INHIBITION OF MORPHINE-TOLERANCE BY NMDA RECEPTOR ANTAGONISTS IN THE FORMALIN TEST

itro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328) was cha racterized in vitro for antagonism of excitatory amino acid receptors, and subsequently tested in vivo and compared with MK-801 for phencycl idine (PCP)-like motor stimulation, antinociception, and effects on mo rphine tolerance in mice. Assayed on rat cerebral cortical glutamate r eceptors expressed in Xenopus oocytes ACEA-1328 showed potent (K-b sim ilar to 40 nM) antagonism at NMDA receptor/glycine sites and moderate (K-b similar to 3 mu M) antagonism at non-NMDA receptors. In both case s inhibition was predominantly competitive. ACEA-1328 was weak, or ina ctive, at NMDA receptor glutamate recognition sites, metabotropic rece ptors and opioid binding sites. In the formalin and rotarod tests ACEA -1328 and MK-801 produced both antinociception and disturbances of mot or coordination. MK-801 caused a PCP-like motor stimulatory effect, wh ereas ACEA-1328 was devoid of such an effect. In tolerance studies, AC EA-1328 and MK-801 each blocked morphine tolerance in the formalin tes t, the effect of ACEA-1328 was dose-dependent. Our data contribute to a growing body of evidence which suggests that activation of NMDA rece ptors is critical for the development of opioid tolerance, and that an tagonism at NMDA receptor/glycine sites may have potential as a means of diminishing tolerance with no PCP-like motor stimulatory side effec ts.