nitroarginine and Substance-Withdrawal-Syndrome

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

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

This study was undertaken to evaluate the effect of nitric oxide (NO) synthase inhibitors on benzodiazepine withdrawal syndrome in mice and rats. Diazepam withdrawal in mice was read out as intensification of the seizures induced by a subthreshold dose of pentetrazole. In rats, the withdrawal syndrome resulting from chronic administration of diazepam, chlordiazepoxide, clonazepam and temazepam was characterized by audiogenic seizures, hypermotility and weight loss. Administration of the non-selective NO synthase inhibitors N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) significantly attenuated the withdrawal syndrome (i.e., pentetrazole-induced seizures) in diazepam-dependent mice. L-NOARG significantly suppressed hypermotility in clonazepam-dependent rats and inhibited the decrease in body weight observed after 12 h of withdrawal in chlordiazepoxide- and clonazepam-dependent rats. Moreover, a clear propensity of L-NOARG to protect benzodiazepine-dependent rats against audiogenic seizures was observed. These findings suggest that the cGMP/NO system may participate in causing the signs of benzodiazepine withdrawal.

Topics: Animals; Benzodiazepines; Body Weight; Cyclic GMP; Enzyme Inhibitors; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Seizures; Substance Withdrawal Syndrome

This study evaluates the effects of three nitric oxide synthase (NOS) inhibitors (L-NNA, L-NAME, L-NMMA) in attenuating the precipitated nicotine withdrawal syndrome in rats. Male albino Wistar rats were made dependent on nicotine by subcutaneous infusion of nicotine (9.0 mg/kg/day) via a 7 day osmotic pump, whereas control rats received saline via osmotic pumps. Test doses of each NOS inhibitor were administered 30 min prior to mecamylamine (1 mg/kg) challenge in control and test rats on the 7th day. Somatic signs of withdrawal were scored for 15 min by using the global Gellert-Holtzman rating scale followed by a measurement of motor activity. A comparison of NOS inhibitors treated rats with the mecamylamine-precipitated nicotine rats showed that at highest dose L-NNA appears to produce a more complete attenuation of all aspects of withdrawal syndrome. On the other hand, L-NAME appears to do so both at moderate and highest doses. This could be due to an incomplete reversal of some signs of withdrawals by L-NMMA. However, motor activity increased in nicotine dependent rats with the administration of NOS inhibitors. This study demonstrates that NO plays an important role in the expression of behavioral signs of nicotine withdrawal syndrome and suggests a potential use of NOS inhibitors as an aid in tobacco smoking cessation.

Topics: Animals; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Enzyme Inhibitors; Male; Mecamylamine; Motor Activity; NG-Nitroarginine Methyl Ester; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Rats, Wistar; Substance Withdrawal Syndrome

The aim of the work was to study the effects of litter and the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) on the behaviour of mice after acute and chronic ethanol administration and withdrawal. Male outbred NIH/S mice, from 21 litters, were distributed among experimental groups and subjected to acute and chronic ethanol administration. After acute or chronic ethanol administration, the effects of L-NOARG on the behaviour of mice in the plus-maze test were studied. Acute ethanol (1 g/kg, i.p.), L-NOARG (20 and 40 mg/kg, i.p.) and their combination induced an anxiolytic effect. Furthermore, the values for the representatives of different litters tended to be either above or below the group mean, irrespective of the drug treatment. Chronic ethanol administration (23 days by inhalation) induced an anxiolytic effect and ethanol withdrawal induced an anxiogenic effect in the plus-maze. The administration of L-NOARG (20 mg/kg, i.p.) induced an anxiolytic effect in control mice and had no effect on ethanol-intoxicated mice, but attenuated the anxiogenic effect of ethanol withdrawal in the plus-maze. However, after chronic ethanol administration and withdrawal, litter had no effect on the behaviour of mice. If the litter is a significant determinant in the behaviour of outbred mice, then the use of information about the litter origin of animals could serve for the purposes of reduction. But only if this information is available from breeders.

