Nitric Oxide Production and Nitric Oxide Synthase Expression in Platelets from Heroin Abusers before and after Ultrarapid Detoxification (original) (raw)
Related papers
Acta Histochemica, 2014
Heroin is one of the most dangerous drugs of abuse, which may exert various neurotoxic actions on the brain (such as gray matter loss, neuronal apoptosis, mitochondrial dysfunction, synaptic defects, depression of adult neurogenensis, as well as development of spongiform leucoencephalopathy). Some of these toxic effects are probably mediated by the gas nitric oxide (NO). We studied by morphometric analysis the numerical density of neurons expressing neuronal nitric oxide synthase (nNOS) in cortical and hypothalamic areas of eight heroin overdose victims and nine matched controls. Heroin addicts showed significantly increased numerical densities of nNOS immunoreactive cells in the right temporal cortex and the left paraventricular nucleus. Remarkably, in heroin abusers, but not in controls, we observed not only immunostained interneurons, but also cortical pyramidal cells. Given that increased cellular expression of nNOS was accompanied by elevated NO generation in brains of heroin addicts, these elevated levels of NO might have contributed to some of the known toxic effects of heroin (for example, reduced adult neurogenesis, mitochondrial pathology or disturbances in synaptic functioning).
Drug and Alcohol Dependence, 2002
Nitric oxide plays a critical role in the immune response, and our studies have shown that heroin induces a reduction in the expression of iNOS, the enzyme responsible for nitric oxide production. The present study evaluated the effect of heroin self-administration on iNOS expression using a three-group design. Group one (self-administration) was trained to press a lever for i.v. administration of heroin. Group two (yoked heroin) received a simultaneous equivalent infusion of heroin determined by the responses of a 'partner' animal in the first group. A third group (yoked saline) also was yoked to the first group, but received i.v. injections of saline. Immediately following the last session, all rats received an injection of lipopolysaccharide (LPS) to induce iNOS expression. About 6 h after the injection of LPS, iNOS mRNA and protein expression were determined in spleen, lung, and liver. Additionally, the accumulation of plasma nitrite/nitrate, the more stable end products of nitric oxide degradation were measured. Although there was not a consistent difference between the self-administering and yoked-heroin animals, the results show that rats will self-administer a sufficient amount of heroin to induce a pronounced, widespread reduction in the expression of iNOS.
Psychopharmacology, 2002
Rationale: Heroin (diacetylmorphine) administration has been shown to alter the induction of nitric oxide, a molecule known to play a critical role in the regulation of immune responses and resistance to infectious challenges. There is evidence that the physiological and behavioral effects of opioids can be conditioned to environmental stimuli associated with drug administration. Objectives: The present study tests whether environmental stimuli paired with the administration of heroin alter the expression of inducible nitric oxide synthase (iNOS), one of the isoforms of the enzyme responsible for nitric oxide production. Methods: The experimental group of rats received three conditioning sessions each involving a subcutaneous injection of heroin (1.0 mg/kg) immediately upon being placed in a chamber that served as the conditioned stimulus. Following the conditioning sessions, the rats remained in their home cages for 6 days to recover from the effects of heroin per se. The rats then were re-exposed to the conditioning chamber in the absence of heroin and immediately following the session were injected subcutaneously with lipopolysaccharide (LPS) to induce iNOS expression. Six hours later, the expression of iNOS messenger ribonucleic acid (mRNA) and protein was determined in spleen, lung, and liver using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting, respectively. Control procedures were used to determine whether the alterations in iNOS expression were due to conditioning processes. Results: The results showed that exposure to the conditioned stimulus produced a pronounced reduction in the expression of iNOS mRNA and protein in spleen, lung, and liver tissue. Control procedures showed that this effect was due to conditioning processes. Conclusions: This study provides the first evidence that heroin-induced alteration of iNOS expression can be conditioned to environmental stimuli, and suggest that environmental stimuli associated with drug use may contribute to the alteration in susceptibility to infection.
Psychopharmacology, 2007
Rationale The administration of heroin has been shown to inhibit the induction of nitric oxide, a molecule known to play a critical role in immune function. Previous research has shown that this alteration can be conditioned to environmental stimuli that have been associated with drug administration. However, it remains unknown whether the conditioned effects of heroin on nitric oxide formation follow accepted principles of learning. Objective This study sought to determine whether manipulations that induce extinction and latent inhibition, two learning paradigms known to reduce the expression of conditioned responses, would alter heroin's conditioned effects on the expression of inducible nitric oxide synthase (iNOS). Materials and methods The conditioning procedure involved repeated pairing of heroin administration with placement into a standard conditioning chamber. Rats were repeatedly exposed to the chambers without heroin reinforcement to determine whether the conditioned response would extinguish. To induce latent inhibition, rats received repeated exposure to the chamber before the start of conditioning to inhibit the acquisition of the conditioned response. Ten days after the final conditioning session, all rats were injected with lipopolysaccharide (LPS) to induce iNOS expression. Spleen and liver tissue were removed to determine iNOS expression using reverse transcriptase polymerase chain reaction. Blood was collected to determine the concentration of nitrite/nitrate.
