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Title: Understanding the role of the endocannabinoid biosynthetic pathways in mediating analgesia
Author: Gaw, Annette Gemma
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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Enhancement of the endocannabinoid (EC) system is analgesic in many models of acute and chronic pain. Current knowledge of EC biosynthetic pathways and their roles in normal physiology and pathophysiology is limited. EC lipids can be measured using LC-MS/MS but there are very few analytical techniques available to measure their biosynthetic precursors and intermediates. This study sought to develop a novel LC-MS/MS to measure EC biosynthetic components and describe their contribution to pain pathophysiology. LC-MS/MS methodology capable of measuring ECs, their biosynthetic precursors and intermediates was developed and applied to rat tissues involved in nociceptive processing. This method measured N-acyl phosphatidyl ethanolamine (NAPE) precursors of the N-acyl ethanolamine (NAE) ECs in rat brain, spinal cord and hind paw skin tissue. Additionally, glycerol-phospho-NAE (GpNAE) components of the GDE1 alternative synthetic pathway were also detected in these tissues demonstrating the functional presence of this pathway. An important finding is the drastic effects of anaesthesia in EC, EC precursor and intermediate levels in the rat spinal cord whereby reductions compared to stunning and decapitation were measured. In the MIA model of OA, EC synthesis is unlikely to contribute'to disease pathology in the spinal cord due to the comparable measurements of EC biosynthetic lipids in both diseased and sham rats. Intraplantar injection of carrageenan reduced EC levels and their related GpNAE intermediates in the rat hindpaw skin demonstrating a close relationship of this biosynthetic pathway and the NAE products in this model. Modulation of the PEA generating NAPE suggests a neuroprotective role following stimulation in Page 11 Understanding the Role of the Endocannabinoid Biosynthet ic Pathways in Mediat ing Analgesia areas of nociceptive processing. NAPE-PLD, the most commonly accepted NAE biosynthetic enzyme, was visualised in spinal cord neuronal cells and hindpaw skin of this model by a newly developed selective immunohistochemistry technique. NAPE-PLD expressing cells were increased in the dorsal horn of the spinal cord following carrageenan injection. Collectively this thesis presents the development and application of novel methodology to understanding the role of EC synthesis in pain pathology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available