Topics: Administration, Inhalation; Animals; Anxiety; Behavior, Animal; Body Weight; Central Nervous System Depressants; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethanol; Housing, Animal; Male; Mice; Nitric Oxide Synthase; Nitroarginine; Substance Withdrawal Syndrome

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

The use of clonazepam in the long-term treatment of epilepsy is greatly inhibited by its capacity to induce tolerance and dependence. A means of preventing or minimizing the tolerance and dependence inducing properties is required. Here the role of nitric oxide in preventing the development of tolerance and withdrawal hyperexcitability was studied. In Wistar rats, clonazepam at a dose of 0.25 mg/kg i.p. twice daily produced tolerance to its anticonvulsant action in 28 days. After sudden cessation of therapy it produced hyperexcitability. Tolerance was shown by a decrease in seizure threshold to near control value while withdrawal hyperexcitability was evidenced by a significant decrease in seizure threshold below the control value. L-Arginine (a donor of nitric oxide) and N omega-nitro-L-arginine (an inhibitor of nitric oxide synthase) were given in doses of 150 mg/kg and 8 mg/kg, respectively on day 1, 3, 7, 14, 21 and 28 with clonazepam. Withdrawal hyperexcitability was seen on day 1, 2 and 4 after cessation of drug therapy. Electroshock was used as a model of epilepsy and seizure thresholds were determined by an up and down method of Kimball et al. L-Arginine was found to inhibit the development tolerance as well as withdrawal hyperexcitability when administered with clonazepam while N omega-L-arginine did not prevent either the development of tolerance or withdrawal hyperexcitability in the electroshock model. In the PTZ model, however, L-arginine had no effect on the anticonvulsant action and withdrawal hyperexcitability while inhibition of nitric oxide synthesis prevented withdrawal hyperexcitability in PTZ-induced seizures.

Topics: Animals; Anticonvulsants; Clonazepam; Drug Tolerance; Female; Male; Nitric Oxide; Nitroarginine; Pentylenetetrazole; Rats; Rats, Wistar; Receptors, GABA; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

The decrease in the seizure threshold for pentylenetetrazole in diazepam-withdrawn mice was not significantly affected by L-arginine (50 and 100 microg/mouse, i.c.v.), which did have an antiseizure effect in chronically vehicle-treated mice. Sodium nitroprusside (25 and 50 microg/mouse, i.c.v.) increased the seizure threshold for pentylenetetrazole in both diazepam-withdrawn mice and chronically vehicle-treated mice. In addition, the antiseizure effect of L-arginine was blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine (NOARG) and the NO scavenger, hemoglobin, while the effect of sodium nitroprusside was inhibited by hemoglobin, but not by NOARG, indicating that the antiseizure effect of L-arginine, but not that of sodium nitroprusside, is mediated by NO production resulting from the activation of NO synthase. Therefore, a decrease in the NO production via NO synthase may be involved in the hypersusceptibility to pentylenetetrazole during diazepam withdrawal.

Topics: Animals; Arginine; Diazepam; Enzyme Inhibitors; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Pentylenetetrazole; Seizures; Substance Withdrawal Syndrome

Cholestasis liver disease is associated with clinical and experimental findings consistent with increased opioidergic neuromodulation, increased plasma total activity, and elevated plasma enkephalin concentrations. The effect of the nitric oxide (NO) synthase inhibitor, L-nitro-arginine (L-NA, 0.03, 0.1, 0.3, 1 mg/kg), and the nitric oxide precursor, L-Arg (30 mg/kg), on antinociception induced by bile duct resection or sham operation, as well as on opioid dependence, was examined in male albino Swiss mice. Repeated (5 days) administration of L-NA attenuated signs of dependence, as assessed by naloxone (5 mg/kg)-precipitated withdrawal, and decreased the antinociception; however, L-Arg potentiated withdrawal signs and increased the antinociception. The results of this study support the involvement of the L-arginine/nitric oxide pathway in the opioidergic-dependent manifestation of cholestasis in an animal model.

