Actions of two new antagonists showing selectivity for different sub‐types of metabotropic glutamate receptor in the neonatal rat spinal cord

Jane, David E.; Jones, Philip L.; Pook, Peter C.K.; Tse, H. W.; Watkins, J. C.

doi:10.1111/j.1476-5381.1994.tb13151.x

Cited by 184 publications

(63 citation statements)

References 21 publications

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“…There is evidence showing that 1S,3R-1S,3R-ACPD does interact with mGluR4 (Thoreson and Miller, 1994;Flor et al, 1995); however, a form of 1S,3R-ACPD-induced presynaptic depression involves a component that is not mediated by the L-AP4 receptor (Cahusac, 1994;Jane et al, 1994;Lovinger and McCool, 1995). Thus, whether 1S,3R-ACPD and L-AP4 act on the same or distinct receptors to suppress synaptic transmission to PMNs remains unclear and requires further analysis.…”

Section: Possible Mechanism and Role Of Multiple Actions Of Mglurs Inmentioning

confidence: 99%

Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons

Dong¹,

Morin²,

Feldman

1996

J. Neurosci.

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To determine physiological roles of metabotropic glutamate receptors (mGluRs) affecting breathing, we examined the effects of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) on synaptic transmission and excitability of phrenic motoneurons (PMNs) in an in vitro neonatal rat brainstem/spinal cord preparation. The effects of 1S,3R-ACPD were multiple, including reduction of inspiratory-modulated synaptic currents and increase of neuronal excitability via an inward current (I acpd ) associated with a decrease of membrane conductance. The mechanism underlying synaptic depression was examined. We found that 1S,3R-ACPD reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. The current induced by exogenous AMPA was not significantly affected by 1S,3R-ACPD. These results suggest that 1S,3R-ACPD-induced reduction of inspiratory synaptic currents is mediated by presynaptic mGluRs. We also examined the ionic basis for I acpd . We found that I acpd had a reversal potential of approximately Ϫ100 mV, close to the estimated E K ϩ (Ϫ95 mV). Elevating extracellular [K ϩ ] to 9 mM reduced the I acpd reversal potential to Ϫ75 mV. The K ϩ channel blocker Ba 2ϩ induced an inward current with a reversal potential at Ϫ93 mV associated with a decrease of membrane conductance, closely resembling the effect of 1S,3R-ACPD. Moreover, Ba 2ϩ occluded 1S,3R-ACPD effects. In the presence of Ba 2ϩ , I acpd and the 1S,3R-ACPD-induced decrease of membrane conductance were diminished. Our data indicate that the dominant component of I acpd results from the blockade of a Ba 2ϩ -sensitive resting K ϩ conductance. We conclude that the activation of mGluRs affects the inspiratory-modulated activity of PMNs via distinct mechanisms at pre-and postsynaptic sites.

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Section: Possible Mechanism and Role Of Multiple Actions Of Mglurs Inmentioning

confidence: 99%

Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons

Dong¹,

Morin²,

Feldman

1996

J. Neurosci.

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“…( (MSPG) and (RS)-ca-methyl-4-phosphonophenylglycine (MPPG) were synthesized as described previously Jane et al, 1994;Kemp et al, 1994b). (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG-IV) was kindly provided by Dr Y. Ohfune (Tokyo). All drugs were made up as stock solutions, dissolved in equimolar NaOH at a concentration of at least 100 times the final concentration and were stored in frozen aliquots.…”

Section: Methodsmentioning

confidence: 99%

Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices

Bushell¹,

Jane²,

Tse³

et al. 1996

British J Pharmacology

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An understanding of the physiological and pathological roles of metabotropic glutamate receptors (mGluRs) is currently hampered by the lack of selective antagonists. Standard extracellular recording techniques were used to investigate the activity of recently reported mGluR antagonists on agonist‐induced depressions of synaptic transmission in the lateral perforant path of hippocampal slices obtained from 12–16 day‐old rats. The group III specific mGluR agonist, (S)‐2‐amino‐4‐phosphonobutanoate (L‐AP4) depressed basal synaptic transmission in a reversible and dose‐dependent manner. The mean (±s.e.mean) depression obtained with 100 μm L‐AP4 (the maximum concentration tested) was 74 ± 3% and the IC50 value was 3 ± 1 μm (n = 5). The selective group II mGluR agonists, (1S,3S)‐1‐aminocyclopentane‐1,3‐dicarboxylate ((1S,3S)‐ACPD) and (2S,1′R,2′R,3′R)‐2‐(2′,3′‐dicarboxycyclopropyl)glycine (DCG‐IV) also depressed basal synaptic transmission in a reversible and dose‐dependent manner. The mean depression obtained with 200 μm (1S,3S)‐ACPD was 83 ± 8% and the IC50 value was 12 ± 3 μm (n = 5). The mean depression obtained with 1 μm DCG‐IV was 73 ± 7% and the IC50 value was 88 ± 15 nM (n = 4). Synaptic depressions induced by the actions of 20 μm (1S,3S)‐ACPD and 10 μm L‐AP4 were antagonized by the mGluR antagonists, (+)‐α‐methyl‐4‐carboxyphenylglycine ((+)‐MCPG), (S)‐2‐methyl‐2‐amino‐4‐phosphonobutanoate (MAP4), (2S, 1′S,2′S)‐2‐methyl‐2‐(2′‐carboxycyclopropyl)glycine (MCCG), (RS)‐α‐methyl‐4‐tetrazolylphenylglycine (MTPG), (RS)‐α‐methyl‐4‐sulphonophenylglycine (MSPG) and (RS)‐α‐methyl‐4‐phosphonophenylglycine (MPPG) (all tested at 500 μm). (+)‐MCPG was a weak antagonist of both L‐AP4 and (1S,3S)‐ACPD‐induced depressions. MCCG was selective towards (1S,3S)‐ACPD, but analysis of its effects were complicated by apparent partial agonist activity. MAP4 showed good selectivity for L‐AP4‐induced effects. The most effective antagonist tested against 10 μm L‐AP4 was MPPG (mean reversal 90 ± 3%; n = 4). In contrast, the most effective antagonist tested against 20 μm (1S,3S)‐ACPD induced depressions was MTPG (mean reversal 64 ± 4%; n = 4). Both antagonists produced parallel shifts in agonist dose‐response curves. Schild analysis yielded estimated KD values of 11.7 μm and 27.5 μm, respectively. Neither antagonist had any effect on basal transmission or on depressions induced by the adenosine receptor agonist, 2‐chloroadenosine (500 nM; n = 3). We conclude that both group II and group III mGluRs can mediate synaptic depressions induced by mGluR agonists in the lateral perforant path. The mGluR antagonists MTPG, MPPG and MAP4 should be useful in determining the roles of group II and III mGluRs in the central nervous system.

