The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine

Opiate or NMDA receptor antagonists given during and/or after the developme nt of tolerance and dependence have been reported to prevent these developm ents. In the present study, MK801 (dizolcipine) and naltrexone (NX), two an tagonists of NMDA and opiate receptors, respectively were used in rats to f ind any correlations between changes in NMDA receptor kinetics, and the int ensity of tolerance and dependence. Thus, six different groups of rats were formed. The rats in the groups were given saline (S) + S, S + morphine (M) , NX + S, NX + M, MK801 + S and MK801 + M, respectively, once per day for 8 days. On day 9, the rats from each group were divided into four subgroups. The rats of the first subgroup were subjected to the determination of tail -flick latency. The rats of the second subgroup were administered 1 mg kg(- 1) naloxone (NL) 2 h after administration of 3 mg kg(-1) M. The rats of the third subgroup were implanted with two M pellets and after 72 h they were challenged with NL. The remaining rats received drugs also on day 9 accordi ng to the previous administration paradigm. Two hours after the administrat ions, their brains were utilised for the determination of NMDA receptor kin etics, employing [H-3]glutamate. The measurement of tail-flick latency show ed the prevention by NX or MK801 of the development of tolerance to M. The rats, which were administered 3 mg kg(-1) M 2 h before 1 mg kg(-1) NL injec tion, on day 9 showed that only NX given previously along with M attenuated the intensity of the development of M dependence. NX administered alone in tensified the development of dependence on a single dose of M. The developm ent of M dependence upon the M pellet implantation was intensified by the p revious administration of NX or MK801 concomitantly with M. The administrat ion of M or MK801 alone, or NX together with M, caused significant upregula tion of NMDA receptors. NX alone, and MK801 given concurrently with M led t o a significant downregulation. So, in light of the previous findings and t he present experimental data it can be said that: (1) supersensitivity to o pioids may be a downregulation of NMDA as well as an upregulation of the op ioid receptor; (2) either upregulation or downregulation of NMDA receptors may facilitate subsequent development of opioid dependence; (3) tolerance t o opioid may necessitate both upregulation of NMDA receptors and downregula tion of opioid receptors; and (4) beneficial effects of opioid antagonists in the treatment of opiate dependence and CNS injuries may be strongly rela ted to the down regulation of NMDA receptors. (C) 1999 Academic Press.