3-4-dicarboxyphenylglycine and Pain

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.

Topics: Animals; Benzoates; Female; Glycine; Humans; Male; Mice, Knockout; Neuroglia; Neurons; Pain; Receptors, Metabotropic Glutamate; Synaptic Transmission

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.

Topics: Amino Acids; Amygdala; Animals; Behavior, Animal; Benzoates; Blotting, Western; Carrageenan; Chromatography, High Pressure Liquid; gamma-Aminobutyric Acid; Glycine; Immunohistochemistry; Inflammation; Male; Medulla Oblongata; Microdialysis; Neuronal Plasticity; Neurotransmitter Agents; Pain; Postural Balance; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensory Thresholds; Serotonin; Thermosensing

The amygdala plays an important role in the emotional-affective component of pain and in pain modulation. Group III metabotropic glutamate receptors (mGluRs) regulate pain-related activity in the amygdala, but the behavioral consequence and contribution of individual subtypes are not known yet. This study determined the effects of mGluR7 and mGluR8 activation in the central nucleus of the amygdala (CeA) on nocifensive and affective pain responses and on pain-related anxiety-like behavior of adult rats. The pain state was induced by intraarticular injections of kaolin/carrageenan into one knee joint to produce a localized monoarthritis. Subtype-selective agonists were administered into the CeA by microdialysis in normal rats and in rats with arthritis. An mGluR7-selective agonist (N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride, AMN082, 25microM) decreased spinal withdrawal reflex thresholds and increased audible and ultrasonic vocalizations evoked by brief (15s) compression of the knee. AMN082 also decreased the open-arm preference in the elevated plus maze (EPM) test, suggesting anxiety-like behavior. In arthritic animals, however, AMN082 failed to modulate the increased spinal reflexes and vocalizations and anxiety-like behavior. An mGluR8-selective agonist (S-3,4-dicarboxyphenylglycine, S-3,4-DCPG, 10microM) had no effect in normal animals but inhibited the increased spinal reflex responses and audible and ultrasonic vocalizations of arthritic rats. S-3,4-DCPG also increased the open-arm choices of arthritic rats, suggesting anxiolytic effects. The results suggest that under normal conditions mGluR7, but not mGluR8, facilitates pain responses and has anxiogenic properties whereas mGluR8, but not mGluR7, can inhibit nocifensive and affective behaviors and anxiety in a model of arthritic pain.

Topics: Amygdala; Animals; Arthritis; Behavior, Animal; Benzhydryl Compounds; Benzoates; Disease Models, Animal; Excitatory Amino Acid Agonists; Glycine; Kaolin; Male; Maze Learning; Microdialysis; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Reflex

In this study, the effect of (S)-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of (S)-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic (S)-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when (S)-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG (RS)-alpha-methylserine-O-phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of (S)-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG (S)-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. (S)-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.

Topics: Analysis of Variance; Animals; Benzhydryl Compounds; Benzoates; Carrageenan; Dinucleoside Phosphates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Excitatory Amino Acid Antagonists; Formaldehyde; Glycine; Hyperalgesia; Inflammation; Male; Mice; Pain; Pain Measurement; Pain Threshold; Phosphoserine; Reaction Time; Receptors, Metabotropic Glutamate