N-Methyl- d-aspartate and α2-adrenergic mechanisms are involved in the depressent action of flupirtine on spinal reflexes in rats

Abstract

In urethane-chloralose anesthetised rats the muscle relaxant activity of flupirtine was investigated on the monosynaptic Hoffmann reflex recorded from plantar foot muscles and on the polysynaptic flexor reflex recorded from tibialis muscle. Intraperitoneal (i.p.; 2.5–25 μmol/kg) and intrathecal (i.t.; 33–330 nmol) administration of flupirtine depressed the polysynaptic flexor reflex in anesthetised rats in a dose-dependent manner without affecting the monosynaptic Hoffmann reflex. Flupirtine produced a similar pattern on spinal reflexes as NMDA receptor antagonists, such as (−)-2-amino-7-phosphonoheptanoic acid (500 nmol i.t.) and memantine (125 μmol/kg i.p.), the benzodiazepines diazepam (18 μmol/kg i.p.) and midazolam (80 nmol i.t.), and the α 2-adrenoceptor agonist tizanidine (2 μmol/kg). In contrast, the GABA A receptor agonist muscimol (21 μmol/kg i.p.; 20 nmol i.t.) and the GABA B receptor agonist baclofen (47 μmol/kg i.p.; 2 nmol i.t.) reduced the magnitude of both the flexor and the Hoffmann reflex, whereas the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 nmol i.t.) depressed the Hoffmann reflex without affecting the flexor reflex. The effect of i.t. injection of flupirtine was prevented by coadministration of the mixed α 1 α 2- adrenoceptor antagonist yohimbine (10 nmol) and the excitatory amino acid N-methyl- d-aspartate (NMDA; 0.1 nmol), but neither by coadministration of the α 1-adrenoceptor antagonist prazosine (10 nmol), the GABA A receptor antagonist bicuculline (1 nmol), the GABA B receptor antagonist phaclofen (100 nmol), the non-NMDA receptor agonist α-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid (ATPA; 0.1 pmol) nor by pre-treatment with the benzodiazepine receptor antagonist flumazenil (16 μmol/kg). These observations suggest that α 2-adrenoceptors and NMDA receptors might be involved in the mediation of the muscle relaxant activity of flupirtine. The presumed NMDA receptor antagonistic effect of flupirtine would be of particular clinical relevance, since flupirtine is free of typical side effects of NMDA receptor antagonists.