ly-341495 and 4-aminopyrrolidine-2-4-dicarboxylic-acid

Transient receptor potential vanilloid 1 (TRPV1) receptors are critical to nociceptive processing. Understanding how these receptors are modulated gives insight to potential therapies for pain. We demonstrate using double labeling immunohistochemistry that Group II metabotropic glutamate receptors (mGluRs) are co-expressed with TRPV1 on rat dorsal root ganglion (DRG) cells. In behavioral studies, intraplantar 0.1 microM APDC, a group II agonist, significantly attenuates capsaicin-induced nociceptive behaviors through a local effect. The APDC-induced inhibition of capsaicin responses is blocked by 1 microM LY341495, a group II antagonist. At the single fiber level, nociceptor responses to capsaicin are significantly decreased following exposure to APDC and this effect is blocked by LY341495. Finally, activation of peripheral group II mGluRs inhibits forskolin-induced thermal hyperalgesia and nociceptor heat sensitization, suggesting group II receptors are negatively coupled to the cAMP/PKA pathway. The data indicate that group II mGluRs and TRPV1 receptors are co-expressed on peripheral nociceptors and activation of mGluRs can inhibit painful sensory transmission following TRPV1 activation. The data are consistent with group II and TRPV1 receptors being linked intracellularly by the cAMP/PKA pathway. Peripheral group II mGluRs are important targets for drug discovery in controlling TRPV1-induced nociception.

Topics: Amino Acids; Animals; Capsaicin; Colforsin; Electrophysiological Phenomena; Ganglia, Spinal; Hot Temperature; Hyperalgesia; Immunohistochemistry; Male; Nociceptors; Pain; Pain Measurement; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; TRPV Cation Channels; Xanthenes

Metabotropic glutamate receptor (mGluR) 2/3 is distributed in neurons and glial cells in many regions of the nervous system, but its role in nociceptive processing is unclear. In this study, we examined the mRNA expressions of mGluR2 and mGluR3, by real-time RT-PCR, in the spinal cord. We further investigated the possible involvement of mGluR2/3 and mechanisms underlying peripheral inflammatory pain induced by subcutaneous complete Freund's adjuvant (CFA) injection. We demonstrate that compared to the controls, the mRNA expression levels of mGluR2 and mGluR3 were significantly higher 4h after CFA injection. Functionally, blocking mGluR2/3 by their antagonist (2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) alleviated the CFA-induced mechanical allodynia and the inhibitory effects were reversed by mGluR2/3 agonist (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R, 4R)-APDC). In addition, a glial metabolism inhibitor dl-fluorocitric acid barium salt (fluorocitric acid) also inhibited the CFA-induced mechanical allodynia in a dose-dependent manner. Remarkably, simultaneous inhibition of mGluR2/3 and glial metabolism had synergistic effects. The co-administration of LY341495 and fluorocitric acid with minimal dosages produced significant more inhibition than the additive effects by the individual inhibitor alone. In summary, our data suggest that spinal mGluR2/3 contributes to the generation of mechanical allodynia induced by peripheral inflammation. We also suggest that involvement of mGluR2/3 in the communication between glial cells and neurons takes part in the processing of nociceptive information.

Topics: Amino Acids; Analgesics; Animals; Citrates; Dose-Response Relationship, Drug; Freund's Adjuvant; Hyperesthesia; Inflammation; Male; Neuroglia; Pain; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Cord; Xanthenes

The present study has examined the anticonvulsant and neuroprotective effect of group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion. Comparable time intervals were used for sacrificing the pups which had received 2R,4R-APDC. Low doses of 2R,4R-APDC (0.05 nmol/side) provided a pronounced anticonvulsant effect which was abolished by pretreatment with a selective group II mGluR antagonist LY341495. Generalized clonic-tonic seizures were completely suppressed and cortical energy metabolite changes which normally accompany these seizures were either normalized (decrease of glucose and glycogen) or markedly reduced (an accumulation of lactate). EEG recordings support the marked anticonvulsant effect of 2R,4R-APDC, nevertheless, this was only partial. In spite of the absence of obvious motor phenomena, isolated spikes or even short periods of partial ictal activity could be observed. Isolated spikes could also be seen in some animals after application of 2R,4R-APDC alone, reflecting most likely subclinical proconvulsant activity of this agonist. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration, as revealed by Fluoro-Jade B staining, was observed in a number of brain regions following infusion of DL-HCA alone (seizure group), whereas 2R,4R-APDC pretreatment provided substantial neuroprotection. The present findings support the possibility that group II mGluRs are a promising target for a novel approach to treating epilepsy.

Topics: Amino Acids; Animals; Animals, Newborn; Anticonvulsants; Behavior, Animal; Brain; Brain Chemistry; Brain Injuries; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Excitatory Amino Acid Antagonists; Fluoresceins; Fluorescent Dyes; Functional Laterality; Glucose; Glycogen; Homocysteine; Lactic Acid; Male; Nerve Degeneration; Organic Chemicals; Proline; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Seizures; Time Factors; Xanthenes

While group II metabotropic glutamate receptors (mGluRs) are known to be expressed in the rat globus pallidus (GP), their functions remain poorly understood. We used standard patch clamping technique in GP slices to determine the effect of group II mGluR activation on excitatory transmission in this region. Activation of group II mGluRs with the group-selective agonist DCG-IV or APDC reduced the amplitude of the evoked excitatory postsynaptic currents (EPSCs) and significantly increased the paired pulse ratio suggesting a presynaptic site of action. This was further supported by double-labeling electron microscopy data showing that group II mGluRs (mGluR2 and 3) immunoreactivity is localized in glutamatergic pre-terminal axons and terminals in the GP. Furthermore, we found that LY 487379, an mGluR2-specific allosteric modulator, significantly potentiated the inhibitory effect of DCG-IV on the excitatory transmission in the GP. Co-incubation with 30 microM LY 487379 increased the potency of DCG-IV about 10-fold in the GP. We were thus able to pharmacologically isolate the mGluR2-mediated function in the rat GP using an mGluR2-specific allosteric modulator. Therefore, our findings do not only shed light on the functions of group II mGluRs in the GP, they also illustrate the therapeutic potential of mGluR-targeting allosteric modulators in neurological disorders such as Parkinson's disease.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Aminobutyrates; Anesthetics, Local; Animals; Animals, Newborn; Cyclopropanes; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Globus Pallidus; Glycine; In Vitro Techniques; Lidocaine; Membrane Potentials; Methoxyhydroxyphenylglycol; Neurons; Patch-Clamp Techniques; Proline; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Sulfonamides; Synaptic Transmission; Xanthenes

Topics: Amino Acids; Animals; Excitatory Amino Acid Antagonists; Extracellular Space; Feedback; Glutamates; Memory, Short-Term; Microinjections; Prefrontal Cortex; Proline; Psychomotor Performance; Rats; Receptors, AMPA; Xanthenes

Topics: Amino Acids; Animals; Astrocytes; Carrier Proteins; Cells, Cultured; Cerebral Cortex; Cystine; Enzyme Activators; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Phosphotransferases; Proline; Rats; Receptors, Metabotropic Glutamate; Xanthenes

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amino Acids; Animals; Dopamine Agonists; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; Motor Activity; Nucleus Accumbens; Proline; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate; Xanthenes