dizocilpine-maleate and Morphine-Dependence

A growing body of evidence indicates that the mesolimbic dopaminergic (DAergic) pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (N.Acc.) play a critical role in the initiation of psychological dependence on morphine. As well as DAergic system, the involvement of non-DAergic neurotransmitter and neuromodulator systems in rewarding effects induced by morphine has been recently documented. We previously demonstrated that the morphine-induced rewarding effect was dramatically suppressed by co-treatment with NMDA receptor antagonists, such as dizocilpine (MK-801), ketamine and ifenprodil. Therefore, we propose here that inhibiting the N-methyl-D-aspartate (NMDA) receptor and its associated protein kinase in the N.Acc. is useful for the treatment for psychological dependence on morphine. The following review provides a summary of recent our findings regarding the role of NMDA receptor and its associated protein kinase in the development of psychological dependence on morphine.

Topics: Animals; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Intracellular Signaling Peptides and Proteins; Ketamine; Membrane Proteins; Mice; Morphine Dependence; Nucleus Accumbens; Piperidines; Protein Kinase C; Receptors, N-Methyl-D-Aspartate; Signal Transduction

NMDA receptors have a significant role in the development of opioid physical dependence. Evidence demonstrated that a drug of abuse enhances neuronal excitability in the Paraventricular Nucleus (PVT). The current research studied whether blocking NMDA receptors through the administration of MK801 in the PVT nucleus could affect the development of Morphine (Mor) dependence and hence the behavioral indices induced by morphine withdrawal in rats.. Male Wistar rats weighing 250-300 g were used. For induction of drug dependence, we injected Mor subcutaneously (s.c.) (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two groups in which the NMDA receptor antagonist, MK801 (20 mM in 0.1 ml), or its vehicle were applied into the PVT nucleus for 7 days before each Mor administration. On day 8, after injection of naloxone (Nal, 2.5 mg/kg, i.p.), withdrawal behaviors were checked for 25 min.. The current results demonstrated that the blockade of the NMDA receptor in the PVT nucleus significantly increased withdrawal behaviors provoked by the application of Nal in morphinedependent (Mor-d) rats.. We concluded that the NMDA receptor in the PVT nucleus changes the development of Mor dependence.

Topics: Animals; Dizocilpine Maleate; Male; Midline Thalamic Nuclei; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

We have previously shown, using radioligand binding studies, that N-methyl-d-aspartate (NMDA) NR1 and NR2A receptor subunits density was decreased in the forebrain of morphine-dependent rats. We have now determined if morphine-dependent rats display regional differences in NMDA receptor expression and whether such changes are functionally relevant. In morphine-dependent rats, the expression of NR1 and NR2A subunits protein, as determined by Western blotting with NMDA receptor subunit antibodies, were decreased in frontal cortex and hippocampus but significantly increased in the nucleus accumbens. The expression of the NR2B subunit was unchanged in all regions examined. In separate groups of morphine-dependent rats, MK-801-induced hyperactivity (thought to be mediated via modulation of nucleus accumbens dopamine release) was significantly enhanced in morphine-dependent animals. Similarly, the MK-801-induced increase of dopamine metabolism was significantly increased in the nucleus accumbens of morphine-dependent animals as compared to sham controls. Results provide both biochemical and behavioural evidence to suggest that NMDA receptor function in the nucleus accumbens, at least with respect to an interaction with the limbic dopamine system, is markedly enhanced in morphine-dependent rats. This increase in function may be associated with an enhanced expression of NMDA receptors, particularly those in the nucleus accumbens containing the NR2A subunit. Taken together, these data support several studies in the literature indicating that NMDA receptors in the nucleus accumbens are involved in the process of opiate dependence.

Topics: Animals; Behavior, Animal; Blotting, Western; Dizocilpine Maleate; Dopamine; Gene Expression; Hippocampus; Hyperkinesis; Limbic System; Male; Morphine; Morphine Dependence; Motor Activity; Narcotics; Nucleus Accumbens; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The effect of aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, on morphine-induced tolerance and dependence in mice was investigated in this study. Acute administration of aminoguanidine (20 mg/kg, p.o.) did not affect the antinociceptive effect of morphine (10 mg/kg, s.c.) as measured by the hot plate test. Repeated administration of aminoguanidine along with morphine attenuated the development of tolerance to the antinociceptive effect of morphine. Also, the development of morphine dependence as assessed by naloxone-precipitated withdrawal manifestations was reduced by co-administration of aminoguanidine. The effect of aminoguanidine on naloxone-precipitated withdrawal was enhanced by concurrent administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (0.25 mg/kg, i.p.) or the non-specific nitric oxide synthase (NOS) inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME; 5 mg/kg, i.p.) and antagonized by concurrent administration of the nitric oxide (NO) precursor, l-arginine (50 mg/kg, p.o.). Concomitantly, the progressive increase in NO production, but not in brain glutamate level, induced by morphine was inhibited by repeated administration of aminoguanidine along with morphine. Similarly, co-administration of aminoguanidine inhibited naloxone-induced NO overproduction, but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The effect of aminoguanidine on naloxone-induced NO overproduction was potentiated by concurrent administration of dizocilpine or l-NAME and antagonized by concurrent administration of l-arginine. These results provide evidence that blockade of NO overproduction, the consequence of NMDA receptor activation, by aminoguanidine, via inhibition of iNOS, can attenuate the development of morphine tolerance and dependence.

