Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test

Kabirullah Lutfy, Ke Zhong Shen, Richard M. Woodward, Eckard Weber

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

5-Nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328) was characterized in vitro for antagonism of excitatory amino acid receptors, and subsequently tested in vivo and compared with MK-801 for phencyclidine (PCP)-like motor stimulation, antinociception, and effects on morphine tolerance in mice. Assayed on rat cerebral cortical glutamate receptors expressed in Xenopus oocytes ACEA-1328 showed potent (K(b) ~ 40 nM) antagonism at NMDA receptor/glycine sites and moderate (K(b) ~ 3 μM) antagonism at non-NMDA receptors. In both cases inhibition was predominantly competitive. ACEA-1328 was weak, or inactive, at NMDA receptor glutamate recognition sites, metabotropic receptors and opioid binding sites. In the formalin and rotarod tests ACEA-1328 and MK-801 produced both antinociception and disturbances of motor coordination. MK-801 caused a PCP-like motor stimulatory effect, whereas ACEA-1328 was devoid of such an effect. In tolerance studies, ACEA-1328 and MK-801 each blocked morphine tolerance in the formalin test, the effect of ACEA-1328 was dose-dependent. Our data contribute to a growing body of evidence which suggests that activation of NMDA receptors is critical for the development of opioid tolerance, and that antagonism at NMDA receptor/glycine sites may have potential as a means of diminishing tolerance with no PCP-like motor stimulatory side effects.

Original languageEnglish (US)
Pages (from-to)171-181
Number of pages11
JournalBrain research
Volume731
Issue number1-2
DOIs
StatePublished - Aug 26 1996

Keywords

  • Antinociception
  • Formalin test
  • Glycine co-agonist site
  • NMDA receptor
  • Tolerance

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Fingerprint Dive into the research topics of 'Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test'. Together they form a unique fingerprint.

Cite this