The activation of the
mu-opioid receptors (MOR) in the central nervous system has a proconvulsant effect and
seizures are a common side effect of high doses of short acting
opioids, like
morphine or
fentanyl. However, the correct assessment of the role of MOR blockade in the initiation and propagation of
epilepsy was hampered by the lack of potent and selective MOR antagonists. In this study we aimed at characterizing the effect of MOR blockade on the seizure threshold in mice using recently developed selective antagonists
antanal-1 and
antanal-2 and a classical MOR antagonist, β-funaltrexamine (β-FNA). The effect of the centrally administered MOR antagonists was characterized in the maximal electroshock seizure threshold (MEST), the 6 Hz psychomotor seizure threshold and the intravenous
pentylenetetrazole (PTZ) seizure threshold test in mice. The acute effect of the studied compounds on skeletal muscular strength in mice was quantified in the grip-strength test.
Antanal-1 and
antanal-2 (30 and 50 nmol/mouse, i.c.v.), but not β-FNA significantly increased the seizure threshold in the MEST test in mice. In the 6-Hz test, all tested MOR antagonists significantly increased the psychomotor seizure threshold and the most potent
anticonvulsant effect was observed for
antanal-2 (2, 10 and 30 nmol/mouse, i.c.v.). The i.c.v. administration of β-FNA (10 and 30 nmol/mouse, i.c.v.),
antanal-1 and
antanal-2 (both 30, 50 and 100 nmol/mouse, i.c.v.) did not produce any significant effect on PTZ seizure threshold, the generalized clonus or the forelimbs tonus. All tested compounds did not affect muscle strength, as determined in the grip strength test. Our study demonstrated that the novel MOR-selective antagonists
antanal-1 and
antanal-2 displayed a potent and dose-dependent
anticonvulsant action involving non-
GABA-ergic, but some other pathways and mechanisms in animal models of epileptic
seizures. We suggest that antanals are promising
drug templates for future
therapeutics, which may be used in the treatment of
epilepsy in humans.