Topics: Analgesics; Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Brain; Dizocilpine Maleate; Drug Tolerance; Enzyme Inhibitors; Glutamates; Guanidines; Male; Mice; Morphine; Morphine Dependence; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitrites; Pain; Pain Measurement; Time Factors

The present study sought to assess whether the blockade of ionotropic glutamate receptors in the ventral tegmental area could modulate morphine withdrawal in morphine-dependent rats and the expression of stable DeltaFosB isoforms in the nucleus accumbens during morphine withdrawal. Rats were injected (i.p.) with increasing doses of morphine for 1 week to develop physical dependence, and withdrawal was then precipitated by one injection of naloxone (2 mg/kg, i.p.). Abstinence signs such as jumping, wet-dog shake, writhing posture, weight loss, and Gellert-Holtzman scale score were recorded to evaluate naloxone-induced morphine withdrawal. Two ionotropic glutamate receptor antagonists, dizocilpine (MK-801) and 6, 7-dinitroquinnoxaline-2, 3-dione (DNQX), were microinjected unilaterally into the ventral tegmental area 30 min before naloxone precipitation. A second injection of naloxone (2 mg/kg i.p.) was given 1 h after the first naloxone injection to sustain a maximal level of withdrawal so that the expression of stable DeltaFosB isoforms in the nucleus accumbens could be measured. This would enable determination of the correlation between the MK-801 or DNQX-induced decrease in somatic withdrawal signs and the change in neuronal activity in the nucleus accumbens. The results showed that both MK-801 and DNQX significantly alleviated all symptoms of morphine withdrawal except for weight loss and reduced the expression of stable DeltaFosB isoforms within the nucleus accumbens. These data suggest that ionotropic glutamatergic neurotransmission in the ventral tegmental area regulates the levels of stable DeltaFosB isoforms in the nucleus accumbens, which play a very important role in modulating opiate withdrawal.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Immunohistochemistry; Male; Microinjections; Morphine; Morphine Dependence; Naloxone; Nucleus Accumbens; Protein Isoforms; Proto-Oncogene Proteins c-fos; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Synaptic Transmission; Ventral Tegmental Area

We investigated how dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, affects the development of morphine dependence in mice. Co-administration of dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days attenuated the development of tolerance to the antinociceptive effects of morphine. The withdrawal manifestation induced by the naloxone-challenge (5 mg/kg) was significantly reduced in mice that were treated with a combination of dizocilpine and morphine, compared to the mice treated with morphine and saline. The present study revealed a significant increase in c-Fos protein expression in the cortex and thalamus of mice showing naloxone-precipitated withdrawal syndrome. The combination of dizocilpine and morphine prevented the increase of c-Fos protein expression in the cortex and thalamus. Interestingly, repeated co-administration of dizocilpine and morphine prevented the withdrawal-induced phosphorylation of Ca2+/calmodulin kinase II (p-CaMK II) in the cortex, but not in the thalamus. Acute dizocilpine treatment prior to the naloxone-challenge and repeated treatment with dizocilpine alone had no effect on analgesia, withdrawal manifestations, p-CaMK II levels or c-Fos protein levels. These results showed that co-administration of dizocilpine and morphine prevented the development of morphine tolerance and dependence and suggested that the preventive effect of dizocilpine results from the regulation of c-Fos protein expression, which is possibly involved in the activation of the Ca2+/calmodulin-dependent signal cascade in the cortex.

Topics: Animals; Blotting, Western; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cell Count; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Gyrus Cinguli; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Neuroprotective Agents; Pain Measurement; Proto-Oncogene Proteins c-fos; Reaction Time; Substance Withdrawal Syndrome; Thalamus

Adaptive changes in neural systems due to chronic opiate exposure are related to the neural plasticity phenomenon, NMDA receptors being implicated in these processes, e.g. tolerance, dependence or withdrawal. In this work, we investigated the effect of two non-competitive NMDA antagonists, memantine and MK-801, in motivational (Conditioned Place Aversion paradigm, CPA) and physical aspects of morphine withdrawal. After the induction of morphine dependence, animals in which the CPA was studied, received memantine (5 and 10 mg/kg) or MK-801 (0.3-0.006 mg/kg) either during the acquisition (conditioning) or expression (test) phase of this procedure. Both drugs were capable of inhibiting conditioned aversion when administered in any phase. In a second experiment, the effects of these drugs were evaluated in the intensity of the physical signs of withdrawal, only memantine administration being efficient. In addition to these studies, the intensity of morphine dependence was investigated under the blockade of NMDA receptors, i.e. morphine was co-administered with memantine or MK-801. These animals did not develop CPA and present less intensity in the physical signs of morphine withdrawal. Our results support the idea that NMDA receptors are involved in the behavioural changes and therefore in the neural adaptations produced by repeated morphine administration.