Up-regulation of neuronal NO synthase immunoreactivity in opiate dependence and withdrawal
Psychopharmacology, 2000
Rationale: Nitric oxide (NO) has been postulated to contribute significantly to analgesic effects of opiates as well as to the development of tolerance and physical dependence to morphine. Objective: The present study was undertaken to determine the effect of chronic morphine treatment and abstinence on the expression of neuronal NO synthase (neuronal NOS, nNOS) in several brain regions of mice. Methods: Seven days after the implantation of a 75 mg morphine pellet, adult male CD1 mice received a SC dose of 1 mg/kg naloxone. Fifteen minutes after the naloxone injection, brains were removed and nNOS expression was studied by using immunohistochemical methods. Results: Morphine-dependence produced an increase in the number of nNOS-positive cells in the main and accessory olfactory bulb, olfactory nuclei, cerebellum, locus coeruleus, medulla oblongata (nucleus of the solitary tract and prepositus hypoglossal nucleus), and a decrease in nNOS immunoreactivity in hypothalamus. The administration of naloxone to morphine-dependent mice to induce abstinence increased nNOS immunoreactivity in the hypothalamus and locus coeruleus. Conclusions: These results indicate that the chronic treatment with morphine leads to alterations in nNOS expression in important regions implicated in the physical tolerance and dependence to opiates and suggest the use of specific inhibitors of this isoform in these conditions.
Morphine-induced nitric oxide production in PC12 cells
Archives of Iranian medicine
The role of nitric oxide (NO) in many well-known effects of morphine is well defined. NO is involved in the signaling pathway of the N-methyl-D-aspartate (NMDA) receptor, which is proposed to mediate some of morphine's effects. This research studies the effect of morphine and NMDA on lipopolysaccharide (LPS)-stimulated NO production by clonal rat pheochromocytoma (PC12) cells. We used the Griess reaction to measure NO concentrations in cell culture medium. PC12 cells that were incubated for 24 h with varying concentrations of morphine (0.1, 1, 10, 100, and 1000µM) plus LPS (1 µg/ml) did not significantly alter the concentration of NO in the medium. However, NO production increased when cells were treated for both 48 h with 100 and 1000 µM morphine and for 72 h with 10,100, and 1000 µM of morphine. After 72 h, 1 µM naloxone significantly decreased NO concentration. Naloxone, at doses of 0.1, 1, and 10µM prevented NO production by 1000 µM of morphine. NMDA (0.1, 1, and 10 µM) did ...
In vivo (Athens, Greece)
The alterations of total nitric oxide (NO) (through total nitrite/nitrate) and inducible nitric oxide synthase (iNOS) concentrations were determined in a population of alcohol-dependent individuals without liver disease upon admission for detoxification, two weeks later and after completion of detoxification (4-6 weeks in total). Thirty-eight men and nine women were included in the study. Endogenous nitrite and total nitrite/nitrate concentrations were measured colorimetrically and iNOS concentration was measured by enzyme-linked immunosorbent assay (ELISA). Endogenous and total nitrite concentrations were found to be diagnostically equally conclusive, whereas iNOS values were not correlated with the other two parameters. All three parameters were significantly higher in alcohol-dependent individuals compared to controls at all time points. The preventive therapeutic use of iNOS inhibitors in alcohol-dependent individuals might avoid the injurious effects of chronic alcohol abuse, a...
Neuroscience Letters, 2004
Brain nitric oxide (NO), recognized as a neurotransmitter or a neuromodulator, is mainly generated either by neuronal NO synthase (NOS) or by inducible NOS. NO has been shown to activate cyclooxygenase (a prostaglandin-forming enzyme) in addition to guanylate cyclase. Recently, we reported that the intracerebroventricularly (i.c.v.) administered corticotropin-releasing hormone (CRH) increases plasma catecholamines through brain cyclooxygenase-dependent mechanisms in rats [Eur. J. Pharmacol. 419 ]. In the present experiments, therefore, we examined whether NO is involved in the CRH-induced increase of plasma catecholamines using urethaneanesthetized rats. I.c.v. administered CRH increased plasma noradrenaline and adrenaline in a dose-dependent manner (0.5, 1.5, and 3.0 nmol/animal). The CRH (1.5 nmol/animal, i.c.v.)-induced increase of plasma catecholamines was reduced by N N -nitro-L-arginine methyl ester (a non-selective inhibitor of NOS) [111 nmol (30 Ag)/animal, i.c.v.], but not by the same dose of N N -nitro-D-arginine methyl ester (an inactive isomer of N N -nitro-L-arginine methyl ester). The CRH-induced increase of plasma catecholamines was also reduced either by cycloheximide (an inhibitor of protein synthesis) [107 nmol (30 Ag)/animal, i.c.v.] or by S-methylisothiourea (an inhibitor of inducible NOS) [71 nmol (20 Ag) and 711 nmol (200 Ag)/animal, i.c.v.]. These results suggest the involvement of brain inducible NOS in the CRH-induced activation of the central sympatho-adrenomedullary outflow in rats. D
Review Paper: Role of Nitric Oxide on Dopamine Release and Morphine-Dependency
The catastrophic effects of opioids use on public health and the economy are documented clearly in numerous studies. Repeated morphine administration can lead to either a decrease (tolerance) or an increase (sensitization) in its behavioral and rewarding effects. Morphine-induced sensitization is a major problem and plays an important role in abuse of the opioid drugs. Studies reported that morphine may exert its effects by the release of nitric oxide (NO). NO is a potent neuromodulator, which is produced by nitric oxide synthase (NOS). However, the exact role of NO in the opioid-induced sensitization is unknown. In this study, we reviewed the role of NO on opioid-induced sensitization in 2 important, rewarding regions of the brain: nucleus accumbens and ventral tegmentum. In addition, we focused on the contribution of NO on opioid-induced sensitization in the limbic system.