dizocilpine-maleate and benzamide

Convincing evidence has accumulated that indicates neuroplastic changes within the spinal cord in response to repeated exposure to opioids. Such neuroplastic changes occur at both cellular and intracellular levels. It has been generally acknowledged that the activation of N-methyl-D-aspartate (NMDA) receptors plays a pivotal role in the development of neuroplastic changes following repeated opioid exposure. Intracellular cascades can also be activated subsequent to NMDA receptor activation. In particular, protein kinase C has been shown to be a key intracellular element that contributes to the behavioral manifestation of neuroplastic changes. Moreover, interactions between NMDA and opioid receptors can lead to potentially irreversible degenerative neuronal changes in the spinal cord in association with the development of opioid tolerance. Interestingly, similar cellular and intracellular changes occur in the spinal cord following peripheral nerve injury. These findings indicate that interactions exist in the spinal cord neural structures between two seemingly unrelated conditions-chronic opioid exposure and a pathological pain state. These observations may help understand mechanisms of chemical intolerance and multiple chemical sensitivity as well as have significant clinical implications in pain management with opioid analgesics.

Topics: Analgesics; Analgesics, Opioid; Animals; Benzamides; Dizocilpine Maleate; Drug Tolerance; Hot Temperature; Humans; Hyperalgesia; Morphine; Multiple Chemical Sensitivity; N-Methylaspartate; Narcotics; Nerve Degeneration; Nerve Tissue Proteins; Neuralgia; Neuronal Plasticity; Nitric Oxide; Phosphorylation; Poly(ADP-ribose) Polymerases; Posterior Horn Cells; Protein Kinase C; Protein Processing, Post-Translational; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Opioid, mu; Sciatic Nerve; Spinal Cord

Previous studies have shown that N-methyl-D-aspartate, the formation of free radicals and poly(ADP-ribose) polymerase are related to methamphetamine-induced neurotoxicity. This study was designed to investigate the involvement of oxidative stress in methamphetamine-induced self-injurious behavior in mice. In this study, methamphetamine (20 mg/kg) induced continuous self-injurious behavior in six of seven mice. N-methyl-D-aspartate-receptor antagonists (MK801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid) significantly attenuated this methamphetamine-induced self-injurious behavior. These results suggest that the activation of N-methyl-D-aspartate receptors is involved in methamphetamine-induced self-injurious behavior. Furthermore, we found that the nonselective nitric oxide synthase inhibitor l-N-nitro-L-arginine methyl ester hydrochloride and the neuronal nitric oxide synthase inhibitor 7-nitroindazole, but not the inducible nitric oxide synthase inhibitor aminoguanidine, the free-radical inhibitors fullerene and 3-methyl-1-phenyl-2-pyrazolin-5-one-186, or the poly(ADP-ribose) polymerase inhibitor benzamide, significantly attenuated methamphetamine-induced self-injurious behavior. The present results show that oxidative stress, which is mediated by the activation of neuronal nitric oxide synthase, is associated with methamphetamine-induced self-injurious behavior. These findings may help us to better understand the clinical phenomenon of self-injurious behavior.

Topics: Animals; Benzamides; Biogenic Amines; Brain Chemistry; Cell Count; Central Nervous System Stimulants; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Immunohistochemistry; Male; Methamphetamine; Mice; Microinjections; Motor Activity; Neostriatum; Oxidative Stress; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Self-Injurious Behavior

An increase in polydrug abuse is a major problem worldwide. A previous study showed that coadministration of methamphetamine and morphine induced lethality in rodents and humans. However, the underlying mechanisms by which the lethality is increased by the coadministration of methamphetamine and morphine have not been fully understood. Therefore, the present study was designed to determine the mechanism of increased lethality induced by methamphetamine and morphine. Coadministered methamphetamine and morphine increased the lethality by more than 70% in BALB/c mice. Pretreatment with NMDA-receptor antagonists, such as MK-801 and 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP), and benzamide [poly(ADP-ribose) polymerase (PARP) inhibitor] significantly attenuated the increased lethality induced by methamphetamine and morphine. Furthermore, the lethal effect induced by methamphetamine and morphine was completely attenuated by immediate cooling after the coadministration of methamphetamine and morphine. It has been reported that methamphetamine-induced neurotoxicity can be blocked by lowering the temperature, and this effect might be mediated by a reduction of release of free radicals. These results suggest that activation of NMDA receptors and PARP play an important role in the increased lethality induced by methamphetamine and morphine.

Topics: Animals; Behavior, Animal; Benzamides; Body Temperature; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Heart; Hypothermia, Induced; Liver; Male; Methamphetamine; Mice; Mice, Inbred BALB C; Morphine; Myocardium; Oxidative Stress; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders; Survival Rate; Time Factors