Topics: Animals; Behavior, Animal; Conditioning, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Memantine; Mice; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Substance Withdrawal Syndrome; Time Factors

The stimulation of glutamate receptors plays a relevant role in the development of behavioral sensitization to psychostimulants, while less clear results have been obtained on their role in morphine sensitization. We addressed this issue by comparing the development of cocaine and morphine sensitization under a continuous s.c. infusion of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (0.1 mg/kg/24 h). Moreover, we studied the expression of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunits in discrete limbic areas of rats sensitized to morphine or cocaine with or without the concomitant dizocilpine infusion. It was observed that dizocilpine infusion did not prevent the development of morphine sensitization, while it prevented the development of tolerance to morphine-induced analgesia. Finally, morphine-sensitized animals did not present any modification in the subunit expression of glutamate receptors in the brain areas examined. In agreement with previous results, we found that dizocilpine infusion prevented the development of cocaine sensitization. Moreover, we observed that rats sensitized to cocaine presented a significant increase in the levels of GLUR1, NR1 and NR2B, in the nucleus accumbens, and of NR2B in the hippocampus compared to control animals. Such modifications were absent in rats administered cocaine under dizocilpine infusion. We conclude that: (i) morphine sensitization is a neuroadaptive phenomenon which does not appear to require NMDA receptor activity in order to develop; (ii) cocaine sensitization is clearly dependent on NMDA receptor activity, as dizocilpine infusion prevented the occurrence of glutamate receptors modifications as well as the development of sensitization.

Topics: Animals; Blotting, Western; Cocaine; Cocaine-Related Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Excitatory Amino Acid Antagonists; Hippocampus; Limbic System; Male; Morphine; Morphine Dependence; Nucleus Accumbens; Pain Measurement; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

Chronic use of morphine leads to physical and psychological dependence. The amygdala is known to be involved in the expression of emotion such as anxiety and fear, and several studies have shown that the central nucleus of the amygdala (CeA) is involved in morphine dependence. In the present study, we investigated the role of glutamate receptors within the CeA in the negative affective component of morphine abstinence by evaluating naloxone-precipitated withdrawal-induced conditioned place aversion (CPA) in morphine-dependent rats. We found that microinjection of the AMPA/kainate-glutamate-receptor antagonist CNQX (30 nmol/side) into the bilateral CeA significantly attenuated the naloxone-precipitated withdrawal-induced CPA, as well as several somatic signs, in morphine-dependent rats, without preference or aversive effects by itself in non-dependent rats. Furthermore, microinjection of the non-competitive NMDA-receptor antagonist MK-801 (30 nmol/side) or competitive NMDA-receptor antagonist D-CPPene (0.01 and 0.1 nmol/side) into the CeA significantly attenuated the naloxone-precipitated morphine withdrawal-induced CPA, but not somatic withdrawal signs. These results suggest that the activation of AMPA /kainate and NMDA receptors within the CeA play a crucial role in the negative affective component of morphine abstinence.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amygdala; Analysis of Variance; Animals; Avoidance Learning; Cerebellar Nuclei; Conditioning, Psychological; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Microinjections; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Substance Withdrawal Syndrome

Numerous data indicate that noncompetitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of physical dependence on opioids when these substances are administered together, and NMDA receptor antagonists are used at lower range of doses. Higher doses of these antagonists can enhance some opioid-induced effects. The present study extends these findings to the effects of NMDA/glycine (glycine(B)) site antagonists. Wistar rats were rendered dependent on morphine by implantation of morphine pellets. Both of the glycine(B) site antagonists used, 7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)-quinolone (L-701,324; 2.5 and 5.0 mg/kg) and 5,7-dichlorokynurenic acid (5,7-DCKA; 25, 50, and 100 mg/kg), suppressed the expression of morphine withdrawal syndrome estimated as wet dog shakes. Furthermore, L-701,324 (2.5 and 5 mg/kg), given twice a day during the development of morphine dependence, attenuated the development of morphine dependence, and the results were comparable to those obtained after administration of noncompetitive NMDA receptor antagonist - MK801 (0.1 mg/kg). Our data suggest that glycine(B) site antagonists may attenuate wet dog shakes (withdrawal) and the development of dependence, both being induced by chronic morphine administration in rats.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Implants; Excitatory Amino Acid Antagonists; Glycine Agents; Kynurenic Acid; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Quinolones; Rats; Rats, Wistar; Receptors, Glycine; Substance Withdrawal Syndrome

This study investigated the effects of the NMDA receptor antagonist MK-801 on the development of morphine dependence in 7-, 14-, and 21-day-old rat pups. For 6.5 days, starting at 1, 8, or 15 days of age, rats were pretreated with MK-801 (0.03 or 0.1 mg/kg, bid) or saline; 15 min later, morphine sulfate (10 mg/kg) or saline was injected to induce opiate dependence. On the afternoon of the seventh day, pups were injected with MK-801 (0.1 mg/kg) or saline and 15 min later with naltrexone (1 mg/kg) to precipitate withdrawal. Pups were then placed in a warm chamber with the litter and their behavior scan-sampled every 15 sec for a total of 15 min. MK-801 failed to inhibit morphine withdrawal in the 7-day-old rat, but did attenuate the development of morphine dependence in both the 14- and 21-day-old rats. These results suggest that the NMDA receptor is not functionally active in opiate withdrawal until around the second to third week of postnatal life in the rat and that there exists a transition period for the NMDA receptor to play a role in the development of opiate dependence and withdrawal.

