6-cyano-7-nitroquinoxaline-2-3-dione and Acute-Disease

The cellular mechanisms involved in the generation of spontaneous epileptiform potentials were investigated in the pirifom cortex of the in vitro isolated guinea-pig brain. A single, unilateral injection of bicuculline (150-200 nmol) in the anterior piriform cortex induced locally spontaneous interictal spikes that recurred with a period of 8.81+/-4.47 s and propagated caudally to the ipsi- and contralateral hemispheres. Simultaneous extra- and intracellular recordings from layer II and III principal cells showed that the spontaneous interictal spike correlates to a burst of action potentials followed by a large afterdepolarization. Intracellular application of the sodium conductance blocker, QX-314 (80 mM), abolished bursting activity and unmasked a high-threshold slow spike enhanced by the calcium chelator EGTA (50 mM). The slow spike was abolished by membrane hyperpolarization and by local perfusion with 2 mM cadmium. The depolarizing potential that followed the primary burst was reduced by arterial perfusion with the N-methyl-D-aspartate receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (100-200 microM). The non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM), completely and reversibly blocked the spontaneous spikes. The interictal spikes were terminated by a large afterpotential blocked either by intracellular QX-314 (80 mM) or by extracellular application of phaclofen and 2-hydroxysaclofen (10 and 4 mM, respectively). The present study demonstrates that, in an acute model of epileptogenesis, spontaneous interictal spikes are fostered by a primary burst of fast action potentials that ride on a regenerative high-threshold, possibly calcium-mediated spike, which activates a recurrent, glutamate-mediated potential responsible for the entrainment of adjacent and remote cortical regions. The bursting activity is controlled by a GABA(B) receptor-mediated inhibitory synaptic potential.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Acute Disease; Animals; Bicuculline; Brain; Cerebral Cortex; Disease Models, Animal; Epilepsies, Partial; Functional Laterality; Glutamic Acid; Guinea Pigs; In Vitro Techniques; Lidocaine; Membrane Potentials; Reaction Time; Synaptic Transmission

Following induction of acute knee joint arthritis in rats, an increase in the release of amino acids in the spinal dorsal horn occurs in two phases: (1) at the time of injection for all amino acids tested; and (2) a late prolonged phase for aspartate (Asp) and glutamate (Glu) (3.5-8 h). In the present study, the increased late phase release of Glu was reversed by posttreatment of the spinal cord with the N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, but not with the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Asp late phase release in arthritic animals was unaffected by posttreatment of the spinal cord with either AP7 or CNQX. Arthritic animals became hyperalgesic to radiant heat stimuli by 4 h and this hyperalgesia was reversed by both CNQX and AP7. During the paw withdrawal latency (PWL) test for heat hyperalgesia, there was an increase in the glycine (Gly) and serine (Ser) concentrations in the dorsal horn. This increase in Gly and Ser was blocked by both CNQX and AP7. Indications of inflammation in arthritic animals posttreated with AP7, including increased joint circumference and temperature, were similar to animals that did not receive antagonists. Arthritic animals posttreated with CNQX, however, showed a reduction in the degree of joint swelling. Thus, both non-NMDA and NMDA receptors appear to play a role in the processing of the information evoked by stimuli in the periphery. The arthritis-induced release of Gly and Ser during the PWL test for heat hyperalgesia appears to be dependent on activation of both non-NMDA and NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Acute Disease; Amino Acids; Analysis of Variance; Animals; Arthritis; Excitatory Amino Acids; Joints; Male; Microdialysis; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, N-Methyl-D-Aspartate; Spinal Cord