Biphasic modulation by mGlu₅ receptors of TRPV1‐mediated intracellular calcium elevation in sensory neurons contributes to heat sensitivity

Abstract

BACKGROUND AND PURPOSEElevation of glutamate, an excitatory amino acid, during inflammation and injury plays a crucial role in the reception and transmission of sensory information via ionotropic and metabotropic receptors. This study aimed to investigate the mechanisms underlying the biphasic effects of metabotropic glutamate mGlu5 receptor activation on responses to noxious heat. EXPERIMENTAL APPROACHWe assessed the effects of intraplantar quisqualate, a non-selective glutamate receptor agonist, on heat and mechanical pain behaviours in mice. In addition, the effects of quisqualate on the intracellular calcium response and on membrane currents mediated by TRPV1 channels, were examined in cultured dorsal root ganglion neurons from mice. KEY RESULTSActivation of mGlu5 receptors in hind paw transiently increased, then decreased, the response to noxious heat. In sensory neurons, activation of mGlu5 receptors potentiated TRPV1-mediated intracellular calcium elevation, while terminating activation of mGlu5 receptors depressed it. TRPV1-induced currents were potentiated by activation of mGlu5 receptors under voltage clamp conditions and these disappeared after washout. However, voltage-gated calcium currents were inhibited by the mGlu5 receptor agonist, even after washout. CONCLUSIONS AND IMPLICATIONSThese results suggest that, in sensory neurons, mGlu5 receptors biphasically modulate TRPV1-mediated intracellular calcium response via transient potentiation of TRPV1 channel-induced currents and persistent inhibition of voltage-gated calcium currents, contributing to heat hyper-and hypoalgesia.

Biphasic modulation of noxious heat sensitivity in sensory neurons by peripheral metabotropic glutamate receptors

“…Our study clarified that agonist removal after activation of mGluR5 caused a significant decrease in the degree of TRPV1-mediated calcium elevation, without decreasing the TRPV1 current [8] . This is the result of persistent inhibition of VGCC currents by mGluR5 activation in capsaicin-sensitive DRG neurons, even after cessation of mGluR5 activation.…”

“…We observed that the presence of mGluR5 ligands potentiated intracellular calcium elevation and current response induced by the TRPV1 agonist capsaicin, in cultured sensory neurons, without changing the capsaicin-sensitive population [8] . Hu et RESEARCH HIGHLIGHT…”

“…Peripheral mGluR5 potentiates and/or directly activates the transient receptor potential cation channel, subtype V member 1 (TRPV1), which results in elevation of noxious heat sensitivity and spontaneous pain [7,8] . We additionally identified a novel hypesthesia system for noxious heat, by which mGluR5 mediates persistent inhibition of voltage-gated calcium channels (VGCC) in sensory neurons [8] .It was previously reported that peripheral mGluR5 activity is closely related to TRPV1 function [7,9] . We observed that the presence of mGluR5 ligands potentiated intracellular calcium elevation and current response induced by the TRPV1 agonist capsaicin, in cultured sensory neurons, without changing the capsaicin-sensitive population [8] .…”

“…We additionally identified a novel hypesthesia system for noxious heat, by which mGluR5 mediates persistent inhibition of voltage-gated calcium channels (VGCC) in sensory neurons [8] .…”

“…The mechanism of acute pain induced by peripheral group I mGluRs, especially mGluR5, has been gradually elucidated by several studies [6,7] . Peripheral mGluR5 potentiates and/or directly activates the transient receptor potential cation channel, subtype V member 1 (TRPV1), which results in elevation of noxious heat sensitivity and spontaneous pain [7,8] . We additionally identified a novel hypesthesia system for noxious heat, by which mGluR5 mediates persistent inhibition of voltage-gated calcium channels (VGCC) in sensory neurons [8] .…”