benzofurans and tizanidine

To explore the therapeutic potential of imidazoline I(1) receptor ligands in motor dysfunction related to the basal ganglia, rigidity was induced in mice by intraperitoneal administration of reserpine. The imidazoline I(1) receptor agonists moxonidine and tizanidine reduced rigidity in a dose-dependent manner. Although rigidity was reduced by efaroxan (an imidazoline I(1) receptor and alpha(2)-adrenoceptor antagonist) and idazoxan (an imidazoline I(1) and I(2) receptor and alpha(2)-adrenoceptor antagonist), SKF86466 and yohimbine, both of which are alpha(2)-adrenoceptor antagonists with no affinity for imidazoline receptors, also suppressed rigidity, suggesting that activation rather than blockade of imidazoline I(1) receptors contributes to reduction of reserpine-induced muscle rigidity.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antiparkinson Agents; Benzazepines; Benzofurans; Clonidine; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Idazoxan; Imidazoles; Imidazoline Receptors; Injections, Intraperitoneal; Ligands; Male; Mice; Muscle Rigidity; Muscle, Skeletal; Parkinsonian Disorders; Reserpine; Time Factors; Yohimbine

The neuronal pathways involved in the muscle relaxant effect of tizanidine were examined by measurement of spinal reflexes in rats. Tizanidine (i.v. and intra-4th ventricular injection) decreased the mono- and disynaptic (the fastest polysynaptic) reflexes (MSR and DSR, respectively) in non-spinalized rats. Depletion of central noradrenaline by 6-hydroxydopamine abolished the depressant effect of tizanidine on the MSR almost completely and attenuated the effect on the DSR. Co-depletion of serotonin by 5,6-dihydroxytryptamine and noradrenaline resulted in more prominent attenuation of tizanidine-induced inhibition of the DSR. Supraspinal receptors were then studied using yohimbine- and some imidazoline-receptor ligands containing an imidazoline moiety. Idazoxan (I1, I2, I3, and alpha2), efaroxan (I1, I3, and alpha2), and RX821002 (I3 and alpha2), but not yohimbine, an alpha2-adrenergic receptor antagonist with no affinity for I receptors, antagonized the inhibitory effects of tizanidine. Thus, supraspinal I receptors (most likely I3) and descending monoaminergic influences are necessary for tizanidine-induced inhibition of spinal segmental reflexes.

Topics: 5,6-Dihydroxytryptamine; Adrenergic Agents; Adrenergic alpha-Antagonists; Animals; Benzofurans; Clonidine; Dose-Response Relationship, Drug; Idazoxan; Imidazoles; Imidazoline Receptors; Male; Muscle Relaxants, Central; Norepinephrine; Oxidopamine; Rats; Rats, Wistar; Receptors, Drug; Reflex, Monosynaptic; Serotonin; Serotonin Agents; Spinal Cord; Sympathetic Nervous System; Time Factors