Metabotropic Glutamate Receptor Subtype 8 in the Amygdala Modulates Thermal Threshold, Neurotransmitter Release, and Rostral Ventromedial Medulla Cell Activity in Inflammatory Pain

Abstract

The amygdala is a crucial area in controlling the threshold of pain and its emotional component. The present study has evaluated the effect of a metabotropic glutamate 8 receptor (mGluR8) stimulation in the central nucleus of the amygdala (CeA) on the thermoceptive threshold and on CeA serotonin (5-HT), glutamate (Glu), and GABA release in normal and carrageenan-induced inflammatory pain conditions in rats. Furthermore, the activity of rostral ventromedial medulla (RVM) putative "pronociceptive" ON and "antinociceptive" OFF cells has been evaluated. (S)-3,4-Dicarboxyphenylglycine [(S)-3,4-DCPG], a selective mGluR8 agonist, administered into the CeA, did not change 5-HT, Glu, and GABA release, or the thermoceptive threshold, nor did it modify the activity of ON and OFF cells of the RVM in normal animals. In rats treated with carrageenan, intra-CeA (S)-3,4-DCPG perfusion produced antinociception, and increased 5-HT and Glu, whereas it decreased GABA release. Intra-CeA (S)-3,4-DCPG inhibited ON and increased OFF cell activities. Furthermore, an increase in mGluR8 gene, protein, and staining, the latter being associated with vesicular GABA transporter-positive profiles, has been found in the CeA after carrageenan-induced inflammatory pain. These results show that stimulation of mGluR8, which was overexpressed within the CeA in inflammatory pain conditions, inhibits nociceptive behavior. Such an effect is associated with an increase in 5-HT and Glu release, a decrease in GABA, and the inhibition of ON-and the stimulation of OFF-cell activities within RVM.

Dorsal striatum metabotropic glutamate receptor 8 affects nocifensive responses and rostral ventromedial medulla cell activity in neuropathic pain conditions

“…(S)-3,4-DCPG has already been shown to inhibit RVM ON cell and enhance OFF cell activity consistently with mGluR 8 -induced antinociception in SNI rats when locally microinjected into the VL PAG or CeA (Marabese et al 2007b;Palazzo et al 2011). A critical finding of this study was, however, that administration of (S)-3,4-DCPG in the DS was devoid of effect in sham-operated rats.…”

“…Indeed, intra-DS administration of (S)-3,4-DCPG did not change thermal nociception, MWT, and the ongoing and tail flick-evoked ON and OFF cell activity in sham-operated animals. Evidence that group III mGluR stimulation inhibits pain in different pathological pain states of various etiologies but not in normal conditions has been already reported (Chen and Pan 2005;Goudet et al 2008;Neugebauer 2006;Palazzo et al 2008Palazzo et al , 2011Palazzo et al , 2013Zhang et al 2009). In particular, we have found that intra-CeA (S)-3,4-DCPG failed to change pain and affective behavior, neurotransmitter release, and RVM cell activity in physiological conditions (Palazzo et al 2008.…”

“…However, intra-DS (S)-3,4-DCPG failed to change pain responses in sham-operated rats. mGluR 8 stimulation has already been evaluated in the VL PAG and CeA, where it reduced pain responses in normal and chronic pain conditions (Marabese et al 2007a(Marabese et al , 2007bPalazzo et al 2008Palazzo et al , 2011) and proved to be associated with GABA decrease and glutamate increase (Marabese et al , 2007aPalazzo et al 2011). Within the nucleus tractus solitarii (NTS), mGluR 8 stimulation produced instead a pain facilitatory effect on cardiac nociception (Liu et al 2012).…”

“…The doses of (S)-3,4-DCPG, VU0155041, LY341495, and AZ12216052 were chosen according to EC 50 /IC 50 and according to our and other in vivo studies using brain local microinjections that have been shown to change pain behavior (Chi et al 2006;Dong et al 2012;Duvoisin et al. 2010; Liu et al 2012;Marabese et al 2007b;Niswender et al 2008;Palazzo et al 2008Palazzo et al , 2011.…”

“…In our previous studies the stimulation of mGluR subtype 8 (mGluR 8 ) by the selective agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] (Thomas et al 2001) in the ventrolateral periaqueductal gray (VL PAG) and central nucleus of the amygdala (CeA) has proven to inhibit pain and associated changes in the rostral ventromedial medulla (RVM) neuron activity in models of neuropathic and inflammatory pain (Marabese et al 2007a;Palazzo et al 2008Palazzo et al , 2011. RVM, a relay station in the pain descending system, contains different pain-responding neurons: ON cells that are activated, OFF cells that are inhibited, and neutral cells that are unaffected by nociceptive stimuli (Fields et al 1983;Heinricher et al 1989).…”