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The sensitisation of TRPV1 mediated responses by Prostaglandin and bradykinin and the signalling pathways involved

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posted on 2015-10-22, 14:48 authored by Sara Abdulrahman M. Aldossary
TRPV1 ion channels have crucial roles in inflammatory hyperalgesia as TRPV1-/- mice show reduced thermal hyperalgesia response in response to tissue inflammation. The activity of TRPV1 is upregulated in the case of inflammation due to the release of different inflammatory mediators which can modulate the function of TRPV1. Bradykinin is an algogenic substance which is released at the site of inflammation and it’s known to produce thermal hyperalgesia. However, the mechanism underlying the sensitising effect of bradykinin has not been full elucidated. The aim of present project is to investigate how bradykinin mediates the sensitisation of capsaicin evoked calcium responses in DRG neurons. With the use of immunocytochemical and morphometric techniques, the present study has demonstrated the expression and distribution of EP4, TRPV1, COX-1 and B2 proteins mainly in small diameter (<1,000μm2) cell bodies of rat DRG neurons which are typically nociceptors. Cultured rat DRG neurons were utilised to elucidate the direct and sensitising effects of bradykinin on sensory neurons. Following direct application of bradykinin, a group of cells evoked calcium responses which were mediated via the B2 receptor. In addition, bradykinin showed the ability to sensitise TRPV1 in the presence of thapsigargin, conditions under which bradykinin does not elicit a Ca2+ responses on its own. With the use of various pharmacological ligands that modulate prostaglandin biosynthesis, the formation of the second messenger, PGE2, acting through EP4 receptors was identified as a key signalling pathway mediating the effect of bradykinin on sensory neurons. The present study provides evidence for a novel signalling pathway through which bradykinin can regulate the TRPV1 ion channel function.

History

Supervisor(s)

Grubb, Blair; Gibson, Claire

Date of award

2015-10-20

Author affiliation

Department of Cell Physiology and Pharmacology

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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