Topics: Acute Disease; Animals; Arginine; Behavior, Animal; Bile Ducts; Cholestasis; Enzyme Inhibitors; Male; Mice; Naloxone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Reaction Time; Substance Withdrawal Syndrome

Following the naloxone administration in bile duct resected animals, striking opioid withdrawal signs are observed due to increased opioidergic tone. Pretreatment of animals with L-nitro arginine, a nitric oxide synthase inhibitor, reduces the naloxone-precipitated withdrawal signs as well as increase the antinociception. The results of this study support evidence for the involvement of the L-arg-nitric oxide pathway in opioidergic-dependent manifestation of cholestasis in an animal model.

Topics: Analgesia; Animals; Behavior, Animal; Cholestasis; Male; Mice; Naloxone; Narcotic Antagonists; Nitroarginine; Opioid Peptides; Pain Measurement; Substance Withdrawal Syndrome

The role of the endothelium-derived relaxing factor (EDRF), nitric oxide (NO), in the withdrawal-induced antihypertensive phenomenon (WAP) of arginine vasopressin (AVP) was studied in conscious unrestrained rats implanted with femoral arterial catheters for the measurement of arterial blood pressure. Cessation of a 3-h intravenous infusion of AVP (20 ng.kg-1.min-1) was followed by a large and long-lasting fall in mean arterial blood pressure below preinfusion control values in spontaneously hypertensive rats (SHR; -47.5 +/- 6.4 mmHg; 1 mmHg = 133.3 Pa) but not in normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) control rats. Chronic treatment of normotensive SD rats with the NO synthesis inhibitor, N omega-nitro-L-arginine (L-NNA; 0.5 g.L-1 in drinking water for 2 weeks), resulted in sustained hypertension. Similar to the SHR model, a large fall in blood pressure (-37.8 +/- 7.7 mmHg) was observed in this model of hypertension following cessation of the AVP infusion. In SHR, inhibition of NO synthesis with L-NNA (0.05 g.L-1 in drinking water for 2 weeks) failed to attenuate the fall in blood pressure following withdrawal of AVP. Chronic treatment with the NO precursor, L-arginine (L-Arg; 1.25 g.L-1 in drinking water for 2 weeks), did not affect the amplitude or the time course of the WAP in SHR. The results indicate that the L-Arg/NO pathway is not essential to the expression of the WAP to AVP in the SHR.

Topics: Animals; Antihypertensive Agents; Arginine; Arginine Vasopressin; Blood Pressure; Enzyme Inhibitors; Hypertension; Male; Nitric Oxide; Nitroarginine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Vasoconstrictor Agents

Rats, which were made chronically alcoholic in combination with L-N(o)-nitro-arginine (L-NNA) treatment (5 mg/kg/day), a nitric oxide (NO) synthase inhibitor, showed a significant decrease in their alcohol preference and hypermotility during the withdrawal period by comparison with chronically alcoholic rats. However, no difference in the global liquid consumption between treated and untreated rats during the withdrawal stage was identified. In addition, the hypervascularization of the cortical area observed after chronic alcoholism was significantly decreased in the rats that had received L-NNA during the alcoholism procedure and was comparable to control rats. Thus, L-NNA alters both the behavioral preference for alcohol after alcoholism and the hypermotility during alcohol withdrawal, thus supporting the hypothesis of a direct implication of NO in alcohol abuse and its withdrawal.

