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.

Lau Hoi Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 134-157). / Abstracts in English and Chinese. / PUBLICATIONS BASED ON WORK IN THIS THESIS --- p.I / ABSTRACT --- p.II / ACKNOWLEDGEMENTS --- p.VI / TABLE OF CONTENTS --- p.VIII / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- General Introduction --- p.1 / Chapter 1.2 --- Emesis --- p.3 / Chapter 1.2.1 --- Introduction --- p.3 / Chapter 1.2.2 --- Retching & Vomiting --- p.3 / Chapter 1.2.3 --- Nausea --- p.4 / Chapter 1.2.4 --- Motor Components of Emetic Reflex --- p.5 / Chapter 1.2.4.1 --- Pre-ejection Phase --- p.5 / Chapter 1.2.4.2 --- Ejection Phase --- p.5 / Chapter 1.2.4.3 --- Post-ejection Phase --- p.6 / Chapter 1.2.5 --- Components of Emetic Reflex --- p.6 / Chapter 1.2.5.1 --- Area Postrema (AP) --- p.6 / Chapter 1.2.5.2 --- Nucleus Tractus Solitarius (NTS) --- p.7 / Chapter 1.2.5.3 --- Vomiting Centre --- p.8 / Chapter 1.2.5.4 --- Vestibular System --- p.10 / Chapter 1.2.5.5 --- Abdominal Visceral Afferents --- p.10 / Chapter 1.2.5.6 --- Forebrain --- p.11 / Chapter 1.2.6 --- Neurotransmitters & Receptors --- p.12 / Chapter 1.2.7 --- Anti-emetics --- p.13 / Chapter 1.3 --- Models of Nausea --- p.16 / Chapter 1.3.1 --- Introduction --- p.16 / Chapter 1.3.2 --- Conditioned Taste Aversion --- p.18 / Chapter 1.3.3 --- Pica Behaviour --- p.20 / Chapter 1.3.4 --- Studies of the Involvement of Vasopressin --- p.21 / Chapter 1.3.5 --- Tachygastria --- p.24 / Chapter 1.3.6 --- Locomotor Activity --- p.26 / Chapter 1.4 --- Markers of Neuronal Activity --- p.27 / Chapter 1.4.1 --- General Comments --- p.27 / Chapter 1.4.2 --- c-fos Expression as a Marker of Neuronal Activity --- p.28 / Chapter 1.4.2.1 --- What is c-fos? --- p.28 / Chapter 1.4.2.2 --- Regulation of c-fos Expression --- p.30 / Chapter 1.4.2.2.1 --- Calcium Response Element --- p.31 / Chapter 1.4.2.2.2 --- Serum Response Element --- p.32 / Chapter 1.4.2.3 --- Types of Receptors Involved in c-fos Expression --- p.32 / Chapter 1.4.2.4 --- Feasibility of Using c-fos Expression as Marker of Cellular Activity --- p.36 / Chapter 1.4.2.5 --- Identification of Emetic Pathway by c-fos Immunohistochemistry --- p.36 / Chapter 1.5 --- Aims & Objectives --- p.37 / Chapter CHAPTER 2 --- METHODS --- p.42 / Chapter 2.1 --- Animals --- p.42 / Chapter 2.1.1 --- Ferrets --- p.42 / Chapter 2.1.2 --- Suncus murinus --- p.42 / Chapter 2.2 --- Measurement of Animal Behaviour --- p.43 / Chapter 2.2.1 --- Experiment Design --- p.43 / Chapter 2.2.2 --- Recording of Animal Behaviour --- p.43 / Chapter 2.2.3 --- Calibration of Equipment Used to Record Spontaneous Locomotor Activity --- p.44 / Chapter 2.2.4 --- Behaviour Recorded by the Observer --- p.45 / Chapter 2.3 --- Administration of Drugs --- p.46 / Chapter 2.3.1 --- Ferrets --- p.46 / Chapter 2.3.1.1 --- General Comments --- p.46 / Chapter 2.3.1.2 --- Drug Antagonism Studies --- p.47 / Chapter 2.3.2 --- Suncus murinus --- p.47 / Chapter 2.3.2.1 --- General Comments --- p.47 / Chapter 2.3.2.2 --- Dose-Response Studies --- p.48 / Chapter 2.3.2.3 --- Drug Antagonism Studies --- p.48 / Chapter 2.4 --- c-fos Expression Studies in Ferret Brainstems --- p.50 / Chapter 2.4.1 --- Animals and Anaesthesia --- p.50 / Chapter 2.4.2 --- Perfusion and fixation --- p.50 / Chapter 