The retrotrapezoid nucleus and the neuromodulation of breathing.

Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO2/H+ and regulate several aspects of breathing, including inspiration and active expiration.

Functional Imaging of Neurotransmitters in Hymenolepis diminuta Treated with Senna Plant Through Light and Confocal Microscopy.

Previous studies have shown the anthelmintic efficacy of Senna alata, Senna alexandrina and Senna occidentalis on the zoonotic parasite Hymenolepis diminuta through microscopic studies on morphological structure. The present study is based on the light and confocal microscopic studies to understand if Senna extracts affect neurotransmitter activity of the parasites. A standard concentration (40 mg/mL) of the three leaf extracts and one set of 0.005 mg/mL concentration of the reference drug praziquantel were tested against the parasites, keeping another set of parasites in phosphate buffer saline as a control. Histochemical studies were carried out using acetylthiocholine iodide as the substrate and acetylcholinesterase as the marker enzyme for studying the expression of the neurotransmitter of the parasite and the staining intensity was observed under a light microscope. Immunohistochemical studies were carried out using anti serotonin primary antibody and fluorescence tagged secondary antibody and observed using confocal microscopy. Intensity of the stain decreases in treated parasites compared with the control which implies loss of activity of the neurotransmitters. These observations indicated that Senna have a strong anthelmintic effect on the parasite model and thus pose as a potential anthelmintic therapy.

Treatment of resistant insomnia and major depression.

Daily rhythms regulate everiday life and sleep/wake alternation is the best expression of this. Disruptions in biological rhythms is strongly associated with mood disorders, often being the major feature of this, major depressive disorder first of all. Although stabilization of rhythms produced by treatments have important outcome on therapeutic efficacy, insomnia often remains an unresolved symptom when major depression has otherwise been successfully treated with antidepressant. We review scientific literature in order to better clarify how to better approach insomnia as a clinical aspect to investigate and to early treat while treating other psychiatric conditions, major depression in particular. Insomnia is associated with impaired quality of life. It can be resolved with adequate diagnosis and treatment: it should be considered a comorbid condition and should be early identificated and treated in a multidisciplinary way, so that the ideal of treatment for patients with treatment resistant insomnia in major depression is an integration of non-pharmacologic measures, along with judicious use of medication, often used as an adjunctive therapy.

Selective pharmacological manipulation of cortical-thalamic co-cultures in a dual-compartment device.

In this study, we demonstrate capabilities to selectively manipulate dissociated co-cultures of neurons plated in dual-compartment devices. Synaptic receptor antagonists and tetrodotoxin solutions were used to selectively control and study the network-wide burst propagation and cell firing in cortical-cortical and cortical-thalamic co-culture systems. The results show that in cortical-thalamic dissociated co-cultures, burst events initiate in the cortical region and propagate to the thalamic region and the burst events in thalamic region can be controlled by blocking the synaptic receptors in the cortical region. Whereas, in cortical-cortical co-culture system, one of the region acts as a site of burst initiation and facilitate propagation of bursts in the entire network. Tetrodotoxin, a sodium channel blocker, when applied to either of the regions blocks the firing of neurons in that particular region with significant influence on the firing of neurons in the other region. The results demonstrate selective pharmacological manipulation capabilities of co-cultures in a dual compartment device and helps understand the effects of neuroactive compounds on networks derived from specific CNS tissues and the dynamic interaction between them.

[Adenosine and homeostatic control of sleep. Actions in target structures of the sleep-wake circuits]. / Adenosina y control homeostático del sueño. Acciones en estructuras diana de los circuitos de vigilia y sueño.

Sleep homeostasis occurs during prolonged wakefulness. Drowsiness and sleep pressure are its behavioral manifestations and, when sleep is allowed, there is a sleep rebound of sufficient duration and intensity to compensate for the previous deprivation. Adenosine is one of the molecules involved in sleep homeostasic regulation. Caffeine and theophylline, stimulants widely consumed by the humans, are antagonists. It is an endogenous factor, resulting from ATP metabolism in neurons and glia. Adenosine accumulates in the extracellular space, where it can exert regulatory actions on the sleep-wakefulness cycle circuits. Adenosine acts through the purinergic receptors A1 and A2. This paper reviews: 1) the metabolic pathways of cerebral adenosine, and the mechanisms of its release by neurons and glia to the extracellular space; 2) the actions of adenosine and its antagonists in regions of the central nervous system related to wakefulness, non-REM sleep, and REM sleep, and 3) the synaptic mechanisms involved in these actions.

Targeting inhibitory neurotransmission in tinnitus.

