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

The current study has investigated the involvement of periaqueductal gray (PAG) metabotropic glutamate subtype 7 and 8 receptors (mGluR7 and mGluR8) in modulating rostral ventromedial medulla (RVM) ongoing and tail flick–related on and off cell activities. Our study has also investigated the role of PAG mGluR7 on thermoceptive threshold and PAG glutamate and GABA release. Intra-ventrolateral PAG ( S)-3,4-dicarboxyphenylglycine [( S)-3,4-DCPG (2 and 4 nmol/rat)] or N,N I-dibenzhydrylethane-1,2-diamin dihydrochloride (AMN082, (1 and 2 nmol/rat), selective mGluR8 and mGluR7 agonists, respectively, caused opposite effects on the ongoing RVM on and off cell activities. Tail flick latency was increased or decreased by ( S)-3,4-DCPG or AMN082 (2 nmol/rat), respectively. ( S)-3,4-DCPG reduced the pause and delayed the onset of the off cell pause. Conversely, AMN082 increased the pause and shortened the onset of off cell pause. ( S)-3,4-DCPG or AMN082 did not change the tail flick-induced onset of on-cell peak firing. The tail flick latency and its related electrophysiological effects induced by ( S)-3,4-DCPG or AMN082 were prevented by (RS)-α-methylserine-o-phosphate (100 nmol/rat), a group III mGluR antagonist. Intra-ventrolateral PAG perfusion with AMN082 (10 and 25 μM), decreased thermoceptive thresholds and glutamate extracellular levels. A decrease in GABA release was also observed. These results show that stimulation of PAG mGluR8 or mGluR7 could either relieve or worsen pain perception. The opposite effects on pain behavior correlate with the opposite roles played by mGluR7 and mGluR8 on glutamate and GABA release and the ongoing and tail flick-related activities of the RVM on and off cells.

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

Journal of Neurophysiology ◽

10.1152/jn.00212.2013 ◽

2014 ◽

Vol 111 (11) ◽

pp. 2196-2209 ◽

Cited By ~ 19

Author(s):

Francesca Rossi ◽

Ida Marabese ◽

Maria De Chiaro ◽

Serena Boccella ◽

Livio Luongo ◽

...

Keyword(s):

Metabotropic Glutamate Receptor ◽

Cell Activity ◽

Dorsal Striatum ◽

Rostral Ventromedial Medulla ◽

Tail Flick ◽

Metabotropic Glutamate ◽

Withdrawal Threshold ◽

Ventromedial Medulla ◽

Stimulation Of

The present study investigated the role of metabotropic glutamate receptor subtype 8 (mGluR8) in the dorsal striatum (DS) in modulating thermonociception and rostral ventromedial medulla (RVM) ON and OFF cell activities in conditions of neuropathic pain induced by spared nerve injury (SNI) of the sciatic nerve in rats. The role of DS mGluR8 on mechanical allodynia was also investigated. Intra-DS ( S)-3,4-dicarboxyphenylglycine [( S)-3,4-DCPG], a selective mGluR8 agonist, did not modify the activity of the ON and OFF cells in sham-operated rats. In SNI rats, which showed a reduction of the mechanical withdrawal threshold, intra-DS microinjection of ( S)-3,4-DCPG inhibited the ongoing and tail flick-evoked activity of the ON cells while increasing the activity of the OFF cells. AZ12216052, a selective mGluR8 positive allosteric modulator (PAM), behaved like ( S)-3,4-DCPG in increasing tail flick latency and OFF cell activity and decreasing ON cell activity in SNI rats only but was less potent. VU0155041, a selective mGluR4 PAM, was ineffective in changing thermal nociception and ON and OFF cell activity in both sham-operated and SNI rats. ( S)-3,4-DCPG did not change mechanical withdrawal threshold in sham-operated rats but increased it in SNI rats. Furthermore, a decreased level of mGluR8 gene and immunoreactivity, expressed on GABAergic terminals, associated with a protein increase was found in the DS of SNI rats. These results suggest that stimulation of mGluR8 inhibits thermoceptive responses and mechanical allodynia. These effects were associated with inhibition of ON cells and stimulation of OFF cells within RVM.

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Group II metabotropic glutamate receptor expressing neurons in anterior cingulate cortex become sensitized after inflammatory and neuropathic pain

Molecular Pain ◽

10.1177/1744806920915339 ◽

2020 ◽

Vol 16 ◽

pp. 174480692091533

Author(s):

Sisi Chen ◽

Feni Kadakia ◽

Steve Davidson

Keyword(s):

Neuropathic Pain ◽

Anterior Cingulate Cortex ◽

Glutamate Receptor ◽

Inflammatory Pain ◽

Metabotropic Glutamate Receptor ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Receptor Subtype ◽

Metabotropic Glutamate ◽

Group Ii

The anterior cingulate cortex is a limbic region associated with the emotional processing of pain. How neuropathic and inflammatory pain models alter the neurophysiology of specific subsets of neurons in the anterior cingulate cortex remains incompletely understood. Here, we used a GRM2Cre:tdtomato reporter mouse line to identify a population of pyramidal neurons selectively localized to layer II/III of the murine anterior cingulate cortex. GRM2encodes the group II metabotropic glutamate receptor subtype 2 which possesses analgesic properties in mouse and human models, although its function in the anterior cingulate cortex is not known. The majority of GRM2-tdtomato anterior cingulate cortex neurons expressed GRM2gene product in situ but did not overlap with cortical markers of local inhibitory interneurons, parvalbumin or somatostatin. Physiological properties of GRM2-tdtomato anterior cingulate cortex neurons were investigated using whole-cell patch clamp techniques in slice from animals with neuropathic or inflammatory pain, and controls. After hind-paw injection of Complete Freund’s Adjuvant or chronic constriction injury, GRM2-tdtomato anterior cingulate cortex neurons exhibited enhanced excitability as measured by an increase in the number of evoked action potentials and a decreased rheobase. This hyperexcitability was reversed pharmacologically by bath application of the metabotropic glutamate receptor subtype 2 agonist (2R, 4R)-4-Aminopyrrolidine-2,4-dicarboxylate APDC (1 µM) in both inflammatory and neuropathic models. We conclude that layer II/III pyramidal GRM2-tdtomato anterior cingulate cortex neurons express functional group II metabotropic glutamate receptors and undergo changes to membrane biophysical properties under conditions of inflammatory and neuropathic pain.

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