enkephalin--ala(2)-mephe(4)-gly(5)- and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

The anterior cingulate cortex (ACC)--which plays a role in pain, emotions and behavior--can generate epileptic seizures. To date, little is known on the neuronal mechanisms leading to epileptiform synchronization in this structure. Therefore, we investigated the role of excitatory and inhibitory synaptic transmission in epileptiform activity in this cortical area. In addition, since the ACC presents with a high density of opioid receptors, we studied the effect of opioid agonism on epileptiform synchronization in this brain region.. We used field and intracellular recordings in conjunction with pharmacological manipulations to characterize the epileptiform activity generated by the rat ACC in a brain slice preparation.. Bath-application of the convulsant 4-aminopyridine (4AP, 50 microM) induced both brief and prolonged periods of epileptiform synchronization resembling interictal- and ictal-like discharges, respectively. Interictal events could occur more frequently before the onset of ictal activity that was contributed by N-methyl-D-aspartate (NMDA) receptors. Mu-opioid receptor activation abolished 4AP-induced ictal events and markedly reduced the occurrence of the pharmacologically isolated GABAergic synchronous potentials. Ictal discharges were replaced by interictal events during GABAergic antagonism; this GABA-independent activity was influenced by subsequent mu-opioid agonist application.. Our results indicate that both glutamatergic and GABAergic signaling contribute to epileptiform synchronization leading to the generation of electrographic ictal events in the ACC. In addition, mu-opioid receptors appear to modulate both excitatory and inhibitory mechanisms, thus influencing epileptiform synchronization in the ACC.

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anticonvulsants; Cortical Synchronization; Electroencephalography; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Epilepsies, Partial; Evoked Potentials; GABA Antagonists; Gyrus Cinguli; In Vitro Techniques; Male; Membrane Potentials; Neural Inhibition; Neurons; Piperazines; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, GABA-A; Receptors, GABA-B; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Opioid, mu; Synaptic Transmission

1. Field potential recordings and measurements of the extracellular concentration of free K+ ([K+]o) and Ca2+ ([Ca2+]o) were made during application of 4-aminopyridine (4-AP, 50 microM) in hippocampal slices that were obtained from 11- to 32-day-old rats. 2. Spontaneous field potentials recorded under this experimental condition in the CA3 stratum radiatum of slices from rats < 23 days old consisted of interictal (duration, 0.2-1.4 s; intervals of occurrence, 0.9-3.4 s) and ictal epileptiform discharges (duration, 5-46 s; intervals of occurrence, 22-259 s) and negative-going potentials that often preceded the onset of ictal discharge. Ictal activity became rare in slices from rats > 25 days old. 3. The negative-going potential (which also corresponded to the ictal discharge onset) was associated with [K+]o increases to 9.4 +/- 3.6 mM (mean +/- S.D.) from 3.25 mM baseline (n = 11 slices). [K+]o remained elevated at 5-6 mM throughout the ictal event. Decreases in [Ca2+]o (from 1.8 mM baseline to 1.3 +/- 0.1 mM, n = 7) were observed during the ictal discharge. 4. Interictal and ictal discharges were abolished by the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX, 10 microM). CNQX and the NMDA receptor antagonist 3-((+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) did not influence negative-going potentials or the associated [K+]o increases (peak values were 8.7 +/- 3.2 mM, n = 8), that were blocked, however, by bicuculline methiodide (BMI, 10 microM). 5. The mu-opioid receptor agonist (D-Ala2,N-Me-Phe4,Gly5-ol)-enkephalin (DAGO, 10 microM) which inhibits GABA release from interneurons, prevented the occurrence of both GABA-mediated synchronous potentials and subsequent ictal discharges (n = 6) as well as the [K+]o elevations. DAGO effects were antagonized by naloxone (10 microM; n = 4). 6. The GABA-mediated [K+]o elevations changed as a function of age. In hippocampal slices obtained from 11- to 17-day-old rats, peak values of 10.6 +/- 2.0 mM (n = 10) and half-width durations of 8.7 +/- 1.3 s (n = 7) were observed. In slices obtained from 25- to 32-day-old animals these parameters were 5.2 +/- 0.5 mM (n = 13) and 4.6 +/- 1.1 s (n = 4), respectively. 7. This study shows that, in the juvenile rat hippocampus, 4-AP induces a glutamatergic independent synchronous potential that is due to GABA released from inhibitory terminals and is associated with an increase in [K+]o. This [K+]o elevation undergoes

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Aging; Analgesics; Animals; Calcium; Electrophysiology; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Excitatory Amino Acid Antagonists; Extracellular Space; Hippocampus; Membrane Potentials; Patch-Clamp Techniques; Piperazines; Potassium; Rats; Receptors, Opioid, mu

The mossy fiber-CA3 synapse displays an N-methyl-D-aspartate-receptor-independent mu-opioid-receptor-dependent form of long-term potentiation (LTP) that is thought not to display cooperativity or associativity with coactive afferents. However, because mossy fiber LTP requires repetitive synaptic activity for its induction, we reevaluated cooperativity and associativity at this synapse by using trains of mossy fiber stimulation. Moderate-, but not low-, intensity trains induced mossy fiber LTP, indicating cooperativity. Low-intensity mossy fiber trains that were normally ineffective in inducing LTP could induce mossy fiber LTP when delivered in conjunction with trains delivered to commissural-CA3 afferents. Associative mossy fiber LTP also could be induced with single mossy fiber pulses when delivered with commissural trains in the presence of a mu-opioid-receptor agonist. Our findings suggest a frequency-dependent variation of Hebbian associative LTP induction that is regulated by the release of endogenous opioid peptides.

Topics: Afferent Pathways; Animals; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Hippocampus; Long-Term Potentiation; Male; Nerve Fibers; Piperazines; Pyramidal Tracts; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, mu; Somatostatin; Synapses; Synaptic Transmission; Time Factors

A single unilateral injection of carrageenan (4.5-6.0 mg in 0.15-0.20 ml saline) into the rat hindpaw induced behavioral hyperalgesia as evidenced by a significant reduction in hindpaw withdrawal latency to a noxious thermal stimulus. The involvement of N-methyl-D-aspartate (NMDA) receptors in this model of hyperalgesia was examined by intrathecal administration of the selective excitatory amino acid (EAA) receptor antagonists: (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), ketamine hydrochloride (ketamine), 7-chlorokynurenic acid (7-Cl kynurenic acid), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The effects of dizocilpine maleate (MK-801) were studied under the same conditions and published previously (Ren et al., 1992) and the data are presented for comparison. While the withdrawal latencies of the non-injected paws and of the paws of naive rats were not significantly affected by application of the EAA receptor antagonists at doses tested, the paw withdrawal latencies of the carrageenan-injected paws were elevated dose dependently. The rank order of potency of these agents to reduce hyperalgesia was: MK-801 greater than or equal to AP-5 greater than or equal to CPP = 7-Cl kynurenic acid = ketamine much greater than CNQX greater than 0. In contrast, intrathecal injection of the opioid receptor agonists, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO, mu-selective) and [D-Pen2,D-Pen5] enkephalin (DPDPE, delta-selective), produced antinociception in both injected and non-injected paws. DAMGO was much more potent, while DPDPE was less potent, than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics; Analysis of Variance; Animals; Behavior, Animal; Carrageenan; Dizocilpine Maleate; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Hyperalgesia; Inflammation; Injections, Spinal; Ketamine; Kynurenic Acid; Male; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Valine