Tinnitus perception depends on the presence of its neural correlates within the auditory neuraxis and associated structures. Targeting specific circuits and receptors within the central nervous system in an effort to relieve the perception of tinnitus and its impact on one's emotional and mental state has become a focus of tinnitus research. One approach is to upregulate endogenous inhibitory neurotransmitter levels (e.g., glycine and GABA) and selectively target inhibitory receptors in key circuits to normalize tinnitus pathophysiology. Thus, the basic functional and molecular properties of two major ligand-gated inhibitory receptor systems, the GABA(A) receptor (GABA(A)R) and glycine receptor (GlyR) are described. Also reviewed is the rationale for targeting inhibition, which stems from reported tinnitus-related homeostatic plasticity of inhibitory neurotransmitter systems and associated enhanced neuronal excitability throughout most central auditory structures. However, the putative role of the medial geniculate body (MGB) in tinnitus has not been previously addressed, specifically in terms of its inhibitory afferents from inferior colliculus and thalamic reticular nucleus and its GABA(A)R functional heterogeneity. This heterogeneous population of GABA(A)Rs, which may be altered in tinnitus pathology, and its key anatomical position in the auditory CNS make the MGB a compelling structure for tinnitus research. Finally, some selective compounds, which enhance tonic inhibition, have successfully ameliorated tinnitus in animal studies, suggesting that the MGB and, to a lesser degree, the auditory cortex may be their primary locus of action. These pharmacological interventions are examined in terms of their mechanism of action and why these agents may be effective in tinnitus treatment. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Distribution of neuromedin S and its receptor NMU2R in pigs.

Neuromedin S (NMS) has been found to be involved in the regulation of the reproductive, endocrine, and immune systems in mammals. However, its function in pigs is currently not well understood. Thus, it is essential and important to characterize the central distribution of NMS mRNA and its receptor, neuromedin U receptor-2 (NMU2R), in pigs for clarifying its physiological functions. In this study, we found that NMS mRNA were densely distributed in the hypothalamus, hypophysis, hippocampus, and brain stem of pigs by in situ hybridization. Moreover, NMS and NMU2R mRNAs was also expressed in the alimentary organs, endocrine and lymphatic organs, and ovaries by semi-Q RT-PCR. All these results suggest that the NMS/NMU2R system plays an important role in modulating various physiological functions in pigs. This research provides useful information for predicting the physiological functions of the NMS/NMU2R system in pigs.

Isolation and characterisation of two cDNAs encoding the neuromedin U receptor from goldfish brain.

Intracerebroventricular administration of neuromedin U (NMU) exerts an anorexigenic effect in a goldfish model. However, little is known about the NMU receptor and its signalling system in fish. In the present study, we isolated and cloned two cDNAs encoding different proteins comprising 429 and 388 amino acid residues from the goldfish brain based on the nucleotide sequences of human NMU receptor 1 (NMU-R1) and receptor 2 (NMU-R2). Hydropathy and phylogenetic analyses suggested that these two proteins were orthologues of NMU-R1 and -R2 of goldfish. We established two human embryonic kidney 293 cell lines stably expressing putative NMU-R1 and -R2, respectively, and showed that NMU induced an increase in intracellular calcium concentration ([Ca(2+)](i)) in these cells. We examined the presence of NMU-R1 and -R2 in the goldfish brain by western blotting analysis using affinity-purified antisera raised against peptide fragments derived from these receptors. NMU-R1-specific and NMU-R2-specific antisera detected a 49-kDa and 45-kDa immunopositive bands, respectively, in the brain extract. The mass of each band corresponded to that of the deduced respective primary structures. Reverse transcriptase-polymerase chain reaction analysis showed that NMU-R1 and -R2 transcripts were detected in several tissues. In particular, both mRNAs were strongly expressed in the goldfish brain. By contrast, NMU-R2 mRNA was also expressed in the gut. These results indicate for the first time that NMU-R orthologues exist in goldfish, and suggest physiological roles of NMU and its receptor system in fish.

The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: a novel pain modulation pathway.

Recently, a series of studies have given rise to and provided evidence for the hypothesis that the nucleus submedius (Sm) in the medial thalamus is involved in modulation of nociception. The Sm, ventrolateral orbital cortex (VLO) and the periaqueductal gray (PAG) constitute a pain modulatory pathway, activation of which leads to activation of the PAG-brainstem descending inhibitory system and depression of the nociceptive inputs in the spinal cord and trigeminal nucleus. Other studies have indicated that the Sm-VLO-PAG pathway plays an important role in the analgesia induced by electroacupuncture stimulation of the acupuncture point (acupoint) for exciting small diameter fiber (A-delta and C group) afferents. Opioid peptides, serotonin, dopamine, glutamate and their related receptors are involved in Sm- and/or VLO-mediated descending antinociception, and a GABAergic disinhibitory mechanism participates in mediating the antinociception induced by activation of mu-opioid receptors, serotonin 1(A) receptors, and dopamine D(2)-like receptors. This review describes these findings, which provide important new insights into the roles of the thalamus and cerebral cortex in descending pain modulation.

