Grayanotoxin-III (
GTX-III) is a constituent in leaves of Pieris japonica D. Don which exhibits, in vitro, the ability to open voltage-sensitive
sodium channels in various excitable tissues. Effects of systemic administration of
GTX-III were studied in vivo using Std-ddy mice. Salivation,
vomiting and
paralysis of the hind paws invariably occurred in mice injected intraperitoneally with 0.1 or 0.25 mg/kg of
GTX-III. The writhing response to an
intraperitoneal injection of
acetic acid was considerably diminished by pretreatment of animals with the toxin. The grayanoid also caused a profound attenuation of the response to caudal compression, while inducing no significant alteration of that to thermal injury. Pretreatment with
GTX-III resulted in a significant decrement of the time required for loss of the righting reflex induced by
pentobarbital, with a concomitant delay in recovery. Mice injected with the toxin exhibited a significant and restorable suppression of coordination, and a long-lasting suppression of spontaneous locomotor activity in both horizontal and vertical directions. Neither
tetrodotoxin (1-5 micrograms/kg, i.p.) nor Ro15-1788 (1-5 mg/kg, i.p.) prevented the
GTX-III-induced suppression of locomotion.
Atropine (5-10 mg/kg, i.p.) failed to antagonize the
GTX-III-induced suppression but protected against salivation induced by the toxin without affecting other symptoms. Intracerebroventricular injection of
quisqualic acid (0.5 microgram), one of the agonists for central
glutamate receptors, but not that of
tetrodotoxin (5 ng) prevented the
GTX-III-induced suppression of horizontal movement. These results suggest that
GTX-III may elicit its depressant action on horizontal locomotion possibly through interacting with central glutamatergic neurons rather than activating voltage-sensitive
sodium channels in the brain. Possible involvement of
muscarinic cholinergic neurons in the
GTX-III-induced salivation is also suggested.