Activation of nociceptors causes them to secrete neuropeptides, such as substance P (SP) and calcitonin-gene related peptide (CGRP). By reacting with receptors on blood vessels these peptides contribute to inflammation by evoking vasodilation and increasing vascular permeability that allows proteins and fluid to leave the blood vessels (plasma extravasation, PE). These substances can also lead to the sensitization of nociceptors and the resulting positive feedback thereby prolongs inflammation and pain. Thus, blocking the release of neuropeptides may have important therapeutic value in pain conditions where neuropeptides have been implicated. Therefore, the aim of this study was to define the time course of changes in vascular permeability and to test the ability of novel agents to modulate this response. PE and vasodilation was evoked by stimulating the saphenous nerve or by injecting the chemical irritant capsaicin into the rat hindpaw. Changes in blood flow were evaluated with a laser Doppler and digitized image analysis was used to measure changes in reflectance of the skin due to accumulation of extravasated (EB) dye. Analysis of the change in pixel intensity in the digitized images revealed that the magnitude of PE was dependent on the stimulus pulse number. Moreover, the time course of enhanced vascular permeability produced by electrical stimulation was a transient event compared to a much longer response with capsaicin. It was also demonstrated that sumatriptan, (a 5-HT1B/D receptor agonist) and botulinum neurotoxin type-A were effective treatments for capsaicin and saphenous nerve induced vasodilation and PE. Neither drug interfered with activation of the SP or CGRP receptor, which may suggest that both drugs work by inhibiting neuropeptide release. Therefore, this study has described the time course of vascular permeability evoked by two different stimuli and has demonstrated the ability of two novel agents to attenuate these responses.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/11107 |
| Date | 28 July 2008 |
| Creators | Carmichael, Nicole |
| Contributors | Charlton, Milton, Dostrovsky, Jonathan O. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
| Format | 2540282 bytes, application/pdf |
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