The research detailed in this thesis consisted of three individual investigations: Firstly, the characterisation of the novel eicosanoid, leukotriene B<sub>4</sub> ethanolamide (LTB<sub>4</sub> ethanolamide), with leukotriene BLT and vanilliod TRPV1 receptors using rat TRPV1-transfected CHO cells, neonatal rat cultured dorsal root ganglion neurones, guinea-pig lung parenchyma and human neutrophils. LTB<sub>4</sub> ethanolamide acts as an antagonist/partial agonist, depending upon receptor expression, at BLT receptors, and as a weak partial agonist at TRPV1 receptors. Secondly, the characterisation of novel compounds at BLT and TRPV1 receptors. These compounds were designed to exhibit antagonism of both these receptors. O-3367and O-3383 act as competitive BLT receptor antagonists with IC<sub>50</sub> values of ~ 60 nM and ~ μM, respectively. O-3367 acts as a competitive antagonist at TRPV1 receptors with an IC<sub>50</sub> values of ~ μM. Thirdly, the effect of cannabinoids have on human neutrophil migration was investigated. Anamdamide, <i>N</i>-arachidonyl dopamine, virodhamine, CP55940, cannabidiol, (+)-cannabidiol and abnormal-cannabidiol all inhibited <i>N</i>-formylmethyionylleucylphenylalainine (fMLP) – induced neutrophil migration in a concentration-dependent manner. Sphingosine-1 –phosphate, a compound structurally related to anandamide was also capable of inhibiting induced migration, whereas palmitoylethanolamide, 2-arachidonylglycerol, Δ<sup>9</sup>tetrahydrocannabinol, O-2654, SR141716A, SR144528, capsazepine and AM630 was not. O-2654 induced a concentration-dependent stimulation of neutrophil migration with an EC<sub>50</sub> of 16.7 nM. The findings suggest cannabinoids function as anti-inflammatory or immunosuppressive agents, by interfering with chemoattractant-induced directional migration of neutrophils.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:430385 |
| Date | January 2006 |
| Creators | McHugh, Douglas |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.001 seconds