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Volume 114, Issue 1
Displaying 1-8 of 8 articles from this issue
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Toshitaka NABESHIMA, Isao MURAOKA1999 Volume 114 Issue 1 Pages 3-11
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThere are at least two classes of σ-receptors, termed σ1 and σ2. Recently, the σ1-receptor has been completely sequenced in different species. The amino acid sequences of the different purified proteins are highly homologous, but it shares no homology to know mammalian proteins. These results suggest that the σ1 receptor is a distinct entity from any often known receptors. σ-Receptors are involved in many physiological functions. Therefore, σ-ligands show many different pharmacological effects such as glucose utilization, neuroprotective, antipsychotic, antidepressive, anxiolytic, nootropic, antiepileptic, antiabuse, antitussive, antidiarrhea, anti-inflammatory, tear protein releasing stimulant and central anti-micturition reflex actions. These results suggest that σ-receptors are very promising targets for the development of new drugs that have new mechanisms of action.View full abstractDownload PDF (10348K) -
Shigeru OKUYAMA1999 Volume 114 Issue 1 Pages 13-23
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThis is a review on the recent results of research on sigma1-receptor antagonists. NE-100, a selective sigma1 receptor antagonist, shows improvement of abnormal behaviors and cognitive dysfunction induced by phencyclidine (PCP). However, NE-100 does not inhibit dopamine agonist-induced behaviors nor induces catalepsy. The mode of action of NE-100 is estimated to be the indirect modulation of the NMDA/PCP-receptor ion channel complex and the modulation of dopamine release from the dopaminergic nerve terminals. The recently reported MS-355/MS-377, which is also a selective sigma1-receptor antagonist, has a similar pharmacological profiles as NE-100, but in addition, MS-355/MS-377 inhibits methamphetamine induced formation of reversal tolerance and also inhibits apomorphine-induced climbing behavior like dopamine D2-receptor antagonists. The report on clinical trial targeting schizophrenia shows results on rimcazole, remoxipride, BMY 14802, panamesine (EMD 57445) and SL 82.0715. Rimcazole was effective in the open study, but the double blind trial was discontinued due to seizure induction. Remoxipride showed efficacy different from those of dopamine D2-receptor antagonists (less extrapyramidal adverse effects), but the trial was discontinued due to occurrence of aplastic anemia. Panamesine and SL 82.0714 showed favorable efficacy in the open studies, but BMY 14802 showed no efficacy in clinical trials.View full abstractDownload PDF (11631K) -
Kiyoshi MATSUNO1999 Volume 114 Issue 1 Pages 25-33
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSBoth traditional and novel sigma (σ)-receptor agonists have been reported to possess anti-amnesic effects in rodents. In particular, the anti-amnesic effects induced by the novel sigma1-receptor agonists, such as (+)-pentazocine, SA4503 and PRE-084, were shown in β amyloid-peptide-induced, basal forebrain (BF)