Topics: Age Factors; Animals; Body Temperature; Body Weight; Central Nervous System; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Routes; Excitatory Amino Acid Antagonists; Male; Morphine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Long-Evans; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

The present study investigated the effect of co-administration of ketanserin, a 5-HT(2A) receptor antagonist and dizocilpine, a non-competitive NMDA receptor antagonist on the development of tolerance and dependence to morphine in mice. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg, twice daily) on day 3 and the degree of tolerance was further enhanced on day 9 and 10. Dizocilpine (0.2 mg/kg, twice daily for 9 days) prevented the development of tolerance to the antinociceptive effect of morphine. Dizocilpine (0.2 mg/kg) or combination of dizocilpine (0.2 mg/kg) and ketanserin (0.5, 1 and 2 mg/kg) acutely on day 10 did not affect morphine tolerance. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) pre-treatment failed to reverse the effect of dizocilpine on morphine tolerance. Dizocilpine (0.2 mg/kg, twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps and diarrhea on day 10 of testing. Similarly, dizocilpine (0.2 mg/kg) acutely on day 10 suppressed the development of morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days and acutely on day 10) pre-treatment reversed the effect of dizocilpine on morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) did not affect development of morphine tolerance and dependence. The present study demonstrated that ketanserin, a 5-HT(2A) receptor antagonist reversed the effect of dizocilpine on morphine dependence. This study gives behavioral evidence to the hypothesis that 5-HT(2A) receptor antagonists facilitate NMDA neurotransmission.

Topics: Animals; Dizocilpine Maleate; Drug Combinations; Drug Tolerance; Excitatory Amino Acid Antagonists; Female; Ketanserin; Mice; Mice, Inbred BALB C; Morphine Dependence; Naloxone; Narcotic Antagonists

Mice were subjected to two successive treatment protocols: first with NMDA receptor channel blockers (14 days, once a day) and second with morphine (5 mg/kg, 8 days, once a day). Treatment with the higher doses of dizocilpine (1 mg/kg), memantine (30 mg/kg), and MRZ 2/576 (30 mg/kg) upon discontinuation revealed only minor behavioral abnormalities attributable to the state of withdrawal. Following repeated administration of low-dose morphine, tolerance to morphine analgesia developed in mice preexposed to dizocilpine (1 mg/kg but not 0.3 mg/kg) but not memantine (10 and 30 mg/kg), MRZ 2/579 (10 and 30 mg/kg), or saline. There were no signs of morphine dependence in any treatment group. Overall, the present study found only minor effects of the subchronic administration of high doses of NMDA receptor channel blockers, suggesting that clinical use of NMDA receptor channel blockers such as memantine will not be accompanied by increased propensity to induction of morphine tolerance and dependence.

Topics: Analgesics, Opioid; Animals; Cyclopentanes; Dizocilpine Maleate; Drug Tolerance; Excitatory Amino Acid Antagonists; Interpersonal Relations; Male; Memantine; Mice; Morphine; Morphine Dependence; Reaction Time; Receptors, N-Methyl-D-Aspartate

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 and the expression of the abstinence syndrome to the opiate in mice. Morphine was administered in a single dose (300 mg/kg) of a slow release preparation. Dizocilpine (0.005 or 0.01 mg/kg given at 3, 12 and 24 h after the priming dose of morphine), ketamine (2, 4 or 8 mg/kg, 30 min before and 3, 6, 9 and 24 h after the priming dose) and DL-(E)-2-amino-4-methyl-5-phosphonopentanoate carboxy-ethylester (CGP 39551) (1.5 or 3 mg/kg, but not 6 or 12 mg/kg 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 single dose, 30 min before (s.c.) naloxone (4 mg/kg)-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.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Drug Tolerance; Excitatory Amino Acid Antagonists; Ketamine; Male; Mice; Morphine; Morphine Dependence; Pain Measurement; Substance Withdrawal Syndrome

Recent studies indicate that morphine dependence, assessed as the severity of naloxone-precipitated opiate withdrawal in rats, is attenuated by dizocipline, a non-competitive, excitatory amino acid antagonist. Because ethanol is a putative excitatory amino acid antagonist, the present study compared the effects of co-administration of ethanol to that of dizocilpine on morphine dependence. Rats were administered morphine (10 mg/kg) twice daily for 9 days. One group received ethanol (1 g/kg) co-administration, another received dizocilpine (0.05 mg/kg) co-administration, and a third served as vehicle controls. On day 10, all rats received naloxone (4 mg/kg) injections and ratings of several classic signs of opiate withdrawal were made. Both ethanol- and dizocilpine-treated rats showed significantly less severe precipitated opiate withdrawal overall, with the ethanol group showing reduced ratings of some specific signs. These results demonstrate that ethanol, like dizocilpine, attenuates the development of morphine dependence. The results are consistent with the action of ethanol at glutamate receptors.

