Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I-III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-beta-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 microM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid-mediated cross talk between glutamatergic and GABAergic synapses within the PAG.
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PMID:Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling. 1821 89

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in humans. They convey extracellular signals into the cell interior by activating intracellular processes such as heterotrimeric G protein-dependent signaling pathways. They are widely distributed in the nervous system, and mediate key physiological processes including cognition, mood, appetite, pain and synaptic transmission. With at least 30% of marketed drugs being GPCR modulators, they are a major therapeutic target in the pharmaceutical industry's drug discovery programs. This review will survey recently patented ligands for GPCRs implicated in CNS disorders, in particular the metabotropic glutamate, adenosine and cannabinoid receptors. Metabotropic glutamate receptors regulate signaling by glutamate, the major excitatory brain neurotransmitter, while adenosine is a ubiquitous neuromodulater mediating diverse physiological effects. Recent patents for ligands of these receptors include mGluR5 antagonists and adenosine A(1) receptor agonists. Cannabinoid receptors remain one of the most important GPCR drug discovery target due to the intense interest in CB(1) receptor antagonists for treating obesity and metabolic syndrome. Such small molecule ligands are the outcome of the continuing focus of many pharmaceutical companies to identify novel GPCR agonist, antagonist or allosteric modulators useful for CNS disorders, for which more effective drugs are eagerly awaited.
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PMID:GPCR drug discovery: novel ligands for CNS receptors. 1822 Dec 21

Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3mg/kg; i.p.) potentiated the effects of a single morphine injection (20mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.
Pain 2008 Sep 30
PMID:Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain. 1844 82

Protein associated with Myc (PAM) is a giant E3 ubiquitin ligase of 510 kDa. Although the role of PAM during neuronal development is well established, very little is known about its function in the regulation of synaptic strength. Here we used multiepitope ligand cartography (MELC) to study protein network profiles associated with PAM during the modulation of synaptic strength. MELC is a novel imaging technology that utilizes biomathematical tools to describe protein networks after consecutive immunohistochemical visualization of up to 100 proteins on the same sample. As an in vivo model to modulate synaptic strength we used the formalin test, a common model for acute and inflammatory pain. MELC analysis was performed with 37 different antibodies or fluorescence tags on spinal cord slices and led to the identification of 1390 PAM-related motifs that distinguish untreated and formalin-treated spinal cords. The majority of these motifs related to ubiquitin-dependent processes and/or the actin cytoskeleton. We detected an intermittent colocalization of PAM and ubiquitin with TSC2, a known substrate of PAM, and the glutamate receptors mGluR5 and GLUR1. Importantly these complexes were detected exclusively in the presence of F-actin. A direct PAM/F-actin interaction was confirmed by colocalization and cosedimentation. The binding of PAM toward F-actin varied strongly between the PAM splice forms found in rat spinal cords. PAM did not ubiquitylate actin or alter actin polymerization and depolymerization. However, F-actin decreased the ubiquitin ligase activity of purified PAM. Because PAM activation is known to involve its translocation, the binding of PAM to F-actin may serve to control its subcellular localization as well as its activity. Taken together we show that defining protein network profiles by topological proteomics analysis is a useful tool to identify previously unknown protein/protein interactions that underlie synaptic processes.
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PMID:Toponomics analysis of functional interactions of the ubiquitin ligase PAM (Protein Associated with Myc) during spinal nociceptive processing. 1875 28

Neurotensin modulates pain via its actions within descending analgesic pathways which include brain regions such as the midbrain periaqueductal grey (PAG). The aim of this study was to examine the cellular actions of neurotensin on PAG neurons. Whole cell patch clamp recordings were made from rat midbrain PAG slices in vitro to examine the postsynaptic effects of neurotensin and its effects on GABA(A) mediated inhibitory postsynaptic currents (IPSCs). Neurotensin (100-300 nM) produced an inward current in subpopulations of opioid sensitive and insensitive PAG neurons which did not reverse over membrane potentials between -50 and -130 mV. The neurotensin induced current was abolished by the NTS1 and NTS1/2 antagonists SR48692 (300 nM) and SR142948A (300 nM). Neurotensin also produced a reduction in the amplitude of evoked IPSCs, but had no effect on the rate and amplitude of TTX-resistant miniature IPSCs. The neurotensin induced inhibition of evoked IPSCs was reduced by the mGluR5 antagonist MPEP (5microM) and abolished by the cannabinoid CB(1) receptor antagonist AM251 (3 microM). These results suggest that neurotensin produces direct neuronal depolarisation via NTS1 receptors and inhibits GABAergic synaptic transmission within the PAG. The inhibition of synaptic transmission is mediated by neuronal excitation and action potential dependent release of glutamate, leading to mGluR5 mediated production of endocannabinoids which activate presynaptic CB(1) receptors. Thus, neurotensin has cellular actions within the PAG which are consistent with both algesic and analgesic activity, some of which are mediated via the endocannabinoid system.
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PMID:Neurotensin inhibition of GABAergic transmission via mGluR-induced endocannabinoid signalling in rat periaqueductal grey. 1935 67

Accumulating evidence indicates that the metabotropic glutamate receptor mGluR5 is involved in the peripheral mechanisms of inflammatory nociception. To investigate whether mGluR5 may mediate the inflammatory pain and thermal hyperalgesia in the dental pulp, we examined the expression of mGluR5 and transient receptor potential vanilloid 1 (TRPV1) in human dental pulp by immunohistochemistry and electron microscopy; mGluR5-immunopositive (+) axons were observed in nerve bundles and branched extensively within the peripheral coronal pulp. Most of the mGluR5+ axons were unmyelinated. A large fraction of these axons (36.5%) were immunostained for TRPV1. Immunoreactivity for mGluR5 and TRPV1 was also observed in odontoblasts. These results support the possibility that the nerve fibers in the dental pulp mediate inflammatory pain and thermal hyperalgesia through coactivation of mGluR5 and TRPV1 and also suggest a possible role for odontoblasts in the transduction of nociceptive signals via mGluR5-mediated mechanism.
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PMID:Expression of metabotropic glutamate receptor mGluR5 in human dental pulp. 1941 84

