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      Neuroimmunomodulatory Actions of Hypothalamic Interferon-α

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          Abstract

          Recent studies have revealed that the brain produces interferon-α (IFN-α) in response to noninflammatory as well as inflammatory stress and that it might have a role in normal physiology. When administered intracerebrally, IFN-α causes diverse effects including fever, anorexia, analgesia and changes in the central neuronal activities. These responses are inhibited by the opioid receptor antagonist naloxone. This is consistent with the reports suggesting that recombinant human (rh) IFN-α binds to opioid receptors in rodent brain membrane. We revealed that rhIFN-α altered the activity of thermosensitive neurons in the medial preoptic area (MPO) and glucose-responsive neurons in the ventromedial hypothalamus in an opioid-receptor-dependent way. As a stress which produces opioid-dependent analgesia is known to suppress the cytotoxicity of splenic natural killer cells, we investigated whether the administration of β-endorphin and rhIFN-α may induce a similar immunosuppression. We found that central, but not peripheral, injection of both compounds inhibited natural killer (NK) cytotoxicity. Further studies revealed that rhIFN-α decreased the activity of MPO neurons via opioid receptors and the altered activity of MPO neurons in turn resulted in the activation of corticotropin-releasing factor neurons, thereby suppressing NK cytotoxicity predominantly through activation of the splenic sympathetic nerve and β-receptor mechanisms in splenocytes. Thus, IFN-α may alter the brain activity to exert a feedback effect on the immune system. Further detailed whole-cell clamping analyses on neuronal mechanisms in rat brain tissue slices showed that the inhibitory effect of rhIFN-α on N-methyl- D-aspartate-induced membrane current responses of MPO neurons was mediated not only by opioid receptors but also by the local production of reactive oxygen intermediates, nitric oxide and prostanoids, possibly due to neuron-glial cell interaction.

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          Most cited references 17

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          Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation.

          The roles of N-methyl-D-aspartate (NMDA) receptors and protein kinase C (PKC) are critical in generating and maintaining a variety of sustained neuronal responses. In the nociceptive (pain-sensing) system, tissue injury or repetitive stimulation of small-diameter afferent fibres triggers a dramatic increase in discharge (wind-up) or prolonged depolarization of spinal cord neurons. This central sensitization can neither be induced nor maintained when NMDA receptor channels are blocked. In the trigeminal subnucleus caudalis (a centre for processing nociceptive information from the orofacial areas), a mu-opioid receptor agonist causes a sustained increase in NMDA-activated currents by activating intracellular PKC. There is also evidence that PKC enhances NMDA-receptor-mediated glutamate responses and regulates long-term potentiation of synaptic transmission. Despite the importance of NMDA-receptors and PKC, the mechanism by which PKC alters the NMDA response has remained unclear. Here we examine the actions of intracellularly applied PKC on NMDA-activated currents in isolated trigeminal neurons. We find that PKC potentiates the NMDA response by increasing the probability of channel openings and by reducing the voltage-dependent Mg2+ block of NMDA-receptor channels.
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            Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?

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              Synthesis of nitric oxide in CNS glial cells.

              Attention has focused on particular neurons as the source of nitric oxide (NO) within the parenchyma of the CNS. In contrast, glial cells have been viewed mainly as potential reservoirs of L-arginine, the substrate for nitric oxide synthase (NOS), and as likely targets for neuronally derived NO because of their proximity and their expression of soluble guanylyl cyclase (sGC). However, it is becoming evident that astrocytes display both constitutive and inducible NOS activity under various conditions, and that activated microglia express an inducible NOS. The NO-producing capacity of oligodendrocytes is not yet known. Glial-derived NO has significant implications for CNS pathophysiology, given the anatomical location and abundance of these cells, and the wide variety of potential interactions that NO can have with cellular biochemistry. Our intention here is to evaluate the evidence for NO production from non-neuronal CNS sources and thus prompt discussion about potential 'nitrinergic' roles for glial cells.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                978-3-8055-6766-4
                978-3-318-00353-6
                1021-7401
                1423-0216
                1998
                August 1998
                04 September 1998
                : 5
                : 3-4
                : 172-177
                Affiliations
                Department of Physiology, Kyushu University Faculty of Medicine, Fukuoka, Japan
                Article
                26334 Neuroimmunomodulation 1998;5:172–177
                10.1159/000026334
                9730683
                © 1998 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                References: 63, Pages: 6
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