Periaqueductal gray metabotropic glutamate receptor subtype 7 and 8 mediate opposite effects on amino acid release, rostral ventromedial medulla cell activities, and thermal nociception.
ABSTRACT The current study has investigated the involvement of periaqueductal gray (PAG) metabotropic glutamate subtype 7 and 8 receptors (mGluR(7) and mGluR(8)) 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 mGluR(7) 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 mGluR(8) and mGluR(7) 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)-alpha-methylserine-o-phosphate (100 nmol/rat), a group III mGluR antagonist. Intra-ventrolateral PAG perfusion with AMN082 (10 and 25 microM), decreased thermoceptive thresholds and glutamate extracellular levels. A decrease in GABA release was also observed. These results show that stimulation of PAG mGluR(8) or mGluR(7) could either relieve or worsen pain perception. The opposite effects on pain behavior correlate with the opposite roles played by mGluR(7) and mGluR(8) on glutamate and GABA release and the ongoing and tail flick-related activities of the RVM on and off cells.
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ABSTRACT: Glutamate is the main excitatory neurotransmitter in the central nervous system, controlling the majority of synapses. Apart from neurodegenerative diseases, growing evidence suggests that glutamate is involved in psychiatric and neurological disorders, including pain. Glutamate signaling is mediated via ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). So far, drugs acting via modulation of glutamatergic system are few in number, and all are associated with iGluRs and important side effects. The glutamatergic system may be finely modulated by mGluRs. Signaling via these receptors is slower and longer-lasting, and permits fine-tuning of glutamate transmission. There have been eight mGluRs cloned to date (mGluR1-mGluR8), and these are further divided into three groups on the basis of sequence homology, pharmacological profile, and second messenger signaling. The pattern of expression of mGluRs along the pain neuraxis makes them suitable substrates for the design of novel analgesics. This review will focus on the supraspinal mGluRs, whose pharmacological manipulation generates a variety of effects, which depend on the synaptic location, the cell type on which they are located, and the expression in particular pain modulation areas, such as the periaqueductal gray, which plays a major role in the descending modulation of pain, and the central nucleus of the amygdala, which is an important center for the processing of emotional information associated with pain. A particular emphasis will also be given to the novel selective mGluR subtype ligands, as well as positive and negative allosteric modulators, which have permitted discrimination of the individual roles of the different mGluR subtypes, and subtle modulation of central nervous system functioning and related disorders.European Journal of Neuroscience 02/2014; 39(3):444-54. · 3.75 Impact Factor
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ABSTRACT: Glutamate is the main excitatory neurotransmitter in the central nervous system and as such controls the majority of synapses. Glutamatergic neurotransmission is mediated via ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). Signaling via mGluRs permits to finely tune, rather than turning on/off, the excitatory neurotransmission as the iGluRs do. Eight mGluRs (mGluR1-8) have been cloned so far, which have been divided into three groups based on sequence homology, pharmacological properties and second messenger signaling. mGluRs are widely expressed both on glia and neurons. On neurons they are located both at postsynaptic (group I) and presynaptic sites (group II and III). Group II and III mGluR stimulation reduces glutamate release, which can prove useful in pathological conditions characterized by elevated glutamatergic neurotransmission which include chronic pain. Indeed, mGluRs are widely distributed on pain neuraxis. The recent development of selective mGluR ligands has permitted investigating the individual role of each mGluR on pain control. The development of (S)-3,4-dicarboxyphenylglycine, a selective mGluR8 agonist, has revealed the mGluR8 role in inhibiting pain and its related affective consequences in chronic pain conditions. mGluR8 proved also to be overexpressed in pain controlling areas during pathological pain guaranteeing the availability of a switch for turning off abnormal pain. Thus, mGluR8 corresponds to an ideal target in designing novel analgesics. This review will focus on the novel insights into the mGluR8 role on pain control, with particular emphasis on the supraspinal descending pathway, an antinociceptive endogenous source, whose activation or disinhibition (via mGluR8) induces analgesia.Amino Acids 03/2014; · 3.91 Impact Factor
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ABSTRACT: Marijuana has been used to relieve pain for centuries. The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2 ) two decades ago. The subsequent identification of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and their biosynthetic and degradation enzymes discloses the therapeutic potential of compounds targeting the endocannabinoid system for pain control. Inhibitors of the anandamide and 2-AG degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, respectively, may be superior to direct cannabinoid receptor ligands as endocannabinoids are synthesized on demand and rapidly degraded, focusing action at generating sites. Recently, a promising strategy for pain relief was revealed in the periaqueductal gray (PAG). It is initiated by Gq -protein-coupled receptor (Gq PCR) activation of the phospholipase C-diacylglycerol lipase enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. Here, we introduce the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, particularly in the PAG. We also review recent studies disclosing the Gq PCR-phospholipase C-diacylglycerol lipase-2-AG retrograde disinhibition mechanism in the PAG, induced by activating several Gq PCRs, including metabotropic glutamatergic (type 5 metabotropic glutamate receptor), muscarinic acetylcholine (M1/M3), and orexin 1 receptors. Disinhibition mediated by type 5 metabotropic glutamate receptor can be initiated by glutamate transporter inhibitors or indirectly by substance P, neurotensin, cholecystokinin and capsaicin. Finally, the putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is discussed.European Journal of Neuroscience 02/2014; 39(3):467-84. · 3.75 Impact Factor