Topics: Animals; Behavior, Animal; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Morphine Dependence; N-Methylaspartate; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

In rodents, noncompetitive and competitive NMDA receptor antagonists have been shown to attenuate and, in some cases, reverse tolerance to the analgesic effects of morphine. However, the ability of these same excitatory amino acid (EAA) receptor antagonists to modulate morphine dependence is controversial, and very little is known about the role of AMPA receptors in morphine dependence. LY293558, a novel, systemically active, competitive AMPA receptor antagonist and the NMDA receptor antagonists, MK-801 and/or LY235959, were evaluated in tolerant or dependent CD-1 mice. In mice rendered tolerant by morphine injection or pellet implantation, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or MK-801 (1 mg/kg per 24 h) attenuated the development of tolerance. Neither LY293558 nor MK-801 produced analgesia or altered the ED50 value of morphine. Continuous s.c. infusion of LY293558 (60 mg/kg per 24 h), MK-801 (1 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) attenuated the development of acute (3 h) morphine dependence (i.e., decreased naloxone-precipitated withdrawal jumping). In contrast, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) did not significantly attenuate the development of chronic dependence produced by morphine pellet implantation. These data indicate that the development of morphine tolerance is more sensitive to modulation by EAA receptor antagonists than is the development of morphine dependence as assessed by naloxone-precipitated withdrawal jumping.

Topics: Acute Disease; Animals; Chronic Disease; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Excitatory Amino Acid Antagonists; Infusions, Parenteral; Isoquinolines; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptors, AMPA; Tetrazoles

The behavioral effects of MK-801 were compared in morphine-dependent and non-dependent mice. The dose of MK-801 selected for these studies was previously demonstrated to attenuate some of the morphine withdrawal signs. Subjects were repeatedly exposed to morphine (8 days, b.i.d., 10-100 mg/kg, s.c.). Twenty-four hours after last morphine injection mice received naloxone (0.1 mg/kg, s.c.) and the observation was commenced. Animals were pretreated with either MK-801 (0.1 mg/kg, i.p.) or saline 30 min prior to testing. It was found that the behavioral effects of MK-801 (decreased sociability, and increased rate of transitions between behavioral elements, locomotion, grooming) were less pronounced in morphine-dependent compared to non-dependent subjects. However, the intensified almost stereotypic eating possibly reflected increased psychotomimetic potency of MK-801 in morphine-withdrawn animals.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Dependence; Motor Activity; N-Methylaspartate; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

MK801, an N-methyl-D-aspartate receptor antagonist, has recently been reported to attenuate tolerance to, and withdrawal from morphine. This study analyzes tolerance and withdrawal in a chronic intrathecal coinfusion model of morphine and MK801.. Intrathecal catheters, attached to 7-day miniosmotic infusion pumps, were implanted in rats and infused with saline, 20 nM/h morphine, MK801 (10 and 3 nM/h) + morphine; and 10 nM/h MK801. Analgesia was measured on the hot plate daily. On the day 7, groups received 3 mg/kg intraperitoneal naloxone and six signs of withdrawal were assessed: vocalization to air motion or light touch, abnormal posture, spontaneous vocalization, escape attempts, "wet dog shakes," and ejaculation. Similar groups were tested only on days 1 and 7. Intrathecal morphine dose-response curves were obtained on day 8. A separate morphine-tolerant group received 10 nM MK801 on day 7. Rats from each group received 10 nM intrathecal morphine 1 week later.. Coinfusion of MK801 with morphine resulted in a dose-dependent preservation of effect, and attenuated three of six signs of withdrawal. Coinfusion of MK801 (10 and 3 nM/h) prevented the reduction of potency observed with morphine alone. ED50 values (maximum percent effect, nM morphine) were: saline (16), morphine (496), MK801 (10 nM/h) + morphine (4), and 10 nM/h MK801 (0.3). Acute administration of MK801 was ineffective in restoring sensitivity to morphine. One week after cessation of infusion, there was no significant difference between groups.. Chronic spinal MK801 attenuates tolerance to, and withdrawal from spinal morphine in a dose-dependent fashion, supporting the hypothesis that N-methyl-D-aspartate receptor activity plays a role in the reorganization of spinal function produced by chronic opioid receptor activation. Chronic intrathecal MK801 appears to sensitize the spinal cord to intrathecal morphine.

Topics: Analgesics, Opioid; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Excitatory Amino Acid Antagonists; Male; Morphine; Morphine Dependence; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

1. The effects of morphine tolerance and abstinence on the binding of [3H]MK-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors were determined in brain regions and spinal cord of the mouse. 2. Male Swiss-Webster mice were rendered tolerant to and physically dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Placebo pellet-implanted mice served as controls. In tolerant (nonabstinent) mice, the pellets were left intact at the time of sacrificing whereas, in the abstinent mice, the pellets were removed 6 hr prior to sacrificing. 3. The binding of [3H]MK-801 to membranes prepared from spinal cord and brain regions (cortex, pons-medulla, hypothalamus, hippocampus, amygdala, striatum, and midbrain) was determined by using a 5 nM concentration of the ligand in the presence of 30 microM glycine and 50 microM of glutamate. 4. In nonabstinent morphine-tolerant mice, the binding of [3H]MK-801 was decreased in pons-medulla and hypothalamus, but was increased in the spinal cord in comparison to that in placebo controls. The reduction in binding in pons-medulla was due to a decrease in the Bmax value; the Kd value remained unchanged. The binding of [3H]MK-801 was increased in the hippocampus of morphine-abstinent mice. 5. These studies demonstrate that NMDA receptors of brain regions and spinal cord are differentially affected in morphine-tolerant and abstinent mice.

