nitroarginine and Morphine-Dependence

The NOS inhibitors L-NARG and L-NAME attenuate weight loss and wet dog shakes, two specific signs of opioid withdrawal in rats. NMMA is more potent than L-NAME, consistent with the in vivo actions of these compounds as inhibitors of NOS. In addition, NMMA antagonizes naloxone-induced jumping in morphine-dependent rats. The NOS inhibitors generally increase teeth chattering in precipitated withdrawal. The profile of the diminished withdrawal signs produced by these drugs differs from that produced by clonidine, which stimulates locomotor activity and does not increase teeth chattering in precipitated opioid withdrawal (Kimes et al. 1990). These findings suggest that administration of inhibitors of NOS may be an effective treatment of the opioid withdrawal syndrome alone or in combination with clonidine (U.S. patent #5,225,40).

Topics: Animals; Arginine; Morphine Dependence; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Substance Withdrawal Syndrome

To investigate the effect of NG-nitro-L-arginine (L-NNA), a nitric oxide synthase (NOS) inhibitor, on the testis cell apoptosis in morphine-dependent rats induced by naloxone and the involved mechanisms.. Forty-eight Wistar rats were randomly divided into a control group, withdrawal group and a therapeutic group. Morphine-dependent rats were given gradually increasing doses of morphine to produce morphine-dependent models, the abstinent syndrome precipitated by naloxone. The inhibiting effect of L-NNA on the abstinent syndrome, and the testis apoptosis, NOS positive cells, calmodulin (CaM) contents, superoxide dismutase (SOD) activity, and glutathione super oxidase (GSHPx) activity of the morphine-dependent rats induced by naloxone were observed and recorded by radioimmunoassay, atomic absorption spectrometry, in situ nick translation (ISNT) and NADPH-d histochemical technique.. Compared with the control rats, the function of the somesthetic motor nerves and autonomic nerves was excessive, the apoptosis and NOS positive cells in the testis were significantly increased (P < 0.05 or P < 0.01), the content of CaM and the activity of SOD and GSHPx were obviously decreased in the morphine-dependent rats induced by naloxone. But L-NNA could significantly inhibit the abstinent syndrome, decrease NOS positive cells and apoptosis, and increase CaM content and the activity of SOD and GSHPx in the testis.. Morphine dependence can induce testis cell apoptosis, an increase in testis NOS positive cells, a decrease in CaM content and the activity of SOD and GSHPx in the testis. L-NNA has the curative effect on the morphine abstinent syndrome, protects testis cells against apoptosis and improves their involved biochemical indexes.

Topics: Animals; Apoptosis; Calmodulin; Disease Models, Animal; Male; Morphine Dependence; Nitric Oxide Synthase; Nitroarginine; Random Allocation; Rats; Rats, Wistar; Spermatozoa; Testis

To investigate the involvement of immunoreactive-dynorphin A in the inhibitory effect of N-nitro-L-arginine on the morphine physical dependence in rats.. The rats were rendered dependent on morphine by subcutaneous administration of morphine solution three times daily in a manner of dose increment of 5 mg.kg(-1) for 6 days. The degree of morphine physical dependence was monitored by scoring the abstinence syndromes precipitated by 5 mg.kg(-1) naloxone of the rats. The expression levels of immunoreactive dynorphin A in tissues were determined using a radioimmunoassay.. Intraperitoneal injection of 5 mg.kg(-1) N-nitro-L-arginine suppresses most of the withdrawal symptoms of morphine dependent rats. N-nitro-L-arginine can elevate the expression of immunoreactive dynorphin.. Chronic N-nitro-L-arginine administration can inhibit the development of morphine physical dependence in a manner of dose-dependence, which is significantly related to its role of regulating the endogeneous dynorphin system.

