Ž . European Journal of Pharmacology 332 1997 257–262 Decrease of tolerance to, and physical dependence on morphine by, glutamate receptor antagonists Paulo Gonzalez, Pilar Cabello, Aniza Germany, Beryl Norris, Enrique Contreras ) ´ Department of Pharmacology, Faculty of Biological Sciences, UniÕersity of Concepcion, P.O. Box 152-C, Concepcion, Chile ´ ´ Received 13 February 1997; revised 28 May 1997; accepted 17 June 1997 Abstract Ž . The effects of the non-competitive antagonists of the glutamate complex receptor, dizocilpine MK 801 and ketamine and of the competitive antagonist CGP 39551 were examined on the induction of tolerance to morphine, the development of physical dependence Ž . and the expression of the abstinence syndrome to the opiate in mice. Morphine was administered in a single dose 300 mgrkg of a slow Ž . Ž release preparation. Dizocilpine 0.005 or 0.01 mgrkg given at 3, 12 and 24 h after the priming dose of morphine , ketamine 2, 4 or 8 . Ž . mgrkg, 30 min before and 3, 6, 9 and 24 h after the priming dose and DL- E -2-amino-4-methyl-5-phosphonopentanoate carboxy-ethyl- Ž .Ž . ester CGP 39551 1.5 or 3 mgrkg, but not 6 or 12 mgrkg 30 min before and 12 and 24 h after the priming dose reduced the intensity of tolerance to, and physical dependence on morphine. The drugs also reduced the intensity of the abstinence behaviour when given in a Ž . Ž . single dose, 30 min before s.c. naloxone 4 mgrkg -precipitated withdrawal syndrome in mice chronically treated with morphine. Thus, the results of this study indicate that competitive and non-competitive NMDA receptor antagonists prevent morphine tolerance and decrease the development of physical dependence on the opiate in mice. q 1997 Elsevier Science B.V. Ž Ž . Keywords: Morphine tolerance; Morphine dependence; Dizocilpine; Ketamine; CGP 39551 DL- E -2-amino-4-methyl-5-phosphonopentanoate carboxy- . ethylester 1. Introduction The wide distribution of excitatory amino acids in the Ž . central nervous system CNS has encouraged the study of their involvement in a variety of CNS functions including Ž nociception transmission Headley and Grillner, 1990; Nasstrom et al., 1992; Marek et al., 1991; Trujillo and ¨ ¨ . Akil, 1991 . In particular, glutamate has received consider- able attention and, based on its pharmacological properties, it is now accepted that its effects are produced by acting on three types of ionotropic receptors, named after the selective agonists, 3-hydroxy-5-methyl-4-isoxazole propi- Ž . onic acid AMPA , kainate and N-methyl-D-aspartate Ž .Ž . NMDA Watkins et al., 1990; Nakanishi, 1992 . Of these, the functions of NMDA have been most clearly defined due to the synthesis of highly specific ligands. Several transmitters and modulators are involved in CNS adaptive processes to chronic opiate administration Ž . Cox, 1993; Mulder and Schoffelmeer, 1993 . Recently, the finding that the non-competitive NMDA receptor an- ) Ž . Corresponding author. Fax: 56-41 245-975. Ž . tagonist, dizocilpine MK 801 , reduces the induction of Ž physical dependence to opiates Lufty et al., 1993; Elliot et . al., 1994 has focused the interest of investigators in the involvement of glutamate in the induction of tolerance and dependence. However, the possible role of this amino acid has not been wholly clarified since other authors have found that the concomitant administration of morphine and non-competitive NMDA receptor antagonists does not af- fect the processes induced by chronic opiate treatment Ž . Marquis et al., 1991; Bell and Beglan, 1995 . On the other hand, most of the available competitive antagonists of NMDA receptors do not enter the brain: accordingly, studies have been carried out with non-competitive antago- nists. Two systemically active competitive NMDA recep- tor antagonists have recently been synthetised; they are Ž . CGP 39551 and CGP 37849 Fagg et al., 1990 . The first of these agents has been reported to decrease the intensity of physical dependence induced in mice by chronic ethanol Ž . administration Ripley and Little, 1995 . Therefore, we set out to examine the influence of CGP 39551 and of other compounds reported to non-competitively antagonize glu- tamate NMDA receptors in the induction of tolerance to and physical dependence on morphine in mice. 0014-2999r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved. Ž . PII S0014-2999 97 01099-6