dizocilpine-maleate and Opioid-Related-Disorders

The present review summarizes the effects of drugs that block N-methyl D-aspartate receptor complex (NMDA-RC) on the development of opiate tolerance and abstinence. Using behavioral pharmacological approaches, pre-clinical studies demonstrate that noncompetitive and competitive NMDA receptor antagonists and glycine binding site antagonists can inhibit opioid tolerance and some symptoms of opioid withdrawal. The biochemical mechanisms underlying the inhibition of NMDA receptor antagonists on opioid tolerance and dependence are discussed. There is some extent of neurotoxicity associated with the therapeutic use of NMDA receptor antagonists.

Topics: Animals; Dizocilpine Maleate; Humans; Isoquinolines; Levulinic Acids; Opioid-Related Disorders; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid

Recent research has demonstrated that N-methyl-D-aspartate (NMDA) receptors, a class of excitatory amino acid receptors, may have an important role in opiate tolerance and physical dependence. Much of the evidence for this has arisen from studies that have examined the effects of NMDA receptor antagonists on these phenomena. This article summarizes research from our laboratory on the effects of NMDA receptor antagonists on opiate tolerance and dependence in rats. Noncompetitive NMDA antagonists, including MK-801, ketamine, phencyclidine, and dextrorphan have been found at low doses to inhibit the development, or acquisition, of opiate tolerance and dependence but not the expression. The results suggest that NMDA receptors have a role in the neural plasticity responsible for tolerance and dependence. Selected theoretical and therapeutic implications of these findings are discussed.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Narcotics; Neuronal Plasticity; Opioid-Related Disorders; Rats; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Substance Withdrawal Syndrome

This laboratory perspective reviews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional data to support previous observations that these NMDA antagonists modulate morphine (mu) opioid tolerance but do not affect U50488H (kappa 1) opioid tolerance. A strategy, which utilizes efficacy as an NMDA receptor antagonist and clinical safety, provides the basis for a discussion of the clinical potential of dextromethorphan, ketamine, and felbamate as modulators of opioid tolerance in pain patients or opioid addicts. The potential use of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors in neuropathic pain is also discussed.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Dextromethorphan; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Isoquinolines; Narcotics; Nitric Oxide Synthase; Opioid-Related Disorders; Pyrrolidines; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, kappa; Receptors, Opioid, mu

Recent studies have led to a greater understanding of the behavioral, cellular, and molecular mechanisms underlying opiate tolerance and physical dependence. Behavioral studies have demonstrated that both direct pharmacological effects and the learning of interactions between drug effects and environmental cues are important in these phenomena. Behavioral studies have also revealed that N-methyl-D-aspartate receptors may play a role in their development (or acquisition). Although in early cellular studies no consistent role was found for opioid receptors or endogenous opioid peptides in opiate tolerance and dependence, recent experiments suggest that beta-endorphin, enkephalin, and dynorphin neurons may indeed have a role. Finally, studies at the molecular level suggest that a functional decoupling of opioid receptors from GTP-binding proteins (G proteins) may be important. In this review, we discuss these disparate findings and present a synthesis that shows how they might together contribute to the phenomena of opiate tolerance and physical dependence.

Topics: Animals; Calcium; Dizocilpine Maleate; Drug Tolerance; Endorphins; Gene Expression Regulation; GTP-Binding Proteins; Humans; Learning; Male; Models, Biological; Narcotics; Neuronal Plasticity; Opioid-Related Disorders; Pro-Opiomelanocortin; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Second Messenger Systems; Substance Withdrawal Syndrome

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

Recurrent relapse is a major problem in treating opiate addiction. Pavlovian conditioning plays a role in recurrent relapse whereby exposure to cues learned during drug intake can precipitate relapse to drug taking. α7 nicotinic acetylcholine receptors (nAChRs) have been implicated in attentional aspects of cognition and mechanisms of learning and memory. In this study we have investigated the role of α7 nAChRs in morphine-conditioned place preference (morphine-CPP). CPP provides a model of associative learning that is pertinent to associative aspects of drug dependence. The α7 nAChR antagonist methyllycaconitine (MLA; 4 mg/kg s.c.) had no effect on the acquisition, maintenance, reconsolidation or extinction of morphine-CPP but selectively attenuated morphine-primed reinstatement of CPP, in both mice and rats. Reinstatement of morphine-CPP in mice was accompanied by a selective increase in [

Topics: Aconitine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; alpha7 Nicotinic Acetylcholine Receptor; Analgesics, Opioid; Animals; Conditioning, Classical; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extinction, Psychological; Hippocampus; Mice; Morphine; Nicotinic Antagonists; Opioid-Related Disorders; Rats; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Recurrence; Tritium

N-Methyl-D: -aspartate (NMDA) receptors have an important role in different forms of behavioral and neural plasticity. Evidence suggests that these receptors may also be involved in plasticity arising from long-term treatment with different drugs of abuse, including tolerance, sensitization, and physical dependence. There is abundant evidence demonstrating that NMDA receptors are involved in tolerance to opiate-induced antinociception; however, the role of these receptors in sensitization to the locomotor effects of opiates is more controversial.. The ability of NMDA receptor antagonists to modify the development of sensitization to the locomotor stimulant effect of three different opiates was examined. In selected studies, the ability of the antagonists to modify tolerance to the antinociceptive effects of the opiates was also examined.. Adult male Sprague-Dawley rats were used to assess the effects of NMDA receptor antagonists (MK-801, memantine or LY235959) on tolerance and sensitization to three opiates: morphine, methadone, or buprenorphine. It was predicted that low, selective doses of the antagonists would inhibit the development of opiate tolerance and sensitization.. Consistent with our predictions, the noncompetitive NMDA receptor antagonists MK-801 and memantine and the competitive NMDA receptor antagonist LY235959 inhibited the development of sensitization to the locomotor stimulant effect of morphine. Additionally, MK-801 inhibited the development of tolerance and sensitization to methadone and buprenorphine in a similar manner.. The results, together with previous research, suggest that NMDA receptors are broadly involved in opiate-induced plasticity, including the development of opiate tolerance and sensitization.

Topics: Animals; Behavior, Animal; Buprenorphine; Dizocilpine Maleate; Drug Tolerance; Excitatory Amino Acid Antagonists; Isoquinolines; Male; Memantine; Methadone; Morphine; Motor Activity; Narcotics; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Five experiments studied the modulation of acute opiate withdrawal by restraint stress. Rats were subjected to a 2-hr restraint stress, and 1, 3, or 7 days later they received a single injection of morphine followed by injection of naloxone. Naloxone precipitated a withdrawal syndrome. This syndrome was enhanced when it occurred 1 day after stress but was reduced when it occurred 7 days after stress. The enhancement of withdrawal by restraint stress was prevented by treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK801 or the glucocorticoid receptor antagonist RU486 prior to stress. Together these experiments show that restraint stress alters vulnerability to opiate withdrawal and identify activation of NMDA and glucocorticoid receptors as causal to this vulnerability.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hormone Antagonists; Male; Mifepristone; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Rats; Rats, Wistar; Receptors, Glucocorticoid; Receptors, N-Methyl-D-Aspartate; Restraint, Physical; Stress, Physiological; Time Factors