6-methyl-2-(phenylethynyl)pyridine and Neuralgia

This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. After theta burst stimulation (TBS) MPEP restored LTP in SNI mice. In combination with PEA, MPEP antagonized the PEA effect on discriminative memory and decreased LTP in SNI mice. The (RS)-4-(1-amino-1-carboxyethyl)phthalic acid (MDCPG), a selective mGluR8 antagonist, did not affect discriminative memory, but it induced a chemical LTP and prevented the enhancement of fEPSPs after TBS in SNI mice which were treated or not treated with PEA. The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain.

Topics: Amides; Animals; Dentate Gyrus; Disease Models, Animal; Ethanolamines; Excitatory Postsynaptic Potentials; Humans; Long-Term Potentiation; Male; Memory; Mice; Neuralgia; Olfactory Cortex; Palmitic Acids; Peripheral Nerve Injuries; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

Chemotherapeutic drugs such as paclitaxel cause painful peripheral neuropathy in many cancer patients and survivors. Although NMDA receptors (NMDARs) at primary afferent terminals are known to be critically involved in chemotherapy-induced chronic pain, the upstream signaling mechanism that leads to presynaptic NMDAR activation is unclear. Group I metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity and NMDAR regulation. Here we report that the Group I mGluR agonist (

Topics: Animals; Antineoplastic Agents, Phytogenic; Behavior, Animal; Cells, Cultured; Evoked Potentials; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Injections, Spinal; Male; Nerve Tissue Proteins; Neuralgia; Neurons, Afferent; Paclitaxel; Protein Kinase C; Protein Kinase Inhibitors; Pyridines; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, N-Methyl-D-Aspartate; Resorcinols; Spinal Cord Dorsal Horn; Synaptosomes

Wallerian degeneration or nerve demyelination, arising from spinal nerve compression, is thought to bring on chronic neuropathic pain. The widely distributed metabotropic glutamate receptor subtype 5 (mGluR5) is involved in modulating nociceptive transmission. The purpose of this study was to investigate the potential effects of mGluR5 on peripheral hypersensitivities after chronic constriction injury (CCI). Sprague-Dawley rats were operated on with four loose ligatures around the sciatic nerve to induce thermal hyperalgesia and mechanical allodynia. Primary afferents in dermis after CCI exhibited progressive decreases, defined as partial cutaneous denervation; importantly, mGluR5 expressions in primary afferents were statistically increased. CCI-induced neuropathic pain behaviors through the intraplantar injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGluR5 antagonist, were dose-dependently attenuated. Furthermore, the most increased mGluR5 expressions in primary afferents surrounded by reactive Schwann cells were observed at the distal CCI stumps of sciatic nerves. In conclusion, these results suggest that nerve demyelination results in the increases of mGluR5 expression in injured primary afferents after CCI; and further suggest that mGluR5 represents a main therapeutic target in developing pharmacological strategies to prevent peripheral hypersensitivities.

Topics: Animals; Demyelinating Diseases; Dermis; Excitatory Amino Acid Antagonists; Hyperalgesia; Immunohistochemistry; Male; Microscopy, Fluorescence; Mononeuropathies; Nerve Fibers; Neuralgia; Neurofilament Proteins; Pain Measurement; Pyridines; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Sciatic Nerve

Peripheral neuropathy is a common adverse effect of bortezomib-based chemotherapy. In this study we have investigated the role played by subtype 5 of metabotropic receptors in bortezomib induced peripheral neuropathy. Rats were administered with bortezomib three times weekly at 0.20 mg/kg for a total of 4 weeks in presence or absence of mGluR5 antagonist MPEP. The animals were submitted to paw-pressure test and tail sensory nerve conduction measurement more times during the treatment and follow-up. Bortezomib treatment induced a progressively increasing hyperalgesia in rat which was accompanied by a significant reduction in sensory nerve conduction velocity (SNCV). MPEP prevented the emergence of bortezomib-induced pain and counteracted SNCV reduction when co-administered with bortezomib treatment. Spinal extracellular glutamate levels increased in rats treated with bortezomib. Bortezomib-induced onset of the hyperalgesia and SNCV decrease could be prevented by agents that promote the reuptake of glutamate maintaining spinal glutamate at basal level. Our data support the manipulation of the glutamatergic system through the mGluR5 receptor in bortezomib induced peripheral neuropathy. The use of antagonists at the mGluR5, initiated at the same time as bortezomib-chemotherapy, might reduce the number of patients who develop painful peripheral chemo-neuropathy.

