Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing

Jones, Carrie K.; Eberle, Elizabeth L.; Peters, Stephen C.; Monn, James A.; Shannon, Harlan E.

doi:10.1016/j.neuropharm.2005.05.008

Cited by 81 publications

(44 citation statements)

References 35 publications

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“…They were first shown to cross the blood-brain barrier (Bond et al, 1997) and then to have neuroprotective (Bond et al, 1998), anxiolytic (Helton et al, 1998), and anti-convulsant properties. The neuroprotective (Bruno et al, 2001), anxiolytic (Walker et al, 2002;Schoepp et al, 2003), and anticonvulsant (Smolders et al, 2004) effects have been confirmed and extended to inflammatory and neuropathic pain (Simmons et al, 2002;Jones et al, 2005) and to animal models of schizophrenia (Moghaddam and Adams, 1998;Cartmell et al, 2000a,b). In human clinical trials, peptide prodrugs of LY354740 and related compounds have shown efficacy in anxiety states (Grillon et al, 2003;Dunayevich et al, 2008) and in schizophrenia (Patil et al, 2007).…”

Section: Implications Of the Observed Strain Differencesmentioning

confidence: 95%

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

Ceolin¹,

Kantamneni²,

Barker³

et al. 2011

J. Neurosci.

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Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.1.0]-hexane2,6-dicarboxylic], an agonist at mGlu2 receptors and an antagonist at mGlu3 receptors in cell lines, to investigate the roles of these receptors in the temporo-ammonic path from entorhinal cortex to CA1-stratum lacunosum moleculare in rat hippocampal slices. Surprisingly, the degree of inhibition of the field EPSP induced by LY395756 fell into two distinct groups, with EC 50 values of Ͻ1 M and Ͼ100 M. In "sensitive" slices, LY395756 had additive actions with a mixed mGlu2/mGlu3 agonist, DCG-IV [(2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine], whereas in "insensitive" slices, LY395756 reduced the effect of DCG-IV, with an IC 50 of ϳ1 M. This separation into sensitive and insensitive slices could be explained by LY395756 acting as an mGlu2 agonist and mGlu3 antagonist, respectively, a finding supported by data from mice lacking these receptors. The heterogeneity was correlated with differences in expression levels of mGlu2 receptors within our Wistar colony and other Wistar substrains. The initial search for a behavioral correlate indicated that rats lacking mGlu2 receptors showed anxiety-like behavior in open-field and elevated plus maze assays. These findings have implications for rat models of psychiatric disease and are especially pertinent given that mGlu2 receptors are targets for compounds under development for anxiety.

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Section: Implications Of the Observed Strain Differencesmentioning

confidence: 95%

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

Ceolin¹,

Kantamneni²,

Barker³

et al. 2011

J. Neurosci.

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“…We tested the validity of this method by investigating the effects of LY354740, a specific agonist of group II mGluRs, and LY341495, a specific antagonist of group II mGluRs (Simmons et al, 2002). We selected these compounds because the role of the basal firing of touch-sensitive nerve fibers in preventing the induction of tactile allodynia may be attributed to sustained activation of group II mGluRs (Simmons et al, 2002;Jones et al, 2005). When a piece of cotton containing LY354740 (10 nM) was placed on the dorsal surface of the spinal cord around the L3-S1 level, tibial nerve cutting failed to induce cortical potentiation within 3 h (Fig.…”

Section: Tactile Allodynia As a Counterpart Of The Sensory Modality Smentioning

confidence: 99%

“…The changes in the spinal neural circuits were triggered by disruption of the afferent basal firing, and this effect was mimicked by the application of a group II mGluR antagonist, while the agonists are known to produce alleviating effects on neuropathic pain (Simmons et al, 2002;Jones et al, 2005). Activation of group II mGluRs reduces presynaptic transmitter release (Goudet et al, 2009), hyperpolarizes postsynaptic neurons by opening G-protein-coupled inward rectifier K ϩ channels (Irie et al, 2006;Lee and Sherman, 2009), and modulates spontaneous Ca 2ϩ spikes (Koga et al, 2010).…”

Section: Spinal Mechanism Underlying the Initial Phase Of Neuropathicmentioning

confidence: 99%

“…Brain structures outside the spinal cord are deeply involved in chronic pain (Flor et al, 1995;Neugebauer et al, 2009). However, agonists of group II mGluRs have alleviating effects on chronic neuropathic pain (Simmons et al, 2002;Jones et al, 2005). Surgical reconstruction of the injured afferent connection also has alleviating effects on chronic neuropathic pain (Inada et al, 2005), suggesting that restoration of the basal firing via the reconstructed afferent pathways may cure chronic neuropathic pain.…”

Section: The Initial Phase Of Neuropathic Pain As a Potential Therapementioning

confidence: 99%

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Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

Komagata

Chen²,

Suzuki³

et al. 2011

J. Neurosci.

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We tested a hypothesis that the spinal plasticity induced within a few hours after nerve injury may produce changes in cortical activities and an initial phase of neuropathic pain. Somatosensory cortical responses elicited by vibratory stimulation were visualized by transcranial flavoprotein fluorescence imaging in mice. These responses were reduced immediately after cutting the sensory nerves. However, the remaining cortical responses mediated by nearby nerves were potentiated within a few hours after nerve cutting. Nerve injury induces neuropathic pain. In the present study, mice exhibited tactile allodynia 1-2 weeks after nerve injury. Lesioning of the ipsilateral dorsal column, mediating tactile cortical responses, abolished somatic cortical responses to tactile stimuli. However, nontactile cortical responses appeared in response to the same tactile stimuli within a few hours after nerve injury, indicating that tactile allodynia was acutely initiated. We investigated the trigger mechanisms underlying the cortical changes. Endogenous glial cell line-derived neurotrophic factor (GDNF), found in the Meissner corpuscles, induced basal firing ϳ0.

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“…These drugs increase acetylation of the transcription factor p65/Re1A, which enhances gene expression of the metabotrobic glutamate receptors (mGlu2) in dorsal root ganglia neurons. Activation of these mGlu2 receptors inhibits primary afferent neurotransmitter release in the dorsal horn of the spinal cord and provides analgesia in animal models of neuropathic pain [158]. TSA also enhances m-opioid receptor transcription [159], indicating partial HDAC modulation of the endogenous opioid system.…”

Section: Intervention: Hdac Inhibitionmentioning

confidence: 99%

Molecular Signatures of Chronic Pain Subtypes

Shaw¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis project continues to be a biomarker discovery program focusing on the causes of persistent pain after traumatic amputation in the combat setting. In the second year we have: 1) maintained the necessary regulatory approval at WRMC and Duke University. We have obtained and maintained documents for approval by MRMC; 2) maintained our interactive, secure web based data collection system; 3) populated our biorepository at Duke with bioresource collected from 71 patients enrolled at WRNMMC; 4) conducted further on-site visits and investigator meetings at WRNMMC; 5) submitted samples to the Duke Core Lab facilities for proteomic, metabolomic, genomic, genetic and epigenetic assays. We have received our initial pilot results and presented these in Washington DC at ASA. We have published two more papers and are now collecting our validation cohort of patients. Our overall progress is slightly ahead of target, given the lengthy administrative delays during year one. Lastly, we have been funded by DOD to conduct an intervention trial at WRNMMC and the Durham VAMC of valproate for the prevention of amputation induced chronic pain.

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Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing

Cited by 81 publications

References 35 publications

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

Molecular Signatures of Chronic Pain Subtypes

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