Nitric oxide and substance dependence

The free-radical gas nitric oxide (NO) plays an important role in a diverse range of physiological processes. It is synthesized from the precursor L-arginine by the enzyme NO synthase (NOS), which transforms L-arginine into NO and citrulline. This synthetic pathway exists in the central nervous system (CNS), and NO appears to be a messenger molecule in the CNS, fulfilling most of the criteria of a neurotransmitter. Recent studies indicate that NO may play an important role in dependence on drugs of abuse. The purpose of this review is to address the role of NO in dependence on substances such as opioids, ethanol, psychostimulants and nicotine. Inhibitors of NOS modulate withdrawal from opioids and ethanol, diminishing many signs of withdrawal. In addition, NOS inhibitors suppress signs of withdrawal from nicotine. These data suggest that NO may be involved in the expression of withdrawal signs, and they leave open the possibility that NO may mediate the development of many of these signs. Although preliminary, data to date suggest that glutamate neurotransmission may be related to these beneficial effects of NOS inhibitors on signs of withdrawal. Emerging data further suggest that NO may have a general role in the dependence potential of various classes of drugs of abuse. Thus, modulation of NO systems may be a potential therapeutic target for treatment of substance abuse.     

Test-specific analgesia elicited by kindled seizures in rats

Analgesia following kindled seizures in rats was studied using a test thought to measure pain integration at 3 levels of the CNS. Seizures caused an elevation of the threshold at which tail shocks elicited multiple squeaks, without affecting single squeak or tail withdrawal thresholds. Opioid involvement was indicated by naloxone's partial blockade of this effect.     

Nitric oxide involvement in the trigeminal hyperalgesia in diabetic rats

Trigeminal hyperalgesia frequently appears in diabetic neuralgia altering the transmission of orofacial sensory information. This study was designed to explore the effects of trigeminal hyperalgesia in streptozotocin-induced diabetes monitoring the expression of nitric oxide synthase in the trigeminal ganglion cells. The threshold to heat noxious stimuli decreased in diabetic animals. The number of NADPH-diaphorase (NADPH-d)-positive neurons significantly decreased in the diabetic rats compared with controls. Insulin treatment prevented the decreased nociceptive threshold and reduction of the number of NADPH-d-positive neurons. These findings point out that there is a relationship between the trigeminal nociceptive perception and NADPH-d neuronal expression suggesting that NO may play a role in the pathogenesis of trigeminal sensory neuropathy.     

Nitric oxide, epileptic seizures, and action of antiepileptic drugs

Nitric oxide (NO) plays a variety of physiological and pathological roles in mammalian cells. In the central nervous system NO may behave as a second messenger, neuromodulator, and neurotransmitter, which may suggest an essential role of this gaseous molecule in epilepsy and epileptogenesis. The aim of this review is to survey the current literature in terms of experimental and clinical evidence of anti- or proconvulsive properties of NO and its implications in the anticonvulsive action of antiepileptic drugs. Up-to-date multiple NO synthase (NOS) inhibitors and donors of NO were used in a plethora of seizure models (e.g. electrically and pharmacologically-evoked convulsions, amygdala-kindled seizures). Reported results vary depending on the seizure model, kind and doses of pharmacological tools used in experiments, and route of drug administration. The most thoroughly tested NOS inhibitor was 7- nitroindazole (7-NI), which presented anticonvulsive properties in most known models of seizures. The clear-cut proconvulsant action of 7-NI was observed only in kainate-, nicotine-, and soman-induced convulsions in rodents. This NOS inhibitor enhanced the anticonvulsant action of almost all available classic and second-generation antiepileptic drugs except tiagabine, felbamate, and topiramate. The effect of NG-nitro-L-arginine methyl ester was not so unambiguous. In pentylenetetrazole, pictotoxin, and N-methyl-Daspartate seizure models the inhibitor exhibited dose-dependent bidirectional action. NG-nitro-L-arginine methyl ester potentiated the efficacy of diazepam and clonazepam, diminished that of valproate and phenobarbital, but did not affect the anticonvulsant action of phenytoin and ethosuximide. On the other hand, NG-nitro-L-arginine, was anticonvulsant in nicotine-, glutamate-, and hyperbaric O2- evoked seizures, and proconvulsant in pilocarpine-, kainate-, bicuculline-, aminophylline-, and 4-aminopyridine-induced convulsions. NG-nitro-L-arginine remained without effect on the anticonvulsant action of both classic (valproate, phenobarbital, diazepam) and new generation (oxcarbazepine, felbamate, and ethosuximide) antiepileptic drugs. The action of ethosuximide was even impaired. Summing up, in the present state of knowledge the only reasonable conclusion is that NO behaves as a neuromodulator with dual - proconvulsive or anticonvulsive - action.     

