Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats

Abstract

Involvement of the K: opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.e. v. administration of the K: agonists U50,488H { trans-3,thiophene-4-acetamide), 50 and 150 f1.g/5f1.l each, dose-dependently decreased the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mglkg s.c.) also attenuated the seizure activity in this model. The specific K: opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 flg/Sfll i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opioids acting through K: receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific ll opioid receptor agonist o-Aia 2 -N-methyi-Phe 4 -Giy 5 -ol-enkephalin (DAMGO, 0.7/.lg/5/.ll i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the K: opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.

Two Types of Epilepsy Models and Processes of Cognition: Pentylenetetrazole Kindling and Absence Epilepsy of WAG/Rij Rats Strain

“…The high number of avoidances in WAG/Rij rats on the first day of active avoidance conditioning was found earlier (Bazyan et al, 2000c;2001). We explain this reaction by the low efficiency of opioid system in WAG/Rij strain (Lason et al, 1990;1994a;1994b;Przewlocka et al, 1995) and as a consequence a low pain threshold and a high level of escape and avoidance motivation. It is shown (Altier & Stewart, 1998;Calabrese 2001) that activation of the DA-ergic system evokes analgesic reaction including activation of the opioid system (Suaudeau & Costentin, 1995;Cook et al, 2000;Magnusson & Fisher, 2000;Gao et al, 2001;Trekova et al, 2001).…”

“…Antagonists of D2 DA receptors increase and agonists decrease of SWDs (De Bruin et al, 2000;Deransart et al, 2000;Midzianovskaya et al, 2001). It is possible the opioid system of brain also controls SWDs (Lason et al, 1990;1994a;1994b;Przewlocka et al, 1995). It is very well known that the mesocorticolimbic DA-ergic system is the system of reinforcement; it actualizes an emotional positive state and is also involved in processes of learning and memory (Wise, 1978(Wise, , 2009Joseph et al, 2003;Bazyan, & Grigoryan, 2006).…”

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…Indeed, i.c.v. administration of U50,488H, which like PDYN-derived peptides, stimulates  opioid receptors, decreased the number and mean duration of SWDs indicating that activation of the  opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats (Przewlocka et al, 1995).  receptor agonists not only act in a way opposite to µ receptor agonists (Lason et al, 1994a), but can also attenuate the µ agonist-induced increase of the number of SWDs; however, this receptor does not seem to be involved in the epileptogenesis process (Przewlocka et al, 1995).…”

“…administration of U50,488H, which like PDYN-derived peptides, stimulates  opioid receptors, decreased the number and mean duration of SWDs indicating that activation of the  opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats (Przewlocka et al, 1995).  receptor agonists not only act in a way opposite to µ receptor agonists (Lason et al, 1994a), but can also attenuate the µ agonist-induced increase of the number of SWDs; however, this receptor does not seem to be involved in the epileptogenesis process (Przewlocka et al, 1995). Concluding, changes in the level of PENK and PDYN in several brain structures may be relevant for the occurrence of SWDs in WAG/Rij rats; however, their role in epileptogenesis (above all for µ receptors) needs to be better defined since the above-summarized experiments were carried out comparing 3 months old vs 6 months old WAG/Rij rats and, therefore, results may be influenced by the fact that rats at 3 months already may have SWDs which might have affected the endogenous opioid system, although tendencies can be inferred from the age dependent differences.…”

“…Instead, a comparable age-related decrease in the PDYN mRNA levels was found in the frontal cortex and, to a lesser extent, in the striatum of both WAG/Rij and ACI rats (Lason et al, 1994b); this may be an independent additional factor facilitating the occurrence of SWDs, since the peptides derived from PDYN, interacting mainly with  receptors, produce antiepileptic effects (Lason et al, 1994b;Przewlocka et al, 1995). Indeed, i.c.v.…”