2.4.3 --- Dehydration of brains --- p.51 / Chapter 2.4.4 --- Embedding of tissue --- p.52 / Chapter 2.4.5 --- Sectioning --- p.52 / Chapter 2.4.6 --- Staining --- p.52 / Chapter 2.4.7 --- Antibodies used --- p.55 / Chapter 2.4.8 --- Positive Control Slides --- p.55 / Chapter 2.5 --- Experimental Design and Statistics --- p.56 / Chapter 2.5.1 --- Randomization of Treatments --- p.56 / Chapter 2.5.2 --- Statistics --- p.57 / Chapter 2.5.2.1 --- Ferrets --- p.57 / Chapter 2.5.2.2 --- Suncus murinus --- p.59 / Chapter 2.6 --- Drugs and Chemicals Used --- p.60 / Chapter 2.6.1 --- Drugs Used --- p.60 / Chapter 2.6.2 --- Chemicals Used --- p.62 / Chapter CHAPTER 3 --- RESULTS --- p.63 / Chapter 3.1 --- Ferret --- p.63 / Chapter 3.1.1 --- "The Effect of Ondansetron and CP-99,994 on Emesis and Locomotor Activity Changes Induced by Cisplatin in the Ferret" --- p.63 / Chapter 3.1.2 --- The Effect of Domperidone on Emesis and Locomotor Activity Changes Induced by Apomorphine in the Ferret --- p.69 / Chapter 3.1.3 --- "The Effect of CP-99,994 on Emesis and Locomotor Activity Changes Induced by Apomorphine in the Ferret" --- p.74 / Chapter 3.1.4 --- c-fos Expression Studies in Ferret Brainstems --- p.79 / Chapter 3.1.4.1 --- Cisplatin-treated Ferrets --- p.79 / Chapter 3.1.4.2 --- Positive Control Slides --- p.84 / Chapter 3.2 --- Suncus murinus --- p.88 / Chapter 3.2.1 --- The Emetic Potential of Nicotine and its Effects on the Spontaneous Locomotor Activity of Suncus murinus --- p.88 / Chapter 3.2.2 --- "The Effect of CP-99,994 on Emesis and Locomotor Activity Changes Induced by Nicotine in Suncus murinus" --- p.92 / Chapter 3.2.3 --- The Emetic Potential of Copper Sulphate and its Effects on the Spontaneous Locomotor Activity of Suncus murinus --- p.95 / Chapter 3.2.4 --- "The Effect of CP-99,994 on Emesis and Locomotor Activity Changes Induced by Copper Sulphate in Suncus murinus" --- p.98 / Chapter 3.2.5 --- The Emetic Potential of Cisplatin and its Effects on the Spontaneous Locomotor Activity of Suncus murinus --- p.101 / Chapter 3.2.6 --- The Effect of Ondansetron on Emesis and Locomotor Activity Changes Induced by Cisplatin in Suncus murinus --- p.104 / Chapter 3.2.7 --- "The Effect of CP-99,994 on Emesis and Locomotor Activity Changes Induced by Cisplatin in Suncus murinus" --- p.107 / Chapter 3.2.8 --- "The Effects of Ondansetron and CP-99,994 on Locomotor Activity in Suncus murinus" --- p.110 / Chapter CHAPTER 4 --- DISCUSSION --- p.113 / Chapter CHAPTER 5 --- GENERAL SUMMARY --- p.130 / REFERENCES --- p.134

Wong Hei Lui. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 192-226). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.vii / Abbreviations --- p.viii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Normal joint --- p.1 / Chapter 1.11 --- Biology of joint --- p.1 / Chapter 1.12 --- Structure of synovial joint --- p.1 / Chapter 1.13 --- Components of the mature synovial joint --- p.3 / Chapter 1.131 --- Articular cartilage --- p.3 / Chapter 1.1311 --- Water --- p.4 / Chapter 1.1312 --- Cartilage matrix --- p.4 / Chapter 1.1313 --- Chondrocyte --- p.5 / Chapter 1.132 --- Synovium --- p.5 / Chapter 1.1321 --- Synovium vasculature --- p.6 / Chapter 1.1322 --- Synovial blood flow --- p.7 / Chapter 1.133 --- Synovial fluid --- p.8 / Chapter 1.134 --- Bone --- p.9 / Chapter 