INHIBITION OF CLONIC SEIZURE-LIKE EXCITATORY EFFECTS INDUCED BY INTRATHECAL MORPHINE USING 2 NMDA RECEPTOR ANTAGONISTS - MK-801 AND ACEA-1011

Microinjection of high doses of morphine into the spinal lumbar intrathecal (i.t.) space of mice produces dose-dependent clonic seizure-like excitatory effects. Naloxone, an opioid antagonist (10 mg/kg, i.p.), injected 5 min prior to i.t. morphine, did not reverse the seizure-like motor effects, suggesting that these effects of morphine are not mediated through opioid receptors. Systemic administration of MK-801, a non-competitive NMDA receptor antagonist (0.01-0.10 mg/kg, i.p.), or ACEA-1011, a novel NMDA receptor/glycine site antagonist (0.5-20.0 mg/kg, i.p.), attenuated the clonic seizure-like excitatory effects induced by i.t. morphine in a dose-dependent manner. Sensorimotor performance of the mice was evaluated using the rotarod test. Although both compounds (MK-801 and ACEA-1011) impaired the sensorimotor performance of mice in a dose-dependent fashion, there was no impairment of motor performance at doses employed to block the excitatory effects induced by i.t. morphine. These data suggest that NMDA receptors play a pivotal role in the clonic seizure-like behaviors induced by i.t. morphine.