Contributions of mGlu1 and mGlu5 receptors to interactions with N-methyl-d-aspartate receptor-mediated responses and nociceptive sensory responses of rat thalamic neurons

doi:10.1016/S0306-4522(00)00265-7

Neuroscience

Volume 100, Issue 2, 14 September 2000, Pages 375-380

https://doi.org/10.1016/S0306-4522(00)00265-7 Get rights and content

Abstract

The nociceptive responses of rat ventrobasal thalamus neurons can be reduced by N-methyl-d-aspartate antagonists and by selective metabotropic glutamate receptor mGlu1 antagonists. The recent development of the mGlu5-selective antagonist 6-methyl-2-(phenylethynyl)-pyridine now allows the direct probing of the possible involvement of mGlu5 receptors in thalamic nociceptive responses. Extracellular recordings were made from single neurons in the ventrobasal thalamus and immediately overlying dorsal thalamic nuclei of adult urethane-anaesthetized rats using multi-barrel electrodes. Responses of neurons to iontophoretic applications of the mGlu5-selective agonist (R,S)-2-chloro-5-hydroxyphenylglycine were selectively reduced during continuous iontophoretic applications of 6-methyl-2-(phenylethynyl)-pyridine. Similar applications of 6-methyl-2-(phenylethynyl)-pyridine reduced neuronal responses to noxious thermal stimuli to 53±9.5% of control responses. Co- application by iontophoresis of N-methyl-d-aspartate and metabotropic glutamate receptor agonists resulted in a mutual potentiation of excitatory responses. This effect could be reduced by either 6-methyl-2-(phenylethynyl)-pyridine or the mGlu1 antagonist LY367385.

These results, taken together with previous data, suggest that acute thalamic nociceptive responses are mediated by a combination of mGlu1, mGlu5 and N-methyl-d-aspartate receptor activation, and that co-activation of these receptors produces a synergistic excitatory effect. Thus blockade of any of these receptor types would have a profound effect on the overall nociceptive response.

Section snippets

Experimental procedures

Experiments were carried out in adult Wistar rats (300–500 g) (Harlan UK Ltd, Bicester, UK) anaesthetized with urethane (1.2 g/kg, i.p), as previously described.³⁴ A tracheal cannulation was made and the rats were allowed to breathe spontaneously. In some animals an external jugular vein was cannulated to allow i.v. administration of drugs. The electrocardiogram waveform and rate was monitored throughout each experiment via limb surface electrodes. The electroencephalogram was recorded and

Metabotropic glutamate receptors and nociceptive responses

The effects of the mGlu5 antagonist MPEP applied iontophoretically on responses to the mGlu5-selective agonist CHPG,¹² the broad-spectrum mGlu agonist ACPD,¹⁰ and NMDA were investigated in 17 neurons. In all of these neurons responses to regular ejections of agonists were recorded over several 5-min cycles prior to the ejection of MPEP. The antagonist was then continuously ejected for one or more agonist ejection cycles, and the MPEP ejection was terminated when a selective effect was seen or

Discussion

In the present study we have found that the mGlu5 antagonist MPEP reduces nociceptive responses of thalamic neurons. In addition, we have confirmed the previous findings by ourselves³⁷ and others¹⁸ that MPEP is a suitable antagonist to block mGlu5 receptor-mediated responses in the brain. It is known that mGlu5 receptors are present in the rat thalamus,1., 26., 32., 43. and it is likely that these receptors are responsible for the excitatory responses seen upon iontophoretic application of

Acknowledgements

We thank F. Gasparini and R. Kuhn for donations of MPEP and B. Clark and A. Kingston for donations of LY367385. This study was supported by Novartis and The Wellcome Trust.

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Contributions of mGlu1 and mGlu5 receptors to interactions with N-methyl-d-aspartate receptor-mediated responses and nociceptive sensory responses of rat thalamic neurons

Abstract

Section snippets

Experimental procedures

Metabotropic glutamate receptors and nociceptive responses

Discussion

Acknowledgements

Neuropharmacology

Pain

Neurosci. Lett.

Neuropharmacology

Neurosci. Lett.

Pain

Neuropharmacology

Pain

Neuropharmacology

Neuron

Brain Res.

Brain Res.

Neurochem. Int.

Prog. Neurobiol.

Neuroscience

Neuropharmacology

Neurosci. Lett.

Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction

J. biol. Chem.

Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems

Nature Neurosci.

Anti-hyperalgesic effects of the novel metabotropic glutamate receptor 5 antagonist methylphenylethynlpyridine, in rat models of inflammatory pain

Br. J. Pharmac.

Glutamate-triggered events inducing corticostriatal long-term depression

J. Neurosci.

Evaluation of the activity of a novel metabotropic glutamate receptor antagonist (±)-2-amino-2-3-cis- and trans-carboxycyclobutyl-3-(9-thioxanthyl acid) in the in vitro neonatal spinal cord and in an in vivo pain model

Neuroscience

Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca²⁺ signal transduction