg) significantly reduced plasma leakage in the bladder (P<0.05), but not the trachea (P>0.05). R116301 (ID50 = 0.7 mumol/kg) and R115614 (ID50 = 1.2 mumol/kg) were able to inhibit the salivation response significantly (P<0.05). / R116301 and R115614 significantly reduced emesis induced by resiniferatoxin, motion, copper sulphate, and cisplatin (P<0.05), in the dose range between 23-70 mumol/kg, s.c. Both antagonists (100-300 nmol, i.c.v.) were also able to reduce cisplatin-induced emesis significantly (P<0.05), but only R116301 (10-300 nmol, i.c.v.) was able to significantly inhibit emesis induced by nicotine and copper sulphate (P<0.05). / The development of tachyldnin NK1 receptor antagonist aprepitant as an effective anti-emetic drug illustrates the importance of NK1 receptors in the emetic reflex. However, the exact anti-emetic mechanism of action is still unknown. The primary aim of the study was to investigate the relative contribution of centrally versus peripherally located NK1 receptors in the emetic reflex in Suncus murinus. The study also investigated the potential contribution of NK2 and NK3 receptors in emesis control. / The present studies demonstrated that R116301 and R115614 exhibited anti-emetic properties against various drugs, motion, and tachykinin receptor agonists. The studies also imply the existence of the classical SP subsite and the septide subsite of the NK1 receptors that are involved in the emetic reflex of Suncus murinus, which suggests that NK1 receptor antagonists that can block both subsites could become effective anti-emetic drugs. The present studies also demonstrated that both NK2 and NK3 receptors maybe involved in emesis control. It is possible that dual NK1/NK2 receptor antagonists or triple NK 1/NK2/NK3 receptor antagonists may have clinical potential as anti-emetic drugs besides the clinically used NK1 receptor antagonists. / The rank order of potency (based on pEC50 values) of tachykinin receptor agonists to contract Suncus murinus ileum was as follow: [Sar9Met(O2)11] substance P (SP) (8.1) > septide (7.9) (both NK1 receptor agonists) > neurokinin A (NKA) (7.7) > SP (7.6) > GR 64349 (NK2 receptor agonist) (7.0). For the NK1 receptor antagonists, the rank order of potency (based on pKB/pA2 values) to inhibit ileal contraction was: R116301 (7.8-8.2) ≈ R115614 (7.7-8.3) > CP-99,994 (6.4-7.3) against various NK1 receptor agonists. Furthermore, NK2 receptor antagonist saredutant (pA2 = 7.3) competitively antagonised GR 64349-induced ileal contraction. / When injected intracerebroventricularly, SP (100 nmol), septide, [Sar 9Met(O2)11] SP, NKA (all at 30 nmol), GR 64349 (10 and 30 nmol), and senktide (NK3 receptor agonist) (3-30 nmol) significantly induced emesis in Suncus murinus (P<0.05). They were also effective in inducing locomotor hyperactivity, ano-genital grooming, circling, face washing, hindlimb licking, scratching, and straub tail (3-30 nmol, P<0.05). R116301 and R115614 (both at 3 and 10 mumol/kg, s.c.) significantly antagonised some of the actions of the agonists including emesis, locomotor hyperactivity, ano-genital grooming, licking, scratching, and straub tail (P<0.05). Saredutant and NK3 receptor antagonist osanetant (both at 30 mumol/kg, s.c.) attenuated emesis induced by GR 64349 and senktide respectively (P<0.05). Saredutant (30 mumol/kg, s.c.) was also able to inhibit GR 64349-induced face washing and scratching, while osanetant (30 mumol/kg, s.c.) also significantly attenuated senktide-induced straub tail (P<0.05). / Cheng, Ho Man Frankie. / "September 2007." / Adviser: John A. Rudd. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4691. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 194-223). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Thesis (Ph. D.)--University of Sydney, 2007. / Title from title screen (viewed 1 November 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Physiology, Faculty of Medicine. Degree awarded 2007 ; thesis submitted 2006. Bibliography: leaves 239-284. Also issued in print.

Thesis (Ph.D.)--University of Wyoming, 2008. / Title from PDF title page (viewed on June 24, 2009). Includes bibliographical references (p. 158-174).

