title: Transient, activity dependent inhibition of transmitter release from low threshold afferents mediated by GABAA receptors in spinal cord lamina III/IV.
abstract: BACKGROUND
  Presynaptic GABAA receptors (GABAARs) located on central terminals of low threshold afferent fibers are thought to be involved in the processing of touch and possibly in the generation of tactile allodynia in chronic pain. These GABAARs mediate primary afferent depolarization (PAD) and modulate transmitter release. The objective of this study was to expand our understanding of the presynaptic inhibitory action of GABA released onto primary afferent central terminals following afferent stimulation.
  
  
  RESULTS
  We recorded evoked postsynaptic excitatory responses (eEPSCs and eEPSPs) from lamina III/IV neurons in spinal cord slices from juvenile rats (P17-P23, either sex), while stimulating dorsal roots. We investigated time and activity dependent changes in glutamate release from low threshold A fibers and the impact of these changes on excitatory drive. Blockade of GABAARs by gabazine potentiated the second eEPSC during a train of four afferent stimuli in a large subset of synapses. This resulted in a corresponding increase of action potential firing after the second stimulus. The potentiating effect of gabazine was due to inhibition of endogenously activated presynaptic GABAARs, because it was not prevented by the blockade of postsynaptic GABAARs through intracellular perfusion of CsF. Exogenous activation of presynaptic GABAARs by muscimol depressed evoked glutamate release at all synapses and increased paired pulse ratio (PPR).
  
  
  CONCLUSIONS
  These observations suggest that afferent driven release of GABA onto low threshold afferent terminals is most effective following the first action potential in a train and serves to suppress the initial strong excitatory drive onto dorsal horn circuitry.
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Campi, 287, 41125, Modena, Italy. chiarabetelli@yahoo.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Betelli
authors.affiliation: Departments of Physiology and Cellular Biophysics, Neuroscience, Columbia University, 630 W. 168th Street, New York, NY, 10032, USA. abmacdermott@gmail.com.
authors.forename: Amy B
authors.initials: AB
authors.lastname: MacDermott
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Campi, 287, 41125, Modena, Italy. bardoni@unimo.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Bardoni
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D008297:Male; D008959:Models, Neurological; D009118:Muscimol / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D018009:Receptors, Glycine / Q000378:metabolism; D012684:Sensory Thresholds / Q000187:drug effects; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D011724:Pyridazines; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D009118:Muscimol; C049853:gabazine