Brain Research, 547 (1991) 77-81 © 1991 Elsevier Science Publishers B.V. 0006-8993/91/$03.50 ADONIS 000689939116524U BRES 16524 77 Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat Przemyslaw Marek, Shamgar Ben-Eliyahu, Michael Gold and John C. Liebeskind Department of Psychology, University of California, Los Angeles, CA 90024 (U.S.A.) (Accepted 13 November 1990) Key words: Morphine; Analgesia; Tolerance; Excitatory amino acid; Kynurenic acid; MK-801 To investigate the possible role of excitatory amino acids (EAAs) in the mechanisms of morphine tolerance, rats were treated either with the wide-spectrumEAA antagonist, kynurenic acid (150mg/kg), or the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist, MK-801 (0.05 mg/kg), during a four-day induction period of morphine tolerance. Morphine was given once daily at a dose of 15 mg/kg. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by both EAA antagonists. Control experiments showed that at the same doses neither acute nor chronic administration of these antagonists affected morphine analgesia itself in a manner that can explain these findings. The possible involvementof EAAs in the mechanism of morphine tolerance is discussed. INTRODUCTION One major problem in the use of opiate analgesic drugs is the tolerance that develops during their chronic administration. Although the phenomenon of tolerance has been investigated for many years, its mechanism is still not well understood. Studies on changes in affinity and number of opiate receptors in tolerant animals have produced conflicting results. The majority, however, report either an absence of tolerance-induced changes in opiate receptors, or changes that correlate poorly with the magnitude and time course of tolerance development (see ref. 12 for review). This absence of correspondence between changes in opiate receptors and the appearance of tolerance may result from the complexity of morphine analgesia. Morphine analgesia undoubtedly involves mul- tiple neurotransmitter systems at spinal and supraspinal levels9A3. Tolerance may reflect changes in any element involved in the mediation or modulation of morphine analgesia. A growing body of evidence suggests that excitatory amino acids (EAAs) are involved in endogenous pain- inhibitory mechanisms. Glutamate was first used as a presumably nonselective neuroexcitant and produced potent analgesia when microinjected into the rat peri- aqueductai gray matter 4'a7 (PAG) and nucleus raphe magnus (NRM) 2. Recently, the existence of multiple EAA receptor subtypes has been demonstrated. The best recognized of them are N-methyl-o-aspartate (NMDA), quisqualate and kainate receptors 14, named for the specific agonists acting at these sites. NMDA, quisqualate and kainate were reported to produce analgesia after microinjecton into the PAG 9. Microinjection of the specific NMDA antagonist, 2-amino-7-phosphonoheptanoate (AP-7), into the PAG significantly diminished the analgesic effects of both NMDA and morphine microinjected into the same site9. Injection of EAA antagonists into NRM attenuated both analgesia 2 and the electrophysiological response 19 of NRM neurons resulting from PAG stimu- lation, supporting the functional role of an EAA link between PAG and NRM in pain inhibition. This link was also confirmed immuno- histochemically 19. Finally, micro- injection of AP-7 into the PAG, and systemic application of a novel NMDA antagonist, MK-801 [(+)-5-methyl- 10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine], blocked stress-induced and morphine analgesia in the mouse 11,16. In the present study we examined the effect of a wide-spectrum EAA antagonist, kynurenic acid, and the specific NMDA antagonist, MK-801, on the development of morphine tolerance. We report that these drugs attenuate the development of morphine tolerance at a dose that does not diminish morphine analgesia. Correspondence: J.C. Liebeskind, Department of Psychology,University of California, Los Angeles, CA 90024-1563, U.S.A.