1.2 --- Pathological processes of arthritis --- p.11 / Chapter 1.21 --- Activation of immune cells in arthritis --- p.11 / Chapter 1.22 --- Synovial proliferation --- p.13 / Chapter 1.221 --- Synovial lining cell activation --- p.13 / Chapter 1.222 --- Pannus invasion --- p.14 / Chapter 1.23 --- Cartilage and bone degradation --- p.14 / Chapter 1.231 --- Depletion of proteoglycan (GAG) --- p.15 / Chapter 1.232 --- Collagen denature --- p.15 / Chapter 1.3 --- Tachykinins (TKs) --- p.17 / Chapter 1.31 --- History --- p.17 / Chapter 1.32 --- "Synthesis, storage and release of TKs" --- p.17 / Chapter 1.33 --- Tachykinin receptors --- p.18 / Chapter 1.331 --- Characterization of NK1 receptor --- p.19 / Chapter 1.332 --- Characterization of NK2 receptor --- p.19 / Chapter 1.333 --- Characterization of NK3 receptor --- p.20 / Chapter 1.34 --- Effector systems of TKs --- p.21 / Chapter 1.35 --- Termination of TK signals --- p.21 / Chapter 1.351 --- Enzymatic breakdown --- p.21 / Chapter 1.352 --- Receptor desensitization --- p.22 / Chapter 1.353 --- Receptor endocytosis --- p.22 / Chapter 1.36 --- TK receptor antagonists --- p.23 / Chapter 1.361 --- Selective NK1 receptor antagonists --- p.23 / Chapter 1.362 --- Selective NK2 receptor antagonists --- p.24 / Chapter 1.363 --- Selective NK3 receptor antagonists --- p.25 / Chapter 1.4 --- Roles of tachykinins in arthritis --- p.28 / Chapter 1.41 --- Correlation between tachykinins and joint inflammation --- p.28 / Chapter 1.42 --- Roles of tachykinins in immune cell activation --- p.30 / Chapter 1.43 --- Roles of tachykinins in synovial proliferation --- p.31 / Chapter 1.44 --- Roles of tachykinins in cartilage degradation --- p.32 / Chapter 1.5 --- Animal model of arthritis --- p.33 / Chapter 1.51 --- Instability model --- p.33 / Chapter 1.52 --- Immobilization model --- p.34 / Chapter 1.53 --- Noxious agent-induced model --- p.34 / Chapter 1.531 --- Collagen-induced erosive arthritis --- p.34 / Chapter 1.532 --- Cartilage oligometric matrix protein-induced arthritis --- p.35 / Chapter 1.533 --- Oil-induced arthritis --- p.35 / Chapter 1.534 --- Streptococcal cell wall-induced arthritis --- p.35 / Chapter 1.535 --- Adjuvant-induced arthritis --- p.36 / Chapter 1.536 --- Pristane-induced arthritis --- p.36 / Chapter 1.6 --- Current anti-arthritic therapies --- p.39 / Chapter 1.61 --- Non steroid anti-inflammatory drugs --- p.39 / Chapter 1.62 --- Glucocorticoid --- p.44 / Chapter 1.63 --- Second-line treatment --- p.46 / Chapter 1.631 --- Sulfasalazine --- p.46 / Chapter 1.632 --- Gold salts --- p.47 / Chapter 1 633 --- D-penicillamine --- p.48 / Chapter 1.634 --- Antimalarial --- p.49 / Chapter 1 .635 --- Methotrexate --- p.51 / Chapter 1.64 --- New trends for treatment of arthritis --- p.53 / Chapter 1.641 --- Anti-cytokine therapy --- p.53 / Chapter 1.642 --- Anti-angiogenesis therapy --- p.54 / Chapter 1.7 --- Aims of study --- p.57 / Chapter Chapter 2 --- Material and drugs --- p.62 / Chapter Chapter 3 --- Methodology --- p.62 / Chapter 3.1 --- Animals used and anaesthetization --- p.62 / Chapter 3.2 --- Measurement of plasma protein extravasation --- p.63 / Chapter 3.3 --- Measurement of knee joint sizes --- p.64 / Chapter 3.4 --- Measurement of knee joint blood flow --- p.65 / Chapter 3.5 --- Measurement of histological changes --- p.65 / Chapter 3.51 --- Dissection and fixation --- p.65 / Chapter 3.52 --- Decalcification --- p.66 / Chapter 3.53 --- Processing --- p.66 / Chapter 3.54 --- Embedding --- p.67 / Chapter 3.55 --- Sectioning --- p.67 / Chapter 3.56 --- Staining --- p.69 / Chapter 3.6 --- Data analysis --- p.69 / Chapter 3.61 --- Scoring systems --- p.72 / Chapter Chapter 4 --- A model of monoarthritis in rats --- p.72 / Chapter 4.1 --- Introduction --- p.72 / Chapter 4.2 --- Method --- p.73 / Chapter 4.3 --- Results --- p.73 / Chapter 4.31 --- Lewis rats --- p.73 / Chapter 4.32 --- Sprague-Dawley (SD) rats --- p.74 / Chapter 4.33 --- Comparison of FCA-induced changes in Lewis and SD rats --- p.74 / Chapter 4.34 --- Histological studies on arthritic SD rats --- p.75 / Chapter 4.4 --- Discussion --- p.93 / Chapter 4.5 --- Conclusions --- p.95 / Chapter Chapter 5 --- Effect of Substance P on adjuvant-induced arthritis --- p.96 / Chapter 5.1 --- Introduction --- p.96 / Chapter 5.2 --- Method --- p.98 / Chapter 5.3 --- Results --- p.99 / Chapter 5.31 --- Evans blue extravasation --- p.99 / Chapter 5.32 --- Joint size --- p.100 / Chapter 5.33 --- Knee joint blood flow --- p.101 / Chapter 5.34 --- Histology results --- p.102 / Chapter 5.341 --- Infiltration of immune cells in synovial tissue --- p.102 / Chapter 5.342 --- Synovial tissue proliferation --- p.102 / Chapter 5.343 --- Cartilage degradation --- p.103 / Chapter 5.344 --- Bone degradation --- p.103 / Chapter 5.4 --- Discussion --- p.120 / Chapter 5.5 --- Conclusions --- p.125 / Chapter Chapter 6 --- Effects of tachykinin receptor antagonists on FCA-induced arthritis / Chapter 6.1 --- Introduction --- p.126 / Chapter 6.2 --- Method --- p.128 / Chapter 6. 21 --- Intravenous NK1 receptor antagonists on FCA-induced arthritis --- p.128 / Chapter 6. 22 --- Intraperitoneal TK receptor antagonists on FCA-induced arthritis --- p.128 / Chapter 6.3 --- Results --- p.129 / Chapter 6.31 --- Intravenous NK1 227}0اreceptor antagonists on FCA-induced arthritis Evans blue extravasation and joint swelling --- p.129 / Chapter 6.32 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced arthritis Evans blue extravasation and joint swelling --- p.129 / Chapter 6.33 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced immune cell accumulation --- p.130 / Chapter 6.34 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced synovial tissue proliferation --- p.131 / Chapter 6.35 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced cartilage degration and bone erosion --- p.131 / Chapter 6.4 --- Discussion --- p.159 / Chapter 6.5 --- Conclusions --- p.162 / Chapter Chapter 7 --- Individual and combined effects of dexamethasone and TK receptor antagonists on FCA-induced arthritis --- p.163 / Chapter 7.1 --- Introduction --- p.163 / Chapter 7.2 --- Method --- p.166 / Chapter 7.3 --- Results --- p.167 / Chapter 7.31 --- Evans blue extravasation --- p.167 / Chapter 7.32 --- Knee joint size --- p.167 / Chapter 7.33 --- Body weight --- p.168 / Chapter 7.34 --- Cellular infiltration --- p.168 / Chapter 7.35 --- Synovial tissue proliferation --- p.168 / Chapter 7.36 --- Cartilage degradation --- p.169 / Chapter 7.4 --- Discussion --- p.184 / Chapter 7.5 --- Conclusions --- p.187 / Chapter Chapter 8 --- General discussions and conclusions --- p.188 / References --- p.192