Topics: Animals; Central Nervous System; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Mice; Morphine; Morphine Dependence; Narcotics; Receptors, N-Methyl-D-Aspartate

We investigated the effect of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin ehydrogen maleate (dizocilpine, MK-801), on hippocampal norepinephrine release in morphine-treated rats in order to clarify the relationship between NMDA receptors and the development of morphine dependence. Naloxone hydrochloride injected subcutaneously (s.c.) into morphine-dependent rats, induced an immediate increase in hippocampal norepinephrine release, which was associated with a typical morphine withdrawal syndrome. The increased norepinephrine levels persisted for at least 2 hr, even after the disappearance of the behavioral withdrawal syndrome. This striking effect of naloxone on hippocampal norepinephrine release was dependent on the duration of the intracerebroventricular (i.c.v.) morphine infusion. Pretreatment with dizocilpine (s.c.) before naloxone challenge reduce the rate of the rise in hippocampal norepinephrine release induced by naloxone in morphine-treated rats. Concurrent infusion (i.c.v.) of dizocilpine and morphine decreased the level of hippocampal norepinephrine release after a naloxone challenge. Both pretreatment with dizocilpine (s.c.) before naxolone injection and infusion (i.c.v.) of dizocilpine suppressed rearing and teeth-chattering signs, but not wet-dog shakes in morphine-treated rats. These results suggest that dizocilpine attenuates the development of morphine dependence through NMDA receptors, and thus that interaction between opioid receptors and NMDA receptors may be involved in the development of morphine dependence.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Hippocampus; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Neuroprotective Agents; Norepinephrine; Rats; Rats, Wistar; Substance Withdrawal Syndrome

N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.

Topics: Animals; Dextromethorphan; Dizocilpine Maleate; Drug Combinations; Drug Tolerance; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Chronic treatment with the dopamine (DA) agonist B-HT 920 (0.25-1 mg/kg) or bromocriptine (1 mg/kg) followed by morphine (10 mg/kg) on days 1-9 prevented the development of tolerance to the antinociceptive effect of morphine as measured by the tail-flick test in mice, but failed to suppress the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps on day 10 of testing. Repeated administration of SKF 38393 (5 mg/kg) followed by morphine for 9 days significantly reduced naloxone-precipitated jumps on day 10 but failed to produce any significant change in tail-flick latency from the saline-pretreated group of mice on days 9 and 10 of testing. Repeated administration of B-HT 920 or bromocriptine enhanced the ability of MK-801 to attenuate the development of morphine tolerance and dependence while SKF 38393 failed to do so. The above data suggest a preferential role of D2 DA receptors in morphine tolerance and D1 receptors in the development of morphine dependence. D2 DA receptor stimulation may also play an important role in enhancing the effectiveness of MK-801 in the treatment of opiate tolerance and dependence.

Topics: Animals; Apomorphine; Azepines; Bromocriptine; Dizocilpine Maleate; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Tolerance; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate

Previous studies in this laboratory have demonstrated that cholinergic receptors within the spinal cord play an important role in the expression of naloxone-precipitated withdrawal symptoms in the morphine-dependent rat. Related cardiovascular studies in non-dependent animals have demonstrated that this spinal cholinergic system is linked to a glutamatergic, NMDA pressor pathway which also involves the participation of a nitric oxide (NO) generating system. The purpose of this study was to determine whether spinal NMDA receptors and/or NO are involved in the expression of morphine withdrawal symptoms. Rats bearing previously implanted intrathecal (IT) catheters were dependent on morphine following chronic i.a. infusion of increasing doses over 5 days. Naloxone (0.5 mg/kg) was administered via the i.a. line to precipitate withdrawal; and both cardiovascular and behavioral symptoms were recorded over 60 min. Pretreatment 20 min before naloxone with IT injection of either of the NMDA receptor antagonists, MK-801 or AP-7 (100-200 nmol), produced a significant reduction in the expression of both the cardiovascular and behavioral symptoms of up to about 60%. IT pretreatment with the NO synthase inhibitor L-NAME--a methyl ester derivative of L-arginine, also produced a dose-dependent, L-arginine reversible inhibition of the cardiovascular (mainly the pressor) component of withdrawal, but had no significant effect on the expression of behavioral signs. In contrast, IT pretreatment with L-NOARG and L-NMMA, non-ester analogs of L-arginine, significantly inhibited the expression of the behavioral signs of withdrawal but did not alter the pressor component. A combined pretreatment with L-NAME and L-NOARG resulted in suppression of both pressor and behavioral components of withdrawal. The anti-withdrawal actions of either class of NO synthase inhibitor could not be attributed to blockade of local muscarinic receptors. These findings are consistent with a role for both spinal NMDA receptors and a NO generating system in the expression of both the behavioral and autonomic components of naloxone-precipitated withdrawal. They also suggest that different structural analogs of L-arginine have different profiles of activity in this regard--opening the possibility that different isozymes of NO synthase located within the same spinal region mediate different physiological or behavioral functions.

