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

Abstract

Release of glutamate during inflammation and injury changes sensitivity and transmission efficiency of noxious sensory information via glutamate receptors. We found that activation of metabotropic glutamate receptor type 5 (mGluR5) transiently increased, and then subsequently decreased, noxious heat sensitivity. Similarly, mGluR5 activation in cultured sensory neurons potentiated intracellular calcium elevation mediated by transient receptor potential channel, subfamily V, member 1 (TRPV1), a noxious heat receptor; subsequent cessation of mGluR5 activation depressed intracellular calcium levels. The underlying mechanisms were potentiation of TRPV1 current in the presence of mGluR5 ligands and persistent inhibition of voltage-gated calcium channels (VGCC), even after mGluR5 ligand washout. Thus, mGluR5 biphasically modulates TRPV1-mediated cellular responses in sensory neurons, which contributes to heat hyper-and hypoalgesia. These phenomena may contribute to changes in noxious heat sensitivity during inflammation and healing. Inflammation results in the release of many chemical mediators, such as bradykinin, histamine, serotonin, prostaglandins etc., which act on local tissues [1,2] . These compounds activate a variety of specific receptors and channels on peripheral sensory nerve terminals, which induce pruritus and pain. Glutamate, a dominant neurotransmitter of central nervous system, is also one of the mediators released from neurons, glia, and damaged cells in peripheral tissue [3][4][5] . It has been proposed that this released glutamate acts in part on group I metabotropic glutamate receptors, consisting of mGluR1 and mGluR5, on peripheral unmyelinated sensory afferents, which contributes to generation and/or potentiation of inflammatory pain [6] . 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] .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] . Hu et RESEARCH HIGHLIGHT