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“…7,8 It has been suggested that Group II mGluRs play an inhibitory role. 9 It has also been reported that the peptide neurotransmitter N-acetylaspartylglutamate (NAAG; reviewed in Neale et al) 10,11 is released from spinal cord cells by depolarizing stimuli and selectively activates mGluR3. 12 Intrathecal administration of NAAG peptidase inhibitors produces an analgesic effect in both inflammatory pain models and in neuropathic pain models.…”

Section: Conclusion : Les Agonistes α-2 Produisent Un Effet Analgésiqmentioning

confidence: 99%

Regional Anesthesia and Pain

Saito

Aoe

Kozikowski

et al. 2006

Can J Anesth/J Can Anesth

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Purpose: Not all bone cancer pain can be effectively treated with current therapies. In the present study, the effects of ip administration of α-2 agonists (dexmedetomidine and clonidine), N-methyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), an N-acetylaspartylglutamate peptidase inhibitor (ZJ-43), and morphine were examined in a mouse bone cancer pain model. Methods:A bone cancer pain model was produced by injection of murine sarcoma cells into the medullary cavity of the distal femur. To estimate the level of bone cancer pain, the number of pain-related behaviours induced by repeated applications of a von Frey monofilament (0.166 g) to the site of tumour cells implantation was counted. Drugs were administered two weeks after the implantation.Results: Morphine produced a significant analgesic effect (P < 0.001). The α-2 agonists produced analgesic effects (P < 0.001) with an efficacy similar to that of morphine, but only at doses that produced severe sedation. MK-801 had only limited analgesic effects, while ketamine produced an analgesic effect (P < 0.001) with the same efficacy as morphine. ZJ-43 (100 mg·kg -1 ) had a significant analgesic effect (P < 0.05) and the effect of ZJ-43 was antagonized by the selective group II metabotropic glutamate receptor (mGluR) antagonist. Conclusion:These data suggest that α-2 agonists produce an analgesic effect only at a sedative dose and that ketamine, but not MK-801, is associated with an analgesic response without overt side effects. The effect of ZJ-43 is mediated by activating group II mGluRs. Objectif : Les douleurs du cancer des os ne sont pas toujours soulagées par les traitements habituels. Dans la présente étude, les effets de l'administration ip d'agonistes α-2 (dexmédétomi-dine et clonidine), d'antagonistes N-méthyl-D-aspartate (NMDA) (MK-801 et kétamine), d'un inhibiteur de N-acétylaspartylgluta-mate peptidase (ZJ-43) et de morphine ont été examinés dans un modèle de douleur du cancer des os chez la souris. Méthode : Un modèle de douleur du cancer des os a été produit en injectant des cellules de sarcome d'Ewing dans la cavité médul-laire distale du fémur. Pour évaluer le niveau de douleur, nous avons calculé le nombre de mouvements reliés à la douleur induite par l'application répétée d'un monofilament von Frey (0,166 g) au site de la tumeur implantée. Les médicaments ont été administrés deux semaines après l'implantation.Résultats : La morphine a produit une analgésie significative (P < 0,001). Les agonistes α-2 ont produit une analgésie (P < 0,001) similaire à celle de la morphine, mais seulement à des doses produisant une sédation importante. Le MK-801 a eu un effet limité et la kétamine a produit une analgésie aussi efficace que celle de la morphine (P < 0,001). ) a eu un effet analgésique significatif (P < 0,05)

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Actions of two new antagonists showing selectivity for different sub‐types of metabotropic glutamate receptor in the neonatal rat spinal cord

Cited by 184 publications

References 21 publications

Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons

Multiple Actions of 1S,3R-ACPD in Modulating Endogenous Synaptic Transmission to Spinal Respiratory Motoneurons

Pharmacological antagonism of the actions of group II and III mGluR agonists in the lateral perforant path of rat hippocampal slices

Regional Anesthesia and Pain

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