Thesis (Ph.D.)--University of Delaware, 2007. / Principal faculty advisor: Anne Skaja Robinson, Dept. of Chemical Engineering. Includes bibliographical references.

Thesis (MSc)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: Hypertensive conditions of pregnancy, such as pre-eclampsia, are the principal direct cause of maternal morbidity and mortality and affect up to 10% of first pregnancies worldwide. The placenta is vital in the pathogenesis of pre-eclampsia since the condition only occurs in the presence of placental tissue and the only cure is delivery of the placenta and the fetus. It has been hypothesised that the placenta may be the source of a circulating factor(s), which transports freely in the maternal system, resulting in the multi-systemic and immunological responses that are characteristic of pre-eclampsia. Among the potential "circulating" candidates currently being investigated worldwide, is the tachykinin member, neurokinin B (NKB). The aim of this project was to use a novel approach and investigate the role of Neurokinin B in pre-eclampsia on a genetic level. This would be achieved by bioinformatie characterisation of the neurokinin B (TAC3) and neurokinin B receptor (TACR3) genes. Samples from thirty pre-eclampsia patients (of whom 10 also had abruptio placentae) and twenty control individuals were used for mutation detection analysis involving Multiphor gel electrophoresis and automated sequencing. Three sequence variants were identified in the TAC3 gene and include: (i) 5' UTR variant (-25 c-t); (ii) intronic variant IVS3-53 (t-g) and (iii) 3' UTR variant exon 7 (479, t-c). Only the -25 c-t variant had been reported before (SNP database). A further two variants were identified in the TACR3 gene: (i) exon 3 variant (nt 857, a-t) and (ii) 3' UTR variant, amplicon 5b (nt 1471, t-c), of which the latter had previously been reported in the SNP database. In the analysis of allele and genotype frequencies, only variant homozygosity for TAC3 -25 c-t could be associated with increased risk of pre-eclampsia (RR 3.33, p=0.03). Follow-up work will include extended genotyping in further stratified and larger patient cohorts and transfection studies to assess splicing potential and functional consequences of the mutant alleles. These data represent the first documented mutation screen of the TAC3 and TACR3 genes and report novel variants in patients with pre-eclampsia. This study contributes to the knowledge of neurokinin B as a circulatory molecule and confirms the heterogeneity of pre-eclampsia. / AFRIKAANSE OPSOMMING: Die belangrikste direkte oorsaak van moedersterftes is hipertensiewe toestande in swangerskap, insluitende pre-eklampsie. Hierdie toestande kompliseer wêreldwyd 10% van alle swangerskappe. Die plasenta is kardinaal in die ontwikkeling van die siekte aangesien dit slegs voorkom terwyl die plasenta in-situ is en die simptome opklaar na verlossing van die plasenta. 'n Moontlike hipotese is dat die plasenta 'n sirkulerende agens afskei wat in die moederlike sisteem beland en die uiteenlopende multi-sistemiese simptome en tekens van die siekte veroorsaak, asook aktivering van die immuunsisteem. Een van die moontlike kandidate wat tans wêreldwyd ondersoek word as moontlike sirkulerende agens, is Neurokinien B (NKB), 'n lid van die Tachikinien familie. Die unieke benadering van hierdie projek was om die rol van Neurokinien B in pre-eklampsie te ondersoek op 'n genetiese grondslag. Dit is bereik deur bio-informatiewe karakterisering van die neurokinien B (TAC3) en neurokinien B reseptor (TACR3) en deur mutasie sifting op DNA monsters van 30 pasiënte met pre-eklampsie (waarvan 10 ook abruptio placentae gehad het) en twintig kontrole individue met behulp van Multiphor gel elektroforese en ge-outomatiseerde volgorde bepaling. Drie volgorde variasies is geïdentifiseer in die TAC3 geen en sluit in: (i) 5' UTR variant (-25 c-t); (ii) introniese variant IVS3-53 (t-g) en (iii) 3' UTR variant in ekson 7 (479, t-e). Slegs die -25 c-t variasie is voorheen raporteer (SNP databasis). Nog twee variante is ook gevind in die TACR3 geen: (i) ekson 3 variant (nt 857, a-t) en (ii) 3' UTR variant, amplikon 5b (nt 1471, t-e); hierdie laaste een is al in die SNP databasis raporteer. In 'n analise van genotipe en allele frekwensies is slegs homosigositeit vir variant TAC3 -25 c-t geassosieër met 'n verhoogde risiko vir preeklampsie (RR 3.33, p=0.03). Verdere werk sal nou fokus op die genotipering van groter en gestratifiseerde pasiënt kohorte en transfeksie studies om splitsing potensiaal en funksionele gevolge van mutante allele te ondersoek. Hierdie data is die eerste gedokumenteerde mutasie sifting van die TAC3 en TACR3 gene en verslag word gelewer van unieke variasies in pasiënte met pre-eklampsie.

