N-METHYL-D-ASPARTATE AND ALPHA(2)-ADRENERGIC MECHANISMS ARE INVOLVED IN THE DEPRESSENT ACTION OF FLUPIRTINE ON SPINAL REFLEXES IN RATS

In urethane-chloralose anesthetised rats the muscle relaxant activity of flupirtine was investigated on the monosynaptic Hoffmann reflex rec orded from plantar foot muscles and on the polysynaptic flexor reflex recorded from tibialis muscle. Intraperitoneal (i.p.; 2.5-25 mu mol/kg ) and intrathecal (i.t.; 33-330 nmol) administration of flupirtine dep ressed the polysynaptic flexor reflex in anesthetised rats in a dose-d ependent manner without affecting the monosynaptic Hoffmann reflex. Fl upirtine produced a similar pattern on spinal reflexes as NMDA recepto r antagonists, such as (-)-2-amino-7-phosphonoheptanoic acid (500 nmol i.t.) and memantine (125 mu mol/kg i.p.), the benzodiazepines diazepa m (18 mu mol/kg i.p.) and midazolam (80 nmol i.t.), and the alpha(2)-a drenoceptor agonist tizanidine (2 mu mol/kg). In contrast, the GABA(A) receptor agonist muscimol (21 mu mol/kg i.p.; 20 nmol i.t.) and the G ABA(B) receptor agonist baclofen (47 mu mol/kg i.p.; 2 nmol i.t.) redu ced the magnitude of both the flexor and the Hoffmann reflex, whereas the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQ X; 10 nmol i.t.) depressed the Hoffmann reflex without affecting the f lexor reflex. The effect of i.t. injection of flupirtine was prevented by coadministration of the mixed alpha(1)/alpha(2)-adrenoceptor antag onist yohimbine (10 nmol) and the excitatory amino acid N-methyl-D-asp artate (NMDA; 0.1 nmol), but neither by coadministration of the alpha( 1)-adrenoceptor antagonist prazosine (10 nmol), the GABA(A) receptor a ntagonist bicuculline (1 nmol), the GABA(B) receptor antagonist phaclo fen (100 nmol), the non-NMDA receptor agonist a-amino-3-hydroxy-5-tert butyl-4-isoxazolepropionic acid (ATPA; 0.1 pmol) nor by pre-treatment with the benzodiazepine receptor antagonist flumazenil (16 mu mol/kg). These observations suggest that alpha(2)-adrenoceptors and NMDA recep tors might be involved in the mediation of the muscle relaxant activit y of flupirtine. The presumed NMDA receptor antagonistic effect of flu pirtine would be of particular clinical relevance, since flupirtine is free of typical side effects of NMDA receptor antagonists.