Group I mGluRs (mGluR1 and 5) pre- and/or postsynaptically regulate synaptic transmission at glutamatergic synapses. By recording spontaneous EPSCs (sEPSCs) in the spinal trigeminal subnucleus oralis (Vo), we here investigated the regulation of glutamatergic transmission through the activation of group I mGluRs. Bath-applied DHPG (10 microM/5 min), activating the group I mGluRs, increased sEPSCs both in frequency and amplitude; particularly, the increased amplitude was long-lasting. The DHPG-induced increases of sEPSC frequency and amplitude were not NMDA receptor-dependent. The DHPG-induced increase in the frequency of sEPSCs, the presynaptic effect being further confirmed by the DHPG effect on paired-pulse ratio of trigeminal tract-evoked EPSCs, an index of presynaptic modulation, was significantly but partially reduced by blockades of voltage-dependent sodium channel, mGluR1 or mGluR5. Interestingly, PKC inhibition markedly enhanced the DHPG-induced increase of sEPSC frequency, which was mainly accomplished through mGluR1, indicating an inhibitory role of PKC. In contrast, the DHPG-induced increase of sEPSC amplitude was not affected by mGluR1 or mGluR5 antagonists although the long-lasting property of the increase was disappeared; however, the increase was completely inhibited by blocking both mGluR1 and mGluR5. Further study of signal transduction mechanisms revealed that PLC and CaMKII mediated the increases of sEPSC in both frequency and amplitude by DHPG, while IP3 receptor, NO and ERK only that of amplitude during DHPG application. Altogether, these results indicate that the activation of group I mGluRs and their signal transduction pathways differentially regulate glutamate release and synaptic responses in Vo, thereby contributing to the processing of somatosensory signals from orofacial region.
Mol Pain 2009 Sep 02
PMID:Signal transduction mechanisms underlying group I mGluR-mediated increase in frequency and amplitude of spontaneous EPSCs in the spinal trigeminal subnucleus oralis of the rat. 1972 70

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E2 (PGE2) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE2-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.
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PMID:Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain. 1983 97

Diabetic neuropathic pain is associated with increased glutamatergic input in the spinal dorsal horn. Group I metabotropic glutamate receptors (mGluRs) are involved in the control of neuronal excitability, but their role in the regulation of synaptic transmission in diabetic neuropathy remains poorly understood. Here we studied the role of spinal mGluR5 and mGluR1 in controlling glutamatergic input in a rat model of painful diabetic neuropathy induced by streptozotocin. Whole-cell patch-clamp recordings of lamina II neurons were performed in spinal cord slices. The amplitude of excitatory post-synaptic currents (EPSCs) evoked from the dorsal root and the frequency of spontaneous EPSCs (sEPSCs) were significantly higher in diabetic than in control rats. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) inhibited evoked EPSCs and sEPSCs more in diabetic than in control rats. Also, the percentage of neurons in which sEPSCs and evoked EPSCs were affected by MPEP or the group I mGluR agonist was significantly higher in diabetic than in control rats. However, blocking mGluR1 had no significant effect on evoked EPSCs and sEPSCs in either groups. The mGluR5 protein level in the dorsal root ganglion, but not in the dorsal spinal cord, was significantly increased in diabetic rats compared with that in control rats. Furthermore, intrathecal administration of MPEP significantly increased the nociceptive pressure threshold only in diabetic rats. These findings suggest that increased mGluR5 expression on primary afferent neurons contributes to increased glutamatergic input to spinal dorsal horn neurons and nociceptive transmission in diabetic neuropathic pain.
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PMID:Regulation of increased glutamatergic input to spinal dorsal horn neurons by mGluR5 in diabetic neuropathic pain. 1984 Feb 19

The anterior cingulate cortex (ACC), a limbic region associated with pain-related working memory and memory acquisition, receives a dense cholinergic innervation. To further understand the role of acetylcholine in ACC, we characterized the firing properties of pyramidal neurons following muscarinic receptor activation. Using whole-cell patch clamp recordings in acute brain slices, we report long-lasting nonsynaptic plateau potentials and persistent firing induced by carbachol (CCh) in pyramidal neurons in layers II/III of rat ACC. CCh responses were abolished by the muscarinic receptor antagonist atropine or by inhibitors of G proteins and phospholipase C. Inhibiting L-type calcium channels with nifedipine, removing extracellular calcium or chelating intracellular calcium with BAPTA also abolished plateau potentials and persistent firing. Blockade of nonselective cation channels with flufenamic acid, 2-aminoethyl diphenylborinate or SKF-96365 suppressed CCh responses and voltage-clamp recordings of CCh-sensitive currents revealed a transient receptor potential canonical-like cationic conductance. The group I metabotropic glutamate receptor (mGluR) agonist (S)-3,5-dihydroxyphenylglycine hydrate induced plateau potentials and persistent firing that were mediated by mGluR5. Our data demonstrate that receptor-operated channels drive calcium-dependent plateau potentials and persistent firing in layers II/III of ACC. Therefore, acetylcholine- and glutamate-evoked persistent activity in ACC may play a mnemonic role by allowing transient storage of information during pain processing.
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PMID:Metabotropic induction of persistent activity in layers II/III of anterior cingulate cortex. 2034 57


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