Signal transduction pathways of group I metabotropic glutamate receptor-induced long-term depression at sensory spinal synapses.
Activation of spinal group I metabotropic glutamate receptors (mGluRs) may have antinociceptive or pro-nociceptive effects in different pain models. Pharmacological activation of group I mGluRs leads to long-term depression (LTD) of synaptic strength between Adelta-fibers and neurons in lamina II of spinal dorsal horn of the rat. Here, we studied the signal transduction pathways involved. Synaptic strength between Adelta-fibers and lamina II neurons was assessed by perforated whole-cell patch-clamp recordings in a spinal cord-dorsal root slice preparation of young rats. Bath application of the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG] produced an LTD of Adelta-fiber-evoked responses. LTD induction by (S)-3,5-DHPG was prevented, when intracellular Ca(2+) stores were depleted by thapsigargin or cyclopiazonic acid (CPA). Preincubation with ryanodine to inhibit Ca(2+)-induced Ca(2+) release had no effect on LTD-induction by (S)-3,5-DHPG. In contrast, pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of inositol-1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) stores prevented LTD induction. Preincubation with the specific protein kinase C (PKC) inhibitors bisindolylmaleimide I (BIM) or chelerythrine, respectively, had no effect. Inhibition of L-type VDCCs by verapamil or nifedipine prevented LTD-induction by (S)-3,5-DHPG. The presently identified signal transduction cascade may be relevant to the long-term depression of sensory information in the spinal cord, including nociception.
Heinke
Bernhard
B
Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
Sandkühler
Jürgen
J
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D012118:Resorcinols / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology*
D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C079215:3,5-dihydroxyphenylglycine; D019284:Thapsigargin; D011493:Protein Kinase C; D002118:Calcium; D005998:Glycine