Nitric oxide involvement in the anxiogenic-like effect of substance P

This study investigates whether nitric oxide (NO) is involved in the anxiogenic profile of action of substance P (SP) in mice in the elevated plus-maze (EPM). Adult Swiss mice were injected with NOS inhibitors such as L-NOARG (20 nmol/kg) i.p., L-NAME (3 nmol per site), 7-NI (0.25 nmol per site) i.c.v. or vehicle (NaCl 0.9% i.p. or PBS i.c.v.). About 30 min (i.p. pretreatment) or 5 min later (i.c.v. pretreatment), the animals received i.c.v. injections of SP (10 pmol) or phosphate buffered saline (PBS) (2 microl). Afterwards, they were observed in the EPM. SP per se reduced the time spent on open arms, an anxiogenic-like effect. This effect was reverted by different NOS inhibitors and the NO donor. NOS inhibitors had no influence on the EPM parameters but the NO-releasing compound SNAP, as well as its parent thiol NAP, increased the animals' locomotor activity. 8-Br-cGMP (20 nmol), a permeable cGMP analog, promoted an anxiogenic-like effect per se and enhanced the SP effect on the EPM. Altogether, these results suggest a putative NO role in the mediation of the anxiogenic-like effect of SP.     

Nitric oxide content measured by ESR-spectroscopy in the rat brain is increased during pentylenetetrazole-induced seizures

Nitric oxide (NO) content in rat cerebral cortex was measured using Electron Spin Resonance (ESR) spectroscopy. A nearly fivefold elevation in NO content was found at the peak time of pentylenetetrazole (PTZ)-induced seizures. The administration of N-nitro-l-arginine (L-NNA), a competitive inhibitor of NO-synthase, at the dose of 250 mg/kg, completely prevented the NO increase induced by PTZ, although clonic convulsions in the animals have been observed. L-NNA (10 mg/kg) was shown to delay the onset of clonic seizures as well as to shorten the latency of the first convulsive twitch. The level of lipid peroxidation secondary products measured as the content of thiobarbituric acid reactive species (TBARS) was increased in the cerebral cortex of PTZ-treated rats. L-NNA (250 mg/kg) failed to prevent the increased TBARS level produced by PTZ. The results support the notion that NO may play a trigger role in the pathophysiology of convulsive seizures.     

Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders.Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine–nitric oxide pathway or not.Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P < 0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine–nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.     

Nitric oxide dependence of glutamate-mediated modulation at a vertebrate neuromuscular junction

Recent evidence has revealed a contribution of glutamate in the stereotyped cholinergic neuromuscular transmission. Indeed, receptors, transporters and glutamate itself are present at the neuromuscular junction (NMJ) while glutamate activation of metabotropic receptors (mGluRs) decreases synaptic transmission and mediates depression through presynaptic mechanisms. However, we have shown that the mGluRs are located postsynaptically, inconsistent with the presynaptic action of glutamate. In the present study, we tested whether nitric oxide (NO) serves as a retrograde messenger mediating the distant effect of glutamate. Glutamate or an mGluR agonist [trans-(1S,3R)-aminocyclopentanedicarboxylic acid (ACPD)] failed to reduce synaptic transmission in the presence of an NOS inhibitor (3Br7NINa, 3-bromo-7-nitroindazole sodium salt). Moreover, application of 3Br7NINa precluded the effect of the mGluR antagonist MCPG [(S)-alpha-methyl-4-carboxyphenylglycine] on high-frequency-induced synaptic depression. Iontophoretic injections of BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N'-tetraacetic acid] in muscle fibres abolished the effect of trans-ACPD on synaptic transmission and blocked the mGluR component of depression, indicating the involvement of muscular calcium in mGluR-induced depression. Also, the use of this protocol unveiled a muscular calcium-dependent potentiating pathway dependent on cyclo-oxygenase activity. In addition, local application of trans-ACPD induced an increase in NO production by muscle fibres visualized with the indicator DAF-FM (4-amino-5-methylamino-2',7'-difluorofluorescein). This was prevented by 3Br7NINa or the iontophoretic injection of BAPTA. Moreover, motor nerve stimulation (50 Hz, 30 s) induced an increase in DAF-FM fluorescence that was abolished by 3Br7NINa and MCPG. Hence, the data suggest that the production of the retrograde molecule NO depends on the postsynaptic calcium-dependent activation of nitric oxide synthase following mGluRs stimulation and is essential for the glutamatergic modulation of synaptic efficacy and plasticity at the NMJ.     