Topics: Animals; Arginine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Morphine Dependence; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Structure-Activity Relationship; Substance Withdrawal Syndrome

1. The effects of morphine tolerance and abstinence on the characteristics of N-methyl-D-aspartate (NMDA) receptors, labeled with [3H]MK-801, were determined in the brain regions and spinal cord of the rat. 2. Male Sprague-Dawley rats were rendered tolerant to and physically dependent on morphine by subcutaneous implantation of six morphine pellets during a 7-day period. In tolerant (non-abstinent) rats, the pellets were left intact at the time of sacrificing, whereas in the abstinent rats the pellets were removed 16 hr prior to sacrificing. 3. The binding of [3H]MK-801, an NMDA receptor antagonist, to membranes prepared from spinal cord and brain regions (cortex, striatum, amygdala, hippocampus, hypothalamus, midbrain and pons-medulla) was determined using 5 nM concentration of the ligand in the presence of 30 microM glycine and 50 microM of glutamate. 4. In non-abstinent morphine tolerant rats, the binding of [3H]MK-801 was decreased by 40 and 33% in the midbrain and spinal cord, respectively, in comparison with their placebo controls. In morphine abstinent rats, the binding of [3H]MK-801 was decreased by 42, 29 and 50% in hypothalamus, midbrain and spinal cord, respectively, in comparison with their placebo controls. The binding of [3H]MK-801 to other brain regions and spinal cord of morphine tolerant and abstinent rats did not differ from their respective placebo controls. 5. Thus, these studies demonstrate, for the first time, that in the presence of glutamate and glycine, NMDA receptors of selected brain regions and spinal cord are down-regulated in rats treated chronically with morphine.

Topics: Animals; Brain Chemistry; Dizocilpine Maleate; Down-Regulation; Glutamic Acid; Glycine; Male; Morphine; Morphine Dependence; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

The effects of acute and chronic administration of (MK-801: [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate) were assessed on morphine dependence in the isolated spinal cord of the neonatal rat and on behavioral measures in intact adult rats. Neonatal rats were treated chronically (3 or 4 days) with injections of either morphine, morphine + MK-801, or saline. Naloxone (10 microM) which increased baseline ventral root spontaneous firing, induced more activity in spinal cords from morphine-treated neonates than in saline controls. In spinal cords from neonates receiving MK-801 with morphine, naloxone-induced spontaneous firing was significantly greater than in saline-treated and morphine alone-treated neonates. Acute MK-801 attenuated naloxone-induced firing in the morphine-treated group. Chronic co-treatment with MK-801 increased locomotor signs of withdrawal and decreased mastication in intact adult rats which had been treated chronically with morphine. MK-801-induced enhancement of morphine withdrawal is consistent with upregulation of NMDA receptors.

Topics: Animals; Animals, Newborn; Behavior, Animal; Dizocilpine Maleate; Drug Synergism; Electrophysiology; Excitatory Amino Acid Antagonists; In Vitro Techniques; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Spinal Cord; Substance Withdrawal Syndrome

The effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 micrograms/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, L-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of L-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Dizocilpine Maleate; Male; Mice; Morphine Dependence; Naltrexone; Nitric Oxide Synthase; omega-N-Methylarginine; Receptors, N-Methyl-D-Aspartate

1. The contribution of various excitatory amino acid (EAA) receptors (NMDA, AMPA/kainate and metabotropic) in the brain to the development of morphine dependence was examined. This was performed by measuring the severity of the precipitated withdrawal syndrome following chronic subcutaneous (s.c.) morphine and intracerebroventricular (i.c.v.) EAA antagonist treatment. 2. Continuous subcutaneous (s.c.) treatment with morphine sulphate (36.65 mumol day-1) produced an intense and reliable naloxone-precipitated withdrawal syndrome. 3. Chronic i.c.v. treatment with antagonists selective for metabotropic and NMDA receptors, but not AMPA/kainate receptors, significantly attenuated abstinence symptoms. Conversely, EAA antagonists had very little effect on non-withdrawal behaviours. 4. These results suggest that, as well as changes elicited by activation of NMDA receptors, metabotropic receptors and intracellular changes in the phosphatidylinositol (PI) second-messenger system or the cyclic adenosine 3',5'-monophosphate (cAMP) second messenger system, to which EAA metabotropic receptors are linked, may be involved in the development of opioid dependence with chronic morphine treatment.

Topics: Alanine; Animals; Anti-Anxiety Agents; Behavior, Animal; Benzoates; Benzodiazepines; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glycine; Injections, Intraventricular; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Rats; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

The effect of chronic administration of morphine to rats on the N-methyl-D-aspartate (NMDA) receptors labeled with [3H]MK-801, a non-competitive antagonist, was determined in brain regions and spinal cord. Male Sprague-Dawley rats were rendered tolerant to and physically dependent on morphine by subcutaneous implantation of 6 morphine pellets during a 7-day period. Each pellet contained 75 mg of morphine free base. Animals serving as controls were similarly implanted with placebo pellets. This procedure resulted in the development of a high degree of tolerance and physical dependence on morphine. Two sets of rats were used. In one, the pellets were left intact at the time of sacrifice (tolerant) and in the other the pellets were removed 16 h prior to sacrificing (abstinent). The binding constants, Bmax and Kd values of [3H]MK-801 were determined in cortex, hippocampus, hypothalamus, corpus striatum, midbrain and spinal cord. In the absence of glycine and glutamate, [3H]MK-801 bound to tissue membranes at a single high affinity site. The Bmax and Kd values of [3H]MK-801 were not altered in any of the tissues of the morphine abstinent rats. The Bmax value of [3H]MK-801 was significantly decreased in cerebral cortex of morphine tolerant rats as compared to their placebo controls but the Kd values did not change. In other brain regions and spinal cord of morphine tolerant rats and their placebo controls, the Bmax and Kd values of [3H]MK 801 did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Dizocilpine Maleate; Down-Regulation; Drug Tolerance; Glutamates; Glutamic Acid; Glycine; Male; Morphine; Morphine Dependence; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Substance Withdrawal Syndrome

