Bradykinin Induces TRPV1 Exocytotic Recruitment in Peptidergic Nociceptors.

Sakthikumar Mathivanan,Antonio Ferrer-Montiel,Isabel Devesa,Jean-Pierre Changeux

doi:10.3389/fphar.2016.00178

Sakthikumar Mathivanan, Antonio Ferrer-Montiel + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2016.00178

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Abstract

Transient receptor potential vanilloid I (TRPV1) sensitization in peripheral nociceptors is a prominent phenomenon that occurs in inflammatory pain conditions. Pro-algesic agents can potentiate TRPV1 activity in nociceptors through both stimulation of its channel gating and mobilization of channels to the neuronal surface in a context dependent manner. A recent study reported that ATP-induced TRPV1 sensitization in peptidergic nociceptors involves the exocytotic release of channels trafficked by large dense core vesicles (LDCVs) that cargo alpha-calcitonin gene related peptide alpha (αCGRP). We hypothesized that, similar to ATP, bradykinin may also use different mechanisms to sensitize TRPV1 channels in peptidergic and non-peptidergic nociceptors. We found that bradykinin notably enhances the excitability of peptidergic nociceptors, and sensitizes TRPV1, primarily through the bradykinin receptor 2 pathway. Notably, bradykinin sensitization of TRPV1 in peptidergic nociceptors was significantly blocked by inhibiting Ca2+-dependent neuronal exocytosis. In addition, silencing αCGRP gene expression, but not substance P, drastically reduced bradykinin-induced TRPV1 sensitization in peptidergic nociceptors. Taken together, these findings indicate that bradykinin-induced sensitization of TRPV1 in peptidergic nociceptors is partially mediated by the exocytotic mobilization of new channels trafficked by αCGRP-loaded LDCVs to the neuronal membrane. Our findings further imply a central role of αCGRP peptidergic nociceptors in peripheral algesic sensitization, and substantiate that inhibition of LDCVs exocytosis is a valuable therapeutic strategy to treat pain, as it concurrently reduces the release of pro-inflammatory peptides and the membrane recruitment of thermoTRP channels.

Highlights

Transient receptor potential vanilloid I (TRPV1) is a non-selective cation channel that can be activated by noxious heat (T ≥ 42◦), vanilloids, protons, voltage, toxins, and membrane derived lipids (Caterina et al, 1997; Zygmunt et al, 1999; Huang et al, 2002; Chu et al, 2003)
isolectin B4 (IB4)+ nociceptors were fluorescently labeled with Alexa-IB4, and nociceptor excitability was evaluated by whole cell patch-clamp
To investigate if BK promotes the membrane mobilization of transient receptor potential vanilloid I (TRPV1) we evaluated the impact of inhibiting neuronal exocytosis of large-dense core vesicle (LDCV) using compound DD04107, a small lipidated peptide that interferes with the formation of the SNARE complex (Camprubí-Robles et al, 2009)

Summary

Introduction

Transient receptor potential vanilloid I (TRPV1) is a non-selective cation channel that can be activated by noxious heat (T ≥ 42◦), vanilloids, protons, voltage, toxins, and membrane derived lipids (Caterina et al, 1997; Zygmunt et al, 1999; Huang et al, 2002; Chu et al, 2003). Evaluation of the cellular mechanism revealed that the neuropeptide αCGRP was essential for the inflammatory recruitment of TRPV1 channels in peptidergic nociceptors. This finding suggests that a similar mechanism may underlie the potentiation of TRPV1 by other pro-inflammatory agents. In support of this tenet, inhibition of TRPV1 recruitment by peptide DD04107, a blocker of neuronal exocytosis (Camprubí-Robles et al, 2009), exhibits notable anti-nociceptive activity in models of inflammatory and neuropathic pain (Ponsati et al, 2012)

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