nitroarginine and Opioid-Related-Disorders

Opioid tolerance can be modulated by the N-methyl-D-aspartate/nitric oxide (NMDA/NO) cascade. Evidence exploring a daily injection paradigm indicates that agents antagonizing NMDA receptors can prevent tolerance to morphine and delta drugs, but not kappa agents. Drugs work regardless of whether they act as competitive or noncompetitive antagonists. Even an agent acting as an antagonist on the glycine site of the NMDA receptor is effective. Blockade of nitric oxide synthase has similar effects on opioid tolerance, preventing morphine and delta tolerance but not that of kappa drugs. Even methylene blue, which can inhibit guanylyl cyclase activity, is effective, presumably by blocking cGMP formation resulting from NO release. These results demonstrate the importance of an intact NMDA/NO cascade in the production of opioid tolerance and open new possibilities in the design of agents acting on opioid tolerance.

Topics: Animals; Arginine; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Morphine; Narcotics; Nitric Oxide Synthase; Nitroarginine; Opioid-Related Disorders; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, delta; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

Four inhibitors of nitric oxide synthase (NOS), administered as acute pretreatments, attenuated several signs of naloxone-precipitated opioid withdrawal in morphine-dependent rats. Profiles of these drugs for inhibiting the expression of withdrawal were similar to that of clonidine, a drug used clinically to treat opioid withdrawal. The nonselective NOS inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, and N(5)-(1-iminoethyl)-L-ornithine, a selective inhibitor of endothelial NOS, Increased blood pressure in awake, morphine-naive and morphine-dependent rats not undergoing withdrawal. 7-Nitroindazole, a selective inhibitor of neuronal NOS, did not elevate blood pressure. Insofar as hypertension is a component of opioid withdrawal in humans, the ability of 7-nitroindazole to attenuate morphine withdrawal in rats without eliciting a vasopressor response suggests that 7-nitroindazole may have human therapeutic potential. Research directions for the continued development of 7-nitroindazole as a therapeutic modality are discussed with respect to issues of physical dependence, tolerance, and safety.

Topics: Adrenergic alpha-Agonists; Animals; Arginine; Blood Pressure; Clonidine; Depression, Chemical; Enzyme Inhibitors; Heart Rate; Indazoles; Morphine; Narcotics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Opioid-Related Disorders; Ornithine; Substance Withdrawal Syndrome

To investigate the role of adenylate cyclase (AC)-cAMP system and Ca2+ system and NO-cGMP signal system and the effects of a NOS inhibitor, NG-nitro-L-arginine (L-NNA) in the neuronal mechanisms of opioid tolerance and dependence.. The experiments were performed in five groups: control group; opioid agonist group; opioid agonist + nalonoxe group; L-NNA + opioid agonist group and L-NNA + opioid agonist + nalonoxe group. The intracellular cAMP and cGMP levels were measured by 3H-cAMP protein binding assay and 3H-cGMP radioimmunoassay, respectively. NOS activity was determined by the conversion of 3H-arginine to 3H-citrulline. The change of [Ca2+]i was studied by the laser scanning confocal microscopy technique. iNOS protein expression was detected using immunohistochemistry with monoclonal antibody of iNOS, and imaging analysis was performed.. Long-term administration of high-selective delta-opioid receptor agonist DPDPE and precipitation of opioid withdrawal by naloxone significantly induced increase of cAMP level and [Ca2+]i in NG-LNCXiNOS cells with stable expression of iNOS gene. The cytosolic iNOS activity and cGMP generation were enhanced by DPDPE dose-dependently. 10(-4) mol/L L-NNA could block opioid agonist-induced AC-cAMP desensitization and activity of NO-cGMP second messenger pathway, but it could not reduce opioid-induced elevation of [Ca2+]i. Furthermore, L-NNA decreased iNOS-specific protein expression in DPDPE-induced tolerance and naloxone-precipited withdrawal cells.. NOS inhibitor may attenuate the development of opioid tolerance and withdrawal via the negative regulation of AC-cAMP system and NO-cGMP system. It can be clinically used to prevent opiate tolerance and addiction.

Topics: Animals; Drug Tolerance; Mice; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroarginine; Opioid-Related Disorders; Receptors, Opioid, delta; Signal Transduction