The destruction of N-methyl-D-aspartate (NMDA) receptor-bearing neurons by insulin-induced hypoglycemia has long been known to be due to excessively released aspartate and glutamate. In this study, the effects of NMDA-bearing neuron destruction by insulin-induced hypoglycemia on the development of morphine (M) physical dependence, which was found related to functional states of NMDA receptors, were investigated. NMDA receptor antagonists CGP 39551 and MK-801 were used to see whether they could change intensity of precipitated abstinence syndrome by preventing destruction. Therefore, two groups of fasting rats injected IP with physiological saline, and another two groups given IP 10 mg/kg CGP 39551 and 0.5 mg/kg MK-801 received 15 IU/kg crystalline zinc insulin IP. After 2 h, the rats were orally given 2 x 4 ml of 5% glucose solution. On the third day, two pellets containing 75 mg base M were SC implanted to all rats. On the sixth day, they were IP given 2 mg/kg naloxone (NL). Then jumps, wet-dog shakes, and defecation were counted while diarrhea and ptosis were rated for 15 min. The rats given insulin manifested significantly more intense NL-precipitated abstinence syndrome than controls. The rats administered CGP 39551 showed a less intense physical dependence than those injected with only insulin. But, the intensity was still significantly higher than controls. In the rats that received MK-801, the abstinence syndrome was more or less equal to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; Animals; Behavior, Animal; Brain; Dizocilpine Maleate; Hypoglycemia; Insulin; Male; Morphine Dependence; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

A potential interaction between MK-801 and the cortical electroencephalographic (EEG) and behavioral expressions of morphine dependence in female Sprague-Dawley rats was assessed. Rats were treated chronically (7 days) with either morphine alone, morphine and MK-801, MK-801 alone or saline vehicle alone. On day 8 all rats received morphine alone followed by naloxone. An additional group received chronic (7 days) morphine alone, followed by MK-801 on day 8 prior to morphine and naloxone. Naloxone-induced EEG complexity in morphine-dependent rats was significantly lower than in chronic saline-treated rats. Total power, mobility, mean frequency, complexity and edge frequency in response to naloxone-induced withdrawal in morphine-dependent rats were significantly altered from those in chronically MK-801 alone-treated rats. No differences were found in the EEG and behavioral responses to naloxone between rats that received chronic MK-801 and those that didn't during chronic morphine treatment. Acute MK-801 prior to naloxone in morphine-dependent rats attenuated the behavioral, but not the EEG response to naloxone-induced withdrawal.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Drug Interactions; Electroencephalography; Female; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Sprague-Dawley

The effects of the excitatory amino acid (EAA) receptor antagonists MK-801 (non-competitive NMDA receptor antagonist), DNQX (competitive non-NMDA receptor antagonist) and 5,7-DCKA (antagonist of glycine site of NMDA receptor) have been examined on the naloxone (4 mg/kg, i.p.)-precipitated withdrawal jumping behaviour in morphine-dependent mice. The results indicate that withdrawal jumping behaviour in morphine-dependent mice was attenuated by all three EAA receptor antagonists, MK-801, DNQX and 5,7-DCKA. However, MK-801, DNQX and 5,7-DCKA inhibited the jumping behaviour in a relatively narrow dose range.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Glycine; Kynurenic Acid; Male; Mice; Morphine Dependence; Naloxone; Quinoxalines; Receptors, Amino Acid; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Substance Withdrawal Syndrome

It has previously been reported that the noncompetitive NMDA receptor antagonists ketamine and dextromethorphan suppressed the naloxone-induced morphine abstinence syndrome. In addition, the previous blockade by ketamine and dextromethorphan of NMDA receptors has been shown to intensify the naloxone-elicited morphine abstinence syndrome. On the basis of this information, another noncompetitive NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-a,d-cyclohepten-5,10-imine maleate (MK 801), was administered to rats in which two morphine-containing (75 x 2 morphine base) pellets had been implanted. The naloxone-precipitated abstinence syndrome in rats injected with 0.3 mg/kg MK 801 36 h after pellet implantation was found significantly more intense than controls whereas the abstinence syndrome in rats that received 0.1 mg/kg MK 801 before naloxone injection was less intense. The intensification by MK 801 given 36 h following pellet implantation was attributed to the further increase in upregulation and supersensitivity of NMDA receptors caused by morphine. The attenuation was explained by the blockade by MK 801 of NMDA receptors as occurred in the case of ketamine and dextromethorphan.

Topics: Animals; Dextromethorphan; Dizocilpine Maleate; Ketamine; Male; Morphine; Morphine Dependence; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome