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The influence of Prostaglandin E2 on bradykinin induced depolarization, generation and conduction of action potentials in the isolated vagus nerve

In this study we have investigated the sensitising effect that PGE2 has on the action of bradykinin (BK) in both depolarising the resting membrane potential and in action potential generation and propagation in the isolated, desheathed vagus nerve of the rat using an extra cellular grease gap recording technique. Treatment with proinflammatory PGE2 (1µM) produced a significant increase in the bradykinin (1µM) induced depolarisation of the vagus nerve but had no effect on the action potential generation and propagation. We hypothesise that this sensitisation is elicited by the vanilloid capsaicin sensitive receptor TRPV1. Activation of intracellular PKA using a membrane-permeant analogue of cyclic AMP i.e. dbcAMP (2mM) also increased the neuronal responses elicited by bradykinin (1µM) in a manner analogous to that produced by PGE2 (1µM). Treatment of the isolated vagus nerve with the phorbol ester PDBu (1µM) directly caused a depolarisation of the isolated vagus nerve as well as increasing the neuronal responses elicited by bradykinin (1µM) in a similar manner to that produced by PGE2 (1µM). Inclusion of a non-specific protein kinase inhibitor staurosporin (1µM) completely suppressed the sensitisation produced by PGE2 (1µM) or PDBu (1µM) but had no effect on the response produced by capsaicin (1µM). The application of the capsaicin antagonist ruthenium red (1µM) completely abolished the sensitisation produced by PGE2 (1µM) PDBu (1µM) and capsaicin (1µM). Taken together, these observations suggest that the PGE2 sensitisation of the BK induced depolarisation is mimicked by both activation of the PKA and PKC signalling pathways by a process that is completely blocked by the TRPV1 antagonist ruthenium red and staurosporin. Suggesting a pivotal role for the TRPV1 channel in the PGE2 and BK induced response.

Mostra/Nascondi contenuto.
Dr Charles Murimi Mugera MSc Pharmacology The influence of PGE on bradykinin-induced depolarisation, generation and 2 conduction of action potentials in the isolated vagus nerve of the rat. Chapter 1.Introduction 1.1. Inflammation and hyperalgesia Inflammation and tissue injury cause an enhanced response to noxious stimuli and a decrease of the pain threshold (Planells-Cases et al., 2005). Inflammatory mediators, released from the injured tissues are well known to produce hyperalgesia (Moriyama et al., 2005). Intradermal injection of some inflammatory mediators directly produces pain while others do not produce pain but potentiate the response to pain. We hypothesize that different inflammatory mediator’s act synergistically to produce the phenomenon of hyperalgesia. In our study we look at two of the most important inflammatory autacoids, bradykinin and PGE, and how their intracellular signalling pathways interact to induce 2 hyperalgesia. 1.2. Bradykinin and hyperalgesia One of the most potent mediators of inflammation is the nonapeptide bradykinin (BK) which is generated in plasma and tissues following injury (Couture et al., 2001). Intradermal injection of bradykinin produces pain in animal models (Inoki et al., 1979) and in man (Meyer et al., 1992) . G-protein activation is an essential component of the bradykinin response, modulated by protein kinase C and lipoxygenase metabolites of arachidonic acid (McGuirk & Dolphin, 1992). BK exerts its biological effects through the activation of the bradykinin B2 receptor which belongs to the rhodopsin family of G protein-coupled receptors (Flavahan & Vanhoutte, 1990; Voyno-Yasenetskaya et al., 1989a; Voyno-Yasenetskaya et al., 1989b) 1 The Wolfson Centre for Age-Related Diseases

International thesis/dissertation

Facoltà: School of Biomedical Sciences

Autore: Charles Mugera Contatta »

Composta da 51 pagine.

 

Questa tesi ha raggiunto 50 click dal 21/09/2010.

 

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