Eight cyclic analogues of Substance P were made in order to investigate the conformation of the C-terminal end of the peptide. These analogues were designed to test three literature models describing the active conformation of substance P. Although the potencies of the analogues were low (in the micromolar range), our results support Cotrait's and Hospital's model (1986). Several substance P antagonists were synthesized. These compounds did not demonstrate agonistic activity nor anatagonistic activity. The tryptophan side chain is contributing to the antagonistic activity of these analogues, and not just the chirality of the α-carbon. Highly potent and selective photoaffinity ligands of H-Tyr-D-Pen-Gly-Phe-D-Pen-OH (DPDPE) and D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH₂ (CTP) were synthesized. These compounds will be useful in the isolation of δ and μ opioid receptors. Several new amino acids designed and synthesized to contain both the natural amino acid side chain and a thiol group which can be used to make disulfide constraints. The racemic amino acids made were as follows: (1) 2-amino-4-methyl-2- [(p-methylbenzyl)thiomethyl] pentanoic acid; (2) 2-amino-2- [(p-methylbenzyl)thiomethyl] -3-phenylpropanoic acid; (3) 2-amino-e- [(p-methylbenzyl)thio] pentanoic acid; and (4) 2-amino-3- [(p-methylbenzyl)-thio] -3-phenyl-pentanoic acid. These amino acids will be useful in the conformational restriction of peptides. To investigate the δ-opioid receptor conformation proposed for DPDPE by Hruby et al. (1988) and the μ-opioid receptor conformation proposed for Tyr-c [Abu₂,Gly,Phe,Leu] by Mierke et al. (1988), constrained phenylalanine amino acids were incorporated into H-Try-D-Pen-Gly-Phe-D-Pen-OH (DPDPE) in the four position. Our results indicate that these models are correct. And in an investigation into the physical-chemical properties of the delta opioid receptor, our results suggest that the δ receptor topochemical site for the Phe⁴ residue contains a partial positive charge on its surface and has specific steric requirements.

Copies of author's previously published articles inserted. / Amendments (2 leaves) in front cover pocket. / Bibliography: leaves 227-259. / xiii, 259 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the contribution of tachykinins, in particular Substance P (SP), to the processes of inflammation. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1993

Goals of this study were to identify and characterize effects of neurokinin A (NKA) in isolated guinea pig hearts. Bradycardia, augmentation of ventricular contractions, and reduction of perfusion pressure were prominent responses to bolus injections of NKA (0.25-25 nmol). NKA was more potent than substance P (SP) in causing bradycardia but did not differ in potency for lowering perfusion pressure. Doses of SP of 25 nmol or less decreased ventricular force, whereas 100 nmol caused a biphasic response. The percent decrease in heart rate produced by 25 nmol NKA was reduced from 58.0 ± 4.8 to 39.6 ± 3.5% in the presence of μM atropine (n = 5). The positive inotropic response to 25 nmol of NKA in spontaneously beating hearts was replaced by a negative inotropic response during pacing (22.5 ± 3.3% increase vs. 11.7 ± 1.7% decrease, n = 5). Reserpine pretreatment did not affect the positive inotropic response to NKA. Specific binding sites for (125)I-labeled NKA were localized to intracardiac ganglia and coronary arteries but not to myocardium. It was concluded that 1) negative chronotropic responses to NKA involve cholinergic and noncholinergic mechanisms, and 2) the positive inotropic response is an indirect action.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.