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Title: Modulation of spinal hyper-excitability by the cannabinoid & vanilloid systems
Author: Woodhams, Stephen George
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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Despite extensive study of the pathophysiology, pain states still represent a significant unmet clinical need. Spinal hyper- excitability is a key feature of acute and chronic pain states, yet the underlying mechanisms are incompletely understood. To this end, the aim of this thesis was to examine the effects of modulation of the spinal cannabinoid and vanilloid receptor systems in rat models of acute and chronic pain. Anti-nociceptive effects of inhibiting spinal cord endocannabinoid (EC) catabolism were investigated. In naive rats, spinal administration of the novel MAGL inhibitor JZL184 (25-100 μg) produced a robust, dose-dependent inhibition of noxious mechanically-evoked (15-26 g) responses of WDR neurones, probably via a CB1 receptor-mediated mechanism. Spinal JZL184 (100 μg) also ablated the expansion of 'WDR receptive fields, a marker of central hyper-excitability, following intra-plantar administration of carrageenan (2 mg/l00 μL). Ex vivo analyses failed to demonstrate the expected concomitant elevation of 2- AG and inhibition of MAGL in whole lumbar spinal cord homogenates. However, in vitro studies confirmed potent inhibition of MAGL by JZL184 (IC50 = 76 - 287 nM in spinal cord), suggesting the effects of this compound are indeed mediated by 2-AG/CB1. Gross tissue analyses may, therefore, be insufficiently sensitive to detect biologically significant local fluctuations in EC signalling. Interestingly, these experiments also revealed substantial heterogeneity of monoglyceride hydrolytic activity in rodent CNS fractions. The involvement of the spinal EC system in both rapid and sustained spinal plasticity in pain states was also assessed. Levels of EC-related molecules, genes, and proteins were measured in spinal cord tissue in the carrageenan model of acute inflammatory pain and the monosodium iodoacetate (MIA) model of chronic joint pain. Significant elevations in AEA were demonstrated in both models, whilst significant increases in DEA, PEA, and 2-AG were observed in the MIA model only. Analysis of gene and protein expression levels suggest the early alterations may be mediated by decreased catabolism, whilst later increases were driven by increased synthesis. Finally, spinal TRPV1 receptors were assessed as a therapeutic target in the MIA model. Substantial progressive increases in spinal TRPV1 expression were demonstrated from post-induction day 14 to 28 following unilateral intra-articular injection of 1mg MIA. These increases were partially correlated with the development of distal allodynia and knee joint pathology, suggesting a role for these receptors in the development of spinal hyper-excitability in this model. Spinal administration of the TRPV1 antagonist JNJ-17203212 (18.75 - 75 μg) produced dose-dependent inhibition of noxious mechanically-evoked responses of WDR neurones to a similar extent in both saline- and MIA-treated rats. However, efficacy of the mid-range dose was positively correlated with the level of spinal TRPV1 expression. These data demonstrate the anti-nociceptive efficacy of modulating the EC and TRPV1 signalling systems. However, the substantial plasticity of these systems demonstrated in nociceptive states warrants further investigation, and may have significant bearing on the future success of such therapeutic approaches.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available