Differential mechanism of trpv1 sensitization in peptidergic and nonpeptidergic nociceptors
- MATHIVANAN, SAKTHIKUMAR
- Antonio Ferrer Montiel Director/a
Universitat de defensa: Universidad Miguel Hernández de Elche
Fecha de defensa: 12 de de maig de 2016
- Manuela García López President/a
- Isabel Devesa Giner Secretari/ària
- Ana Gomis García Vocal
- José Antonio Lamas Castro Vocal
- John Fergus Wesseling Vocal
Tipus: Tesi
Resum
TRPV1 is a polymodal, non selective cation channel which acts as a major integrator of painful stimuli in nociceptors. During inflammation, the release of inflammatory mediators act on TRPV1 leading to enhanced nociceptor excitability and thermal hyperalgesia. Acute inflammatory sensitization of TRPV1 involves both the modification of channel gating properties by phosphorylation and recruitment of new channels to the neuronal surface. Mobilization of TRPV1 channel to the plasma membrane by some pro- inflammatory mediators occurs through SNARE-dependent exocytosis, but the exact mechanism involved remains to be elucidated. We hypothesize that the inflammatory recruitment of channels occurs in the neuronal subpopulation which contains neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP), also called peptidergic nociceptors. Therefore, we have investigated the underlying mechanism of pro- inflammatory mediators Adenosine triphosphate (ATP) and Bradykinin (BK) induced inflammatory sensitization of TRPV1 in cultured nociceptors containing both peptidergic and nonpeptidergic subpopulations. We have performed functional analysis using patch clamp electrophysiology and micro electrode array (MEA) technique. We found that the inhibition of neuronal exocytosis results in decreased inflammatory sensitization of TRPV1 induced by both ATP and Bradykinin in peptidergic nociceptors where membrane recruitment of the channel is essential. In addition, knocking out of αCGRP leads to the reduction of inflammatory sensitization of TRPV1. Hence, this study reveals that both ATP and Bradykinin induces regulated exocytosis of TRPV1 in peptidergic nociceptors where αCGRP plays a significant role. Furthermore, our result validates the therapeutic potential of DD04107 on lessening inflammatory pain through modulation of regulated exocytosis of TRPV1.