Topics: Animals; Dose-Response Relationship, Drug; Dynorphins; Male; Morphine Dependence; Nitroarginine; Rats; Rats, Sprague-Dawley

The possible involvement of nitric oxide (NO) in morphine-induced catalepsy and hyperthermia was studied in morphine-dependent rats. Four days repeated injection regimen was used to induce morphine dependence, which was assessed by naloxone challenge (0.5 mg x kg(-1), s.c.). Pretreatment of rats with the NO synthase inhibitor, N(G)-nitro-L-arginine (L-NA, 8 mg x kg(-1) twice daily, i.p.) potentiated the cataleptic response of morphine as shown by a rightward shift in the morphine-log dose-response curve. Prior treatment of rats with the NO precursor, L-arginine (200 mg x kg(-1), twice daily, i.p.) abolished the potent effect of L-NA and restored the cataleptic scores to levels similar to those of morphine-dependent rats. The same dose of L-NA significantly blocked morphine-induced hyperthermia at the dose levels of morphine (15-105 mg x kg(-1)) and this effect was reversed by L-arginine. These data provide the first experimental evidence that NO is involved in morphine induced catalepsy and hyperthermia and demonstrated that blockade of NO synthesis may suggest a dangerous interaction with opioids in the control of motor function.

Topics: Animals; Arginine; Catalepsy; Enzyme Inhibitors; Fever; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Substance Withdrawal Syndrome

Two potent inhibitors of nitric oxide synthase (NOS), namely, NG-nitro-L-arginine (NNA) and NG-monomethyl-L-arginine (NMMA) were administered intracerebroventricularly (i.c.v.) in morphine-dependent mice to investigate their effects on abrupt withdrawal and naltrexone-precipitated abstinence signs. Male Swiss-Webster mice were rendered dependent on morphine by subcutaneous implantation of a morphine pellet containing 75 mg of morphine base. Mice implanted with placebo pellets served as controls. NMMA or NNA administered i.c.v. had minimal effects on body weight loss and hypothermia that occur during abrupt withdrawal of morphine. When administered i.c.v., both NNA or NMMA (0.1, 1 and 10 micrograms/mouse) dose-dependently inhibited naltrexone-induced stereotyped jumping behavior in mice. I.c.v. administration of NMMA also attenuated withdrawal induced fecal pellet formation. This effect, however, was not dose-dependent. In conclusion, these results suggest that brain NO plays an important role in the expression of behavioral signs of morphine withdrawal syndrome. In addition, these results support the idea that NOS inhibitors may be potentially useful in the treatment of opioid withdrawal syndrome.

Topics: Animals; Behavior, Animal; Central Nervous System; Dose-Response Relationship, Drug; Enzyme Inhibitors; Injections, Intraventricular; Male; Mice; Morphine Dependence; Naltrexone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Substance Withdrawal Syndrome

The effect of the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 5-20 mg/kg i.p.) and NG-nitro-L-arginine (NO2Arg, 5-20 mg/kg i.p.) on morphine-induced analgesia, as well as on morphine induced tolerance and dependence was examined in male albino Swiss mice. Neither acute nor repeated (for 5 days) administration of the nitric oxide synthase inhibitor, L-NAME affected the morphine induced analgesia, as measured by hot plate and tail-flick tests. On the other hand, administration of L-NAME or NO2Arg along with morphine prevented the development of tolerance to the analgesic effect of morphine for at least 7 days, whereas the analgesic effect of morphine alone disappeared after 5 days. L-NAME and NO2Arg also attenuated some signs of morphine dependence, as assessed by naloxone (2 mg/kg)-precipitated withdrawal. These results indicate that NO may play a role in the development of morphine tolerance and dependence.

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Animals; Arginine; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine

The effect of intraperitoneally administered nitric oxide (NO) synthase inhibitors has been examined on the naloxone-precipitated withdrawal syndrome in morphine-dependent mice. L-NAME (30-200 mg/kg) and L-NOARG (7.5-50 mg/kg) induced a significant decrease of naloxone-precipitated withdrawal jumping and diarrhoea. However, L-NMMA (3.5-100 mg/kg), considered as a less potent NO synthase inhibitor, did not significantly affect the withdrawal signs in mice. Although a specificity of NO synthase inhibitors is not fully established, these results indicate that inhibition of NO synthesis in the central nervous system and periphery may significantly affect the morphine withdrawal phenomena. Accordingly, this study suggests an involvement of NO in morphine withdrawal syndrome.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Behavior, Animal; Diarrhea; Male; Mice; Morphine Dependence; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Substance Withdrawal Syndrome