The mu-opioid receptor-selective peptide antagonists, antanal-1 and antanal-2, produce anticonvulsant effects in mice

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.

► The activation of the mu-opioid receptors (MOR) has a proconvulsant effect
► Selective MOR antagonists were tested in different seizure threshold tests in mice
► All tested MOR antagonists significantly increased the psychomotor seizure threshold
► The most potent anticonvulsant effect was observed for antanal-2
► Antanal-1 and antanal-2 are promising drug templates for the treatment of epilepsy