Morphine Tolerance and Dependence in Mice with History of Repeated Exposures to NMDA Receptor Channel Blockers (original) (raw)
Related papers
Naunyn-Schmiedeberg's archives of pharmacology, 1998
Development of tolerance to opiates involves various neurochemically and pharmacologically distinct processes. For instance, the diversity of opiate tolerance has been suggested by experiments comparing the establishment of diminished response to different effects of opiate agonists. Antagonists acting at N-methyl-D-aspartate (NMDA) receptors has become a very useful tool for studying opiate tolerance mechanisms since these drugs have been shown to retard the development of tolerance to analgesic properties of opiates. The present study compared the ability of two NMDA receptor channel blockers, dizocilpine and memantine, to affect the development of tolerance to morphine analgesia induced by repeated social defeat or by repeated morphine administrations. Male BALB/c mice were assessed for the tail-flick response before and after the defeat in five social confrontations, or before and after repeated morphine injections (20 mg/kg, s.c., once daily for 8 days). Repeated morphine injections were explicitly paired with environmental cues. Socially-defeated as well as morphine-treated mice developed significant tolerance to morphine analgesia. Separate groups of mice were exposed to repeated social confrontations or injections of morphine with each defeat or morphine injection followed by administration of either dizocilpine (0.03-0.3 mg/kg, i.p.) or low-affinity channel blocker memantine (3-30 mg/kg, i.p.). Both dizocilpine and memantine were effective in preventing the development of repeated morphine-induced tolerance to acute morphine analgesia. Treatments with NMDA receptor antagonists that retarded development of non-associative tolerance also suppressed the establishment of associative tolerance significantly. Social defeat-induced tolerance was prevented by dizocilpine but not by memantine. Our results suggest some degree of similarity in the mechanisms of morphine analgesic toler-ance induced by pharmacological, contextual and social stimuli.
Pharmacological Research, 1999
Opiate or NMDA receptor antagonists given during andror after the development of tolerance and dependence have been reported to prevent these developments. In the Ž . Ž . 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 Ž . groups of rats were formed. The rats in the groups were given saline S q S, Sq morphine Ž . M , NXq S, NXq M, MK801q S and MK801q 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 y1 Ž . subgroup were administered 1 mg kg naloxone NL 2 h after administration of 3 mg kg y1 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 according to the previous administration paradigm. Two hours after the administrations, their brains w 3 x were utilised for the determination of NMDA receptor kinetics, employing H 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 y1 M 2 h before 1 mg kg y1 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 Ž . 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 Ž . receptor; 2 either upregulation or downregulation of NMDA receptors may facilitate Ž . subsequent development of opioid dependence; 3 tolerance to opioid may necessitate Ž . 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.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000
The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, ve-hicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.
Previous chronic blockade of NMDA receptors intensifies morphine dependence in rats
Pharmacology Biochemistry and Behavior, 1991
KOYUNCUOt~LU, H. AND F. ARICIOOLU. Previous chronic blockade of NMDA receptors intensifies morphine dependence in rats. PHARMACOL BIOCHEM BEHAV 39(3) 575-579, 1991.--Chronic exposure of receptors to antagonists generally results in upregulation and/or supersensitivity. On the other hand, the noncompetitive NMDA receptor antagonists ketamine (K) and dextromethorphan (DM) suppress opiate abstinence syndrome by blocking NMDA receptors. Therefore, 40 mg/kg ketamine (K), 5 mg/kg dextromethorphan (DM), 5 mg/kg morphine (M) and 2 mg/kg naloxone (NL) alone or in combination with NL were IP administered to the rats five times during the daytime only for five days to see whether they would intensify abstinence syndrome through upregulation and/or supersensitivity of NMDA receptors. Three days following the implantation of three M-containing pellets, abstinence syndrome was brought about by 2 mg/kg NL injection. Jumping, wet dog shake, writhing, teeth chattering, diarrhoea, defecation and ptosis were observed for ten rain. All drugs used alone or in combination with NL increased the intensity of abstinence syndrome. Since K and DM are noncompetitive NMDA receptor antagonists, the intensifying effect of NL or M was considered to be related to their interactions with NMDA receptors. Furthermore, on the basis of the results of the previous and present study, NL was claimed to act on NMDA receptors, like other opioids, but with higher affinity for and weaker blocking effect on NMDA receptors.
Effects of short-acting NMDA receptor antagonist MRZ 2/576 on morphine tolerance development in mice
Naunyn-schmiedebergs Archives of Pharmacology, 2000
The present study sought to evaluate the ability of a short-acting glycineB site NMDA receptor antagonist, MRZ 2/576, to affect morphine tolerance development in mice. It was found that MRZ 2/576 (10 mg/kg, i.p.) significantly retarded development of morphine analgesic tolerance (20 mg/kg, s.c., 8 days, once a day; tail-flick test) when administered 120 min or 150 min after each daily morphine injection. MRZ 2/576 did not affect the development of morphine tolerance when administered immediately, 15, 30, 60, 90, 180, 240, 300 or 360 min after the daily morphine injections. Thus, short-acting NMDA receptor antagonists may be useful in exploring the temporal characteristics of opioid tolerance (i.e., periods after morphine injection that are critical for tolerance induction) and the present study suggests that after morphine administration there is a period of NMDA receptors activation crucial for the development of tolerance.