Spinal cord seizures elicited by high pressures of helium.

Rats with complete spinal transections were compressed in helium-oxygen to 120 bars. Tremors and increased EMG activity in limbs rostral as well as caudal to the lesions were observed beginning at 30 bars. Spinal seizures occurred at 95 bars, similar to cortical seizure thresholds of intact rats. Denervated limbs remained flaccid throughout the dives. No rostro-caudal progression of symptoms was evident in normal animals, but fluctuation of symptoms with increasing pressure was frequently observed. These findings are consistent with the hypothesis that the effects of pressure on aggregates of neurons exceed those on isolated components.     

Nitric oxide regulates astrocyte maturation in the hippocampus: involvement of NOS2

Neurons and astrocytes are generated sequentially from radial glia. Once neurogenesis is completed, radial glia starts to differentiate into immature astrocytes. Astrocytes then maturate and change their morphology and electrophysiological properties. Neurotrophic cytokines or bone morphogenetic proteins have been identified as inducers of the developmental switch from neurogenesis to astrogenesis. However, the factors and mechanisms regulating the late differentiation of radial glia and the subsequent astrocyte maturation are poorly described. We used two independent approaches to examine the role of nitric oxide (NO) in the process of astrogenesis and maturation of astrocytes. First using a pharmacological approach, we depleted NO from developing hippocampus by intraventricular injection of a specific scavenger. Then by a genetic approach, we analyzed a nitric oxide synthase-2 (NOS2) knockout mouse. In both models, we found that differentiation of RC2-positive radial glia into late GFAP-positive radial glia was impaired. The cell-fate analysis after incorporation of BrdU demonstrated that astrogenesis was not altered upon NOS2 deficiency. Maturation of astrocytes was assessed by electrophysiological recordings at P7 and functional analysis. In wild type, 20% of astrocytes were immature as shown by their non-linear I/V relationship and high membrane resistance, whereas in NOS2-/- hippocampus, 51% of the astrocytes displayed an immature profile. The reduced branching of astrocytes upon NOS2 deficiency and their low content in connexin-43 further confirmed their immature profile. Our results highlight a novel developmental role of NO and NOS2 in the differentiation of radial glia and the maturation of astrocytes.     

Nitric oxide and sleep

Nitric oxide (NO) is a biological messenger synthesized by three main isoforms of NO synthase (NOS): neuronal (nNOS, constitutive calcium dependent), endothelial (eNOS, constitutive, calcium dependent) and inducible (iNOS, calcium independent). NOS is distributed in the brain either in circumscribed neuronal sets or in sparse interneurons. Within the laterodorsal tegmentum (LDT), pedunculopontine tegmentum and dorsal raphe nucleus, NOS-containing neurons overlap neurons grouped according to their contribution to sleep mechanisms. The main target for NO is the soluble guanylate cyclase that triggers an overproduction of cyclic guanosine monophosphate. NO in neurons of the pontine tegmentum facilitates sleep (particularly rapid-eye-movement sleep), and NO contained within the LDT intervenes in modulating the discharge of the neurons through an auto-inhibitory process involving the co-synthesized neurotransmitters. Moreover, NO synthesized within cholinergic neurons of the basal forebrain, while under control of the LDT, may modulate the spectral components of the EEG instead of the amounts of different sleep states. Finally, impairment of NO production (e.g. neurodegeneration, iNOS induction) has identifiable effects, including ageing, neuropathologies and parasitaemia.     