Topics: Alcohol Drinking; Alcoholism; Animals; Central Nervous System Depressants; Cerebral Cortex; Cerebrovascular Circulation; Enzyme Inhibitors; Ethanol; Male; Microcirculation; Motor Activity; Neovascularization, Pathologic; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Neuropeptide FF (NPFF) has certain antiopiate actions and may play a role in opiate tolerance and dependence. Third ventricle injection of 10 micrograms NPFF induces a quasimorphine abstinence syndrome in opiate-naive rats. Nitric oxide synthesis may also contribute to opiate tolerance and dependence. The present study tests the hypothesis that NPFF acts through stimulation of nitric oxide synthase (NOS). Third ventricular injection of 10 micrograms NPFF precipitated an average of 46 abstinence-like signs during a 20-min observation. Pretreatment (30 min earlier) with 7.5 or 15 mg/kg s.c. of the NOS inhibitor nitro-L-arginine (L-NNA) resulted in a significant and dose-dependent alleviation of NPFF-induced abstinence-like signs. The anti-NPFF activity of 15 mg/kg L-NNA was blocked by 750 mg/kg L-arginine, but not by the same amount of D-arginine, indicating that L-NNA attenuates NPFF activity through a stereospecific inhibition of NOS.

Topics: Animals; Arginine; Cerebral Ventricles; Enzyme Inhibitors; Injections, Intraventricular; Male; Narcotic Antagonists; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Rats; Rats, Sprague-Dawley; Stereoisomerism; Stereotyped Behavior; 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

Clinical observations and laboratory investigations suggest that gender and menstrual status modulate cerebrovascular reactivity. We prepared 7 groups of rabbits (I) males (II) oophorectomized untreated females, (III) testosterone treated oophorectomized females, (IV) superovulated females, (V) superovulated estrogen withdrawn females, (VI) estrogen treated oophorectomized females, and (VII) estrogen withdrawn females to mimic phases of the estrous cycle and compare cerebral basilar artery reactivity to serotonin (5-HT) and norepinephrine (NE) in vitro. Basilar artery sensitivity to 5-HT vasoconstriction was increased in oophorectomized, acutely estrogen withdrawn females (Group VII) when compared to estrogen maintained and the other groups (p < 0.0001). There was a significant reduction in 5-HT sensitivity in superovulated females (Group IV) (p < 0.001). The change in 5-HT sensitivity is selective and was not observed for NE. Nitroarginine treatment and mechanical denudement resulted in higher Tmax and lower ED50 for both NE and 5-HT regardless of hormonal manipulation. We conclude that estrogen withdrawal increases 5-HT vasoreactivity by an endothelium independent mechanism.

Topics: Animals; Arginine; Basilar Artery; Endothelium, Vascular; Estradiol; Estrogen Replacement Therapy; Estrogens; Female; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitroarginine; Ovariectomy; Rabbits; Serotonin; Substance Withdrawal Syndrome; Superovulation; Testosterone

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

The nitric oxide synthase inhibitor NG-nitro-L-arginine (NO2Arg) blocks morphine tolerance in mice. After implantation of morphine pellets the analgesic response decreases from 100% on the first day to 0% on the third. Coadministration of NO2Arg along with the pellets markedly retards the development of tolerance; 60% of mice are analgesic after 3 days, and 50% of mice are analgesic after 5 days. In a daily injection paradigm the analgesic response to morphine is reduced from 60% to 0% by 5 days. Concomitant administration of morphine along with NO2Arg at doses of 2 mg/kg per day prevents tolerance for 4 weeks. A single NO2Arg dose retards morphine tolerance for several days, and dosing every 4 days is almost as effective as daily NO2Arg. NO2Arg slowly reverses preexisting tolerance over 5 days despite the continued administration of morphine along with NO2Arg. NO2Arg also reduces dependence and reverses previously established dependence. NO2Arg does not prevent tolerance to analgesia mediated by the kappa 1 agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolindinyl)cyclohexyl]- benzene-acetamide (U50,488H) or the kappa 3 agent naloxone benzoylhydrazone, indicating a selective action of NO in the mechanisms of mu tolerance and dependence.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amino Acid Oxidoreductases; Analgesics; Animals; Arginine; Drug Administration Schedule; Drug Tolerance; Male; Mice; Mice, Inbred Strains; Morphine; Nitric Oxide Synthase; Nitroarginine; Pyrrolidines; Receptors, Opioid, kappa; Substance Withdrawal Syndrome; Time Factors