Modulation of Morphine Analgesia and Tolerance in Rats by NMDA Receptor Antagonists
Neurophysiology, 2012
The efficacy of opioids in chronic pain treatment is limited because of the development of opioid tolerance. We investigated the role of N-methyl-D-aspartate (NMDA) receptor antagonists (NMDAR Ants) in morphine analgesia and tolerance in rats. To induce the morphine tolerance, experimental rats received morphine (50 mg/kg; subcutaneously) once daily for 3 days. After the last dose of morphine was injected on day 4 and morphine tolerance was evaluated, analgesic effects of ketamine, dizocilpine (MK-801, a non-competitive NMDAR Ant), LY235959 (a competitive NMDAR Ant), cis-2,3-piperidinedicarboxylic acid (PDA, an NMDAR agonist), and morphine were estimated with 30-min-long intervals (0, 30, 60, 90, and 120 min) by the tail-flick and hot-plate algesia tests (n = 6 in each studied group). As was found, ketamine, MK-801, and LY235959 significantly attenuated the development of morphine tolerance (P < 0.05). On the other hand, PDA somewhat increased the development of this tolerance, but the difference was not statistically significant (P > 0.05). Our data indicate that NMDAR Ants attenuate the development of morphine tolerance, significantly affecting the effects of morphine analgesia in rats.
Peripherally acting NMDA receptor/glycine site receptor antagonists inhibit morphine tolerance
Neuropharmacology, 2005
The present study focused on the role of peripheral ionotropic N-methyl-D-aspartate (NMDA) receptors in the development of tolerance to morphine-induced antinociception. An initial experiment revealed that NMDA channel blocker memantine, and NMDA receptor/glycine B site antagonist MRZ 2/576 inhibited maximal electroshock-induced convulsions (MES) in female NMR mice with respective potency of 5.93 and 20.8 mg/kg, while other NMDA receptor/glycine B site antagonists MRZ 2/596 and MDL 105,519 were ineffective, supporting lack of CNS activity of the latter two agents. This observation was also supported by bloodbrain barrier experiments in vitro. In male Swiss mice, morphine (10 mg/kg) given for 6 days twice a day (b.i.d.) produced tolerance to its antinociceptive effects in the tail-flick test. The NMDA receptor/glycine B site antagonists, MRZ 2/576 at 0.03, 0.1, 0.3 mg/kg and MRZ 2/596 at 0.1, 0.3, 3 and 10 mg/kg attenuated the development of morphine tolerance. Similarly, in male C57/Bl mice, morphine (10 mg/kg) given for 6 days b.i.d. produced tolerance to its antinociceptive effects in the tail-flick test. Like in Swiss mice, in C57/Bl mice morphine tolerance was attenuated by both MRZ 2/576 and MRZ 2/596. Another NMDA receptor/glycine B site receptor antagonist, MDL 105,519 (that very weakly penetrates to the central nervous system) also inhibited morphine tolerance at the dose of 1 but not 0.1 mg/kg. Moreover, both naloxone hydrochloride (5 and 50 mg/kg) and centrally inactive naloxone methiodide (50 mg/kg) inhibited morphine tolerance suggesting the involvement of peripheral opioid receptors in this phenomenon. The present data suggest that blockade of NMDA receptor/glycine B sites in the periphery may attenuate tolerance to the antinociceptive effects of morphine.
Biological Psychiatry
The glycine site 324), and uncompetitive (MRZ 2/579) NMDA receptor antagonists inhibited morphine-produced behaviors related to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects of glycine/NMDA antagonists were not dose-dependent. Mice which were morphine-free for 3 days still displayed a significant severity of the withdrawal syndrome when challenged again with naloxone. This extinction of a residual morphine dependence was markedly diminished by treatment with similar doses of NMDA receptor antagonists at the test following the wash-out period. The rewarding impact of morphine was investigated in rats using the place preference (CPP) paradigm. All NMDA receptor antagonists (2.5 -10 mg/kg) inhibited both the acquisition and expression of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA receptor antagonists given for 3 days after the end of conditioning did not influence the extinction of morphine-induced CPP. Microdialysis studies revealed that the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA receptor antagonist. These data suggest that novel glycine site and uncompetitive NMDA receptor antagonists may have therapeutic potential in the treatment of opioid abuse.
The Journal of Neuroscience, 2003
Tolerance and physical dependence caused by chronic treatment of narcotics are good models to study basic neuronal plasticity. Activation of the NMDA subtype of the glutamate receptor has been implicated as an anti-opioid system in the development of morphine analgesic tolerance and dependence. The present study examines the specific role of the ϵ1 subunit of the NMDA receptor using mice lacking the gene encoding ϵ1 subunit of the NMDA receptor (GluRϵ1-/-mice). GluRϵ1-/-mice showed significant enhancement and prolongation of morphine anti-nociception, compared with wild-type GluRϵ1+/+mice. GluRϵ1-/-mice also showed a marked loss of the analgesic tolerance after repeated morphine treatments. In C57BL/6J mice treated with chronic morphine after tolerance paradigm, the GluRϵ1 protein expression significantly increased in periaqueductal gray matter (PAG), ventral tegmental area (VTA) and nucleus accumbens (NAc), but not amygdala or hippocampus. The rescue of GluRϵ1 protein by electropor...
Ontogeny of NMDA receptor-mediated morphine tolerance in the postnatal rat
Pain, 2003
N-methyl-D-aspartate (NMDA) receptor antagonists are effective in inhibiting the development of morphine tolerance in adult rats. But NMDA receptors undergo dramatic change during the first few weeks of the postnatal life in the rat, and it is unknown whether NMDA receptor antagonists can inhibit the acquisition of opiate tolerance in the developing organism. Here, we investigated the effects of two NMDA receptor antagonists MK-801 and dextromethorphan on the development of morphine tolerance in 7-, 14-, and 21-day-old rats. NMDA receptor antagonists are not effective in attenuating morphine tolerance in the neonatal rat whereas they were partially effected in the 14-day-old and fully effective in rats as old or older than 21 days of age. These data suggest that there exists a transition age, around the second postnatal week in the rat, for the NMDA receptor to play a role in the development of morphine tolerance.