Nitric oxide and nitric oxide synthase in Huntington's disease

Nitric oxide (NO) is a biologically active inorganic molecule produced when the semiessential amino acid l-arginine is converted to l-citrulline and NO via the enzyme nitric oxide synthase (NOS). NO is known to be involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission, neuromodulation, and inflammation, to name only a few. During neuropathological conditions, the production of NO can be either protective or toxic, dependent on the stage of the disease, the isoforms of NOS involved, and the initial pathological event. This paper reviews the properties of NO and NOS and the pathophysiology of Huntington's disease (HD). It discusses ways in which NO and NOS may interact with the protein product of HD and reviews data implicating NOS in the neuropathology of HD. This is followed by a synthesis of current information regarding how NO/NOS may contribute to HD-related pathology and identification of areas for potential future research.     

Nitric oxide and multiple sclerosis

Nitric oxide (NO) is a free radical signaling molecule with remarkably complex biochemistry. Its involvement in multiple sclerosis (MS) had been postulated soon after the discovery of the critical role NO plays in inflammation. However, the extent of NO’s contribution to MS is not yet understood, party due to the often opposing roles that NO can play in cellular processes. This review briefly covers new developments in the area of NO that may be relevant to MS. It also describes recent progress in understanding the role of NO in MS, new potential targets of the action of NO in the cell, and prospects for NO-based therapies.     

The effects of coenzyme Q10 on seizures in mice: The involvement of nitric oxide

Coenzyme Q10 is a potent antioxidant in both mitochondria and lipid membranes. It has also been recognized to have an effect on gene expression. This study was designed to investigate whether acute or subchronic treatment with coenzyme Q10 altered the seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated the involvement of nitric oxide in the effects of coenzyme Q10 in pentylenetetrazole-induced seizure models. Acute oral treatment with different doses of coenzyme Q10 did not affect the seizure in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole, and electroshock models in mice. Subchronic oral administration of coenzyme Q10 (100 mg/kg or more) increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole and at the doses of 25 mg/kg or more increased the seizure threshold induced by intravenous infusion of pentylenetetrazole. Subchronic doses of coenzyme Q10 (50 mg/kg or more) also decreased the incidence of tonic seizures in the electroshock-induced seizure model. Moreover, acute treatment with the precursor of nitric oxide synthesis, l-arginine (60 mg/kg), led to a significant potentiation of the antiseizure effects of subchronic administration of coenzyme Q10 (400 mg/kg in intraperitoneal and 6.25 mg/kg in intravenous pentylenetetrazole tests). Acute treatment with l-NAME (5 mg/kg), a nonspecific nitric oxide synthase inhibitor, significantly attenuated the antiseizure effects of subchronic doses of coenzyme Q10 in both seizure models induced by pentylenetetrazole. On the other hand, acute administration of aminoguanidine (100 mg/kg), a specific inducible nitric oxide synthase inhibitor, did not affect the seizures in mice treated with subchronic doses of coenzyme Q10 in both intraperitoneal and intravenous pentylenetetrazole tests. In conclusion, only subchronic and not acute administration of coenzyme Q10 attenuated seizures induced by pentylenetetrazole or electroshock. We also demonstrated, for the first time, the interaction between nitric oxide and coenzyme Q10 in antiseizure activity probably through the induction of constitutive nitric oxide synthase.     

Nitric oxide in primary headaches

The molecular mechanisms that underlie the primary headaches-migraine, cluster headache and tension-type headache-have not yet been clarified. On the basis of studies in headache induced by intravenous infusions of glyceryl trinitrate (an exogenous nitric oxide donor) and histamine (which liberates nitric oxide from vascular endothelium), it has been suggested that nitric oxide is a likely candidate responsible molecule. The present review deals with the biology of this small messenger molecule, and the updated scientific evidence that suggests a key role for this molecule in primary headaches. This evidence suggests that the release of nitric oxide from blood vessels, perivascular nerve endings or from brain tissue is an important molecular trigger mechanism in spontaneous headache pain. Pilot trials have shown efficacy of a nitric oxide synthase inhibitor in both migraine attacks and chronic tension-type headache. These observations suggest new approaches to the pharmacological treatment of headache.     

一氧化氮／一氧化氮合酶与神经创伤

一氧化氮是一种简单的气体分子,可在哺乳类神经细胞内经一氧化氮合酶作用产生。ＮＯ在神经创伤修复中的多重作用近年来已受到越来越多的重视。本文对ＮＯ／ＮＯＳ与神经创伤和再生之间的关系作一综述。