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The Journal of Neuroscience, December 1, 1998, 18(23):10180-10188

Antisense Ablation of Type I Metabotropic Glutamate Receptor mGluR₁ Inhibits Spinal Nociceptive Transmission

Marie R. Young¹, Gordon Blackburn-Munro¹, Tracey Dickinson¹, Melanie J. Johnson², Heather Anderson¹, Immaculate Nakalembe¹, and Susan M. Fleetwood-Walker¹

¹ Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom, and ² Medical Research Council Brain Metabolism Unit, Edinburgh EH8 9JZ, United Kingdom

Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR₁ and mGluR₅) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR₁ expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR₁ antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55°C) over a period of 4-7 d. This correlated with a selective reduction in mGluR₁, but not mGluR₅, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3,5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR₅ agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR₁ sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR₁ antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.

Key words: metabotropic glutamate receptors; mGluR₁; mGluR₅; dorsal horn; nociception; antisense oligodeoxynucleotide probe

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182310180-09$05.00/0

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