Topics: Analgesics; Animals; Boronic Acids; Bortezomib; Ceftriaxone; Cell Line, Tumor; Cell Survival; Central Nervous System Agents; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Hyperalgesia; Injections, Spinal; Male; Neural Conduction; Neuralgia; Peripheral Nervous System Diseases; Pyrazines; Pyridines; Random Allocation; Rats; Receptor, Metabotropic Glutamate 5

The metabotropic glutamate 5 (mGlu5) receptor is involved in both pain processing and modulation of µ-opioid induced antinociception and antihyperalgesia. Systemic mGlu5 receptor antagonists 2-methyl-6-phenylethynylpyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine (MTEP) provide antihyperalgesic effects in various pain models, but few studies have shown their interaction with morphine in neuropathic pain models. The aim of this study is to compare the effects of systemic and intrathecal MPEP/MTEP on morphine efficacy and tolerance in rats with chronic neuropathic pain. L5-6 spinal nerve ligation (SNL) was used to establish neuropathic pain model in rats. The Von Frey test and the hot water tail flick test were employed as behavior tests. Low, medium and high doses of MPEP/MTEP were tested for their effect on both acute morphine efficacy and chronic morphine tolerance. SNL provides sustained neuropathic pain on the ipsilateral hind paw of rats. Both systemic and intrathecal MPEP/MTEP had antiallodynia effects and boosted morphine's efficacy in a dose-dependent manner in the Von Frey tests but not in the tail flick tests. In fact, high doses of MTEP and MPEP attenuated morphine's antinociceptive effect in the latter test. After intrathecal chronic co-administration with morphine, low-doses of MTEP/MPEP attenuated morphine tolerance in both tests. Systemically, only MTEP attenuated morphine tolerance, and only in the Von Frey tests, not in the tail flick tests, whereas MPEP had no effect on morphine tolerance in either tests. The therapeutic use of mGlu5 receptor antagonists may have distinct effects in different pain models.

Topics: Analgesics; Animals; Behavior, Animal; Drug Interactions; Drug Tolerance; Injections; Ligation; Male; Morphine; Neuralgia; Nociception; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Spinal Nerves; Thiazoles

This study analyzed the effect of intra-ventrolateral periaqueductal grey (VL PAG) cannabinoid receptor (CB) stimulation on pain responses and rostral ventromedial medulla (RVM) neural activity in the chronic constriction injury (CCI) model of neuropathic pain in rats. Interaction between CB1 and metabotropic glutamate 1 and 5 (mGlu(1)/mGlu(5)) receptors was also investigated together with the expression of the CB1 receptor associated Gαi3 and cannabinoid receptor interacting 1a (CRIP 1a) proteins and the endocannabinoid synthesising and hydrolysing enzymes. In rats not subjected to CCI-induced pain, intra-VL PAG (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) (2-4-8 nmol), a CB receptor agonist, increased the tail flick latency and changed the ongoing activity of RVM OFF and the tail flick-related activity of the ON and OFF cells, accordingly. These effects were prevented by SR141716A and MPEP, selective CB(1) and mGlu(5) receptor antagonists, respectively, though not by CPCCOEt, a selective mGlu(1) receptor antagonist. A higher dose up to 16 nmol of WIN 55,212-2 was necessary to increase tail flick latency and change ON and OFF cell activity in CCI rats. Consistently, CCI rats showed a decrease in the expression of CB(1) receptors, NAPE-PLD, Gαi3 and CRIP 1a proteins;the expression of diacylglycerol lipase A (DAGLA) was increased while fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) did not change. As in control rats, MPEP and SR141716A also blocked WIN 55,212-2- induced effects in CCI rats. These data demonstrate a down regulation of the endocannabinoid system and a functional interaction between mGlu(5) and CB(1) receptors for cannabinoid-mediated effect in the PAG-RVM pain circuitry in neuropathic pain inflicted rats.

Topics: Analgesics; Animals; Benzoxazines; Disease Models, Animal; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Medulla Oblongata; Morpholines; Naphthalenes; Neuralgia; Periaqueductal Gray; Piperidines; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Rimonabant