| Abstract No.: | B-B2062 |
| Country: | Canada |
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| Title: | OPIOID-MEDIATED MODULATION OF ANTERIOR CINGULATE CORTEX NETWORKS |
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| Authors/Affiliations: | 2 Gabriella Panuccio*; 2 Giulia Curia; 1 Alfredo Colosimo; 2 Massimo Avoli;
1 Dept. of Human Physiology and Pharmacology, Sapienza University; 2 Depts. of Neurology and Neurosurgery, and Physiology, Montreal Neurological Institute, McGill University;
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| Content: | Objectives: The anterior cingulate cortex (ACC) is a limbic structure mediating autonomic and motor responses, emotional states and goal-directed behaviour. Hyperactivity of this brain region accounts for the manifestation of cingulate epilepsy, a partial epileptic disorder characterized by a wide variety of clinical symptoms that emphasize the different roles played by this cortical area. The mechanisms leading to epileptiform synchronization in the ACC are yet to be thoroughly investigated. Moreover, the role played by mu-opioid receptors, which are highly expressed in this brain region, is still contradictory. Therefore, we sought to determine: (i) the physiological and pharmacological features of epileptiform activity generated by ACC networks; (ii) the role played by both excitatory and inhibitory neurotransmission; (iii) the effect of mu-opioid receptor activation.
Materials and Methods: Extracellular field potential recordings along with pharmacological manipulations were performed in the deep layers of ACC coronal brain slices obtained from adult, male Sprague-Dawley rats (250-300 g), using the 4-aminopyridine (4AP, 50 µM) model of acute epilepsy. All drugs were bath-applied.
Results: (i) 4AP-induced epileptiform activity was characterized by the initial appearance of brief (mean duration= 1.4±0.2 s; mean interval= 17.1±0.8 s; n= 226 events) interictal-like events followed by prolonged (mean duration= 36.0±3.6 s; mean interval= 338.9±32.1 s; n= 124 events) ictal-like discharges. Moreover, interictal-like activity was characterized by a three-phase acceleration pattern with maximal event frequency preceding the onset of an ictal discharge. (ii) Ictal-like activity no longer persisted after NMDA receptor blockade by the antagonist CPP (10 µM) and turned into brief epileptiform discharges when inhibitory neurotransmission was blocked by concomitant application of the GABAergic antagonists CGP55845 (4 µM) and Picrotoxin (PTX, 50 µM). Interictal-like events were not affected by NMDA antagonism, but decreased in amplitude after further application of the AMPA/Kainate receptor antagonist CNQX (10 µM) and were eventually abolished by subsequent application of PTX (50 µM). (iii) Mu-opioid receptor activation by the exogenous selective agonist DAGO (10 µM) reversibly abolished ictal-like discharges while changing the pattern of occurrence of interictal-like events. Moreover, this pharmacological procedure slowed down both excitatory and inhibitory network activities recorded after pharmacological isolation.
Conclusion: (i) 4AP-induced epileptiform activity in the ACC is characterized by the generation of both brief and prolonged synchronous discharges resembling interictal and ictal events respectively. A positive relation exists between interictal- and ictal-like activities, suggesting that interictal events may sustain network synchronization leading to the onset of ictal discharges. (ii) NMDA receptor activation is necessary but not sufficient to sustain ictal synchronization and GABA is required for the generation of ictal-like discharges; interictal events depend on the activation of both glutamate- and GABAA–mediated conductances. (iii) Mu-opioid receptor activation by exogenous agonist controls epileptiform synchronization by modulating both excitatory and inhibitory network activities, abolishing ictal discharges and modulating the pattern of occurrence of interictal events. |
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