Filicene obtained from Adiantum cuneatum interacts with the cholinergic, dopaminergic, glutamatergic, GABAergic, and tachykinergic systems to exert antinociceptive effect in mice.

In the present study, we describe the antinociceptive effect of filicene, a triterpene isolated from Adiantum cuneatum (Adiantaceae) leaves, in several models of pain in mice. When evaluated against acetic acid-induced abdominal constrictions, filicene (10, 30 and 60 mg/kg, i.p.) produced dose-related inhibition of the number of constrictions, being several times more potent [ID(50)=9.17 (6.27-13.18) mg/kg] than acetaminophen [ID(50)=18.8 (15.7-22.6) mg/kg], diclofenac [ID(50)=12.1(9.40-15.6) mg/kg] and acetylsalicylic acid [ID(50)=24.0(13.1-43.8) mg/kg] in the same doses as those used for the standard drugs. Filicene also produced dose-related inhibition of the pain caused by capsaicin and glutamate, with mean ID(50) values of 11.7 (8.51-16.0) mg/kg and <10 mg/kg, respectively. Its antinociceptive action was significantly reversed by atropine, haloperidol, GABA(A) and GABA(B) antagonists (bicuculline and phaclofen, respectively), but was not affected by L-arginine-nitric oxide, serotonin, adrenergic and the opioid systems. Together, these results indicate that the mechanisms involved in its action are not completely understood, but seem to involve interaction with the cholinergic, dopaminergic, glutamatergic, GABAergic and tachykinergic systems.

Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons.

It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies. For example, both metabotropic glutamate receptor (mGluR) and muscarinic Ach receptor (mAchR) activation can cause rhythmic bursting at alpha/theta frequencies. Interestingly, key differences exist between mGluR- and mAchR-induced bursting, with the former involving extensive dendritic Ca2+ electrogenesis and being mimicked by a non-specific block of K+ channels with Ba2+, whereas the latter appears to be more reliant on proximal Na+ channels and a prominent spike afterdepolarization (ADP). This likely relates to the differential somatodendritic distribution of mGluRs and mAChRs and may have important functional consequences. We also show here that in similarity to some neocortical neurons, inhibiting large-conductance Ca2+-activated K+ channels in TC neurons can lead to fast rhythmic bursting (FRB) at approximately 40 Hz. This activity also appears to rely on a Na+ channel-dependent spike ADP and may occur in vivo during natural wakefulness. Taken together, these results show that TC neurons are considerably more flexible than generally thought and strongly endorse a role for the thalamus in promoting a range of cognitively-relevant brain rhythms.

Cancer chemotherapy-induced nausea and vomiting: role of mediators, development of drugs and treatment methods.

The development of serotonin 5-HT3 receptor antagonists dramatically improved the treatment of chemotherapy-induced nausea and vomiting. Ondansetron, a serotonin 5-HT3 receptor antagonist in combination with dexamethasone is widely used to treat chemotherapy-induced nausea and vomiting. This treatment regimen is effective against acute nausea and vomiting, but fails to control delayed nausea and vomiting. Metoclopramide along with other antiemetics are used to treat delayed nausea and vomiting. The high doses of metoclopramide needed may produce extra pyramidal side effects. The recent developments of 5-HT3 and dopamine D2 dual receptor antagonists have been found to exhibit a broad spectrum of activity against peripherally and centrally acting stimuli, but are not much effective against delayed emesis associated with chemotherapy. In various animal models, neurokinin NK1 receptor antagonists showed promising results against acute and delayed emesis, but the clinical trials revealed that triple therapy (NK1 receptor antagonist, 5-HT3 receptor antagonist and dexamethasone) is superior than standard therapy (5-HT3 receptor antagonist & dexamethasone) or NK1 receptor antagonist alone, in controlling acute as well as delayed nausea and vomiting. Ginger, which is used traditionally for controlling emesis induced by various stimuli, also showed good activity against chemotherapy-induced nausea and vomiting in animal models. Non-pharmacological methods such as acupressure and acustimulation are good adjunct methods in treating nausea and vomiting. Since many mediators are involved in emesis induced by chemotherapy, cocktail treatment is proven to be more efficacious than a single drug, but increases treatment costs. So there is a need of further research in this field to get economically useful methods for the treatment of acute and delayed chemotherapy-induced nausea and vomiting.

[Postamputation phantom limb pain -- comes the solution into view?]. / Phantomschmerz nach Beinamputation -- ist die Lösung in Sicht?

About 70 % of amputees will suffer from phantom limb pain sooner or later. Nearly all of the amputees will feel some phantom sensations. Phantom limb pain not only impairs quality of life, but also impedes considerably social rehabilitation. Therefore effective strategies of prevention and treatment are urgently required. So far, none of the more than 40 treatment methods has proven to be really effective. It is to be expected that the latest theories regarding the emergence of phantom limb pain, which were developed on the basis of modern neuroimaging techniques, will lead to considerable progress. Accordingly the key to success is influencing cortical reorganization and preventing or extinguishing a pain memory. The demonstrable influence on central activities implicates several preventive and therapeutic modalities, i. e. absolute analgesia before amputation for a longer period of time and reduction of cortical reorganization by drugs, behaviour interventions and/or suggestion.

Mechanism of action of St John's wort in depression : what is known?

Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.

Antischizophrenic activity independent of dopamine D2 blockade.

Currently, the drug therapy of schizophrenia consists of blockade of central dopamine D2 receptors. There is, however, an urgent medical need for alternative, more effective treatments. Clinical and preclinical literature suggests that stimulation of AMPA-type glutamate receptors may be involved in positive symptoms of schizophrenia, whereas hypofunctionality of NMDA-type glutamate receptors may be involved in negative symptoms and cognitive deficits. Several pharmacological approaches are conceivable to prevent stimulation of AMPA receptors (AMPA receptor blockade, metabotropic glutamate receptors (mGlu(2) receptor) stimulation or lamotrigine-like Na(+)/Ca(2+) channel blockade). Similarly, several pharmacological principles are conceivable to enhance neurotransmission at NMDA receptors (catechol-o-methyl transferase inhibition, glycine uptake blockade, glutathione suppletion and others). In this review, the possible pharmacological approaches and their respective advantages and disadvantages are discussed.

Synthesis and biological evaluation of hyperforin analogues. Part I. Modification of the enolized cyclohexanedione moiety.

Modification of the St. John's wort acylphloroglucinol constituent, hyperforin (1), by acylation, alkylation, and oxidation resulted in detrimental effects on the inhibition of the synaptosomal accumulation of serotonin, showing the existence of definite structure-activity relationships in this in vitro test system and highlighting the role of the enolized cyclohexanedione moiety for activity on neurotransmitter reuptake.

Long-term potentiation in spinothalamic neurons.

Sensitization of nociceptive dorsal horn neurons, including spinothalamic tract (STT) cells, is thought to underlie the development of secondary hyperalgesia and allodynia following tissue injury. In central sensitization, responses to stimulation of sensory receptors are enhanced without any change in the excitability of the primary afferent neurons. We hypothesize that central sensitization of STT neurons is a variety of long-term potentiation (LTP). Evidence that LTP occurs in the spinal cord is reviewed. Neurotransmitters that trigger central sensitization include excitatory amino acids and peptides. Evidence for this is that co-activation of N-methyl-D-aspartate and NK1 receptors can produce long-lasting increases in the responses of STT cells, and antagonists of these receptors prevent central sensitization. Responses to excitatory amino acids increase and those to inhibitory amino acids decrease during central sensitization, presumably accounting for the changed excitability of STT cells. We believe these changes result from the activation of signal transduction pathways, including the protein kinase C, NO/protein kinase G and protein kinase A cascades. Recent evidence shows that calcium/calmodulin dependent kinase II (CaMKII) is also upregulated early in the process of central sensitization and that several types of ionotropic glutamate receptors become phosphorylated. It is proposed that the phosphorylation of neurotransmitter receptors leads to alterations in the sensitivity of these receptors and to central sensitization. Comparable events occur during LTP in brain structures.

[Mechanism of action of St. Johns wort extract]. / Zum Wirkungsmechanismus von Johanniskraut-Extrakt.

Over the last few years St-John's wort preparations have been used in large quantities in Germany for treating mild to moderate depression. In the meantime the antidepressive action of these extracts has been proved in numerous placebo-controlled studies. Furthermore, a considerably lower adverse effect rate compared with classic antidepressants has been established. Analogously to other antidepressants, subchronic St-John's wort treatment of rats showed significant down-regulation of beta receptor density and a significant increase in 5HT2 receptors. The extract also exhibited antidepressant activity in animal pharmacological models of depression. Interest is now focused on identifying the underlying pharmacological mechanisms of action of this phytotherapeutic agent. Like other working parties, we were only able to identify a weak inhibitory effect of the extract and the pure substance hypericin on the monoamine oxidases A and B. Similarly to synthetic antidepressants, St-John's wort exerts marked inhibitory effects on synaptosomal uptake of serotonin and noradrenaline. However, dopamine and uptake and neuronal uptake of GABA and L-glutamate are also inhibited. These effects may mainly be attributed to the substance hyperforin contained in the extract. An additional, as yet unknown, pharmacological mechanism of action of St-John's wort extracts is beginning to emerge. Although hyperforin shows similar properties to classical antidepressants, there are indications of a novel mechanism of action. Our laboratory is currently investigating the means by which St-John's wort extract, or its constituent hyperforin, develops its antidepressant action.