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

Brain Res. 1996 Aug 26;731(1-2):171-81. doi: 10.1016/0006-8993(96)00469-6.

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 (Kb approximately 40 nM) antagonism at NMDA receptor/glycine sites and moderate (Kb approximately 3 microM) 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Binding, Competitive / physiology
  • Brain Chemistry
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Tolerance*
  • Electrophysiology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Formaldehyde
  • Gene Expression / physiology
  • Locomotion / drug effects
  • Male
  • Mice
  • Morphine / pharmacology*
  • Motor Activity / drug effects
  • Narcotics / pharmacology*
  • Nociceptors / drug effects
  • Oocytes / physiology
  • Quinoxalines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Xenopus laevis

Substances

  • ACEA 1328
  • Excitatory Amino Acid Antagonists
  • Narcotics
  • Quinoxalines
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Formaldehyde
  • Dizocilpine Maleate
  • Morphine