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

Pharmacol Res. 1999 Apr;39(4):311-9. doi: 10.1006/phrs.1998.0443.


Opiate or NMDA receptor antagonists given during and/or after the development of tolerance and dependence have been reported to prevent these developments. In the present study, MK801 (dizolcipine) and naltrexone (NX), two antagonists of NMDA and opiate receptors, respectively were used in rats to find any correlations between changes in NMDA receptor kinetics, and the intensity 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-1M. 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 according to the previous administration paradigm. Two hours after the administrations, their brains were utilised for the determination of NMDA receptor kinetics, employing [3H]glutamate. The measurement of tail-flick latency showed the prevention by NX or MK801 of the development of tolerance to M. The rats, which were administered 3 mg kg-1M 2 h before 1 mg kg-1 NL injection, on day 9 showed that only NX given previously along with M attenuated the intensity of the development of M dependence. NX administered alone intensified the development of dependence on a single dose of M. The development of M dependence upon the M pellet implantation was intensified by the previous administration of NX or MK801 concomitantly with M. The administration of M or MK801 alone, or NX together with M, caused significant upregulation of NMDA receptors. NX alone, and MK801 given concurrently with M led to a significant downregulation. So, in light of the previous findings and the present experimental data it can be said that: (1) supersensitivity to opioids may be a downregulation of NMDA as well as an upregulation of the opioid receptor; (2) either upregulation or downregulation of NMDA receptors may facilitate subsequent development of opioid dependence; (3) tolerance to opioid may necessitate both upregulation of NMDA receptors and downregulation of opioid receptors; and (4) beneficial effects of opioid antagonists in the treatment of opiate dependence and CNS injuries may be strongly related to the down regulation of NMDA receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / toxicity*
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Dizocilpine Maleate / pharmacology
  • Drug Tolerance / physiology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Kinetics
  • Male
  • Morphine / toxicity*
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain Measurement / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Substance-Related Disorders / etiology
  • Substance-Related Disorders / metabolism*
  • Substance-Related Disorders / prevention & control


  • Analgesics, Opioid
  • Excitatory Amino Acid Antagonists
  • Narcotic Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Naltrexone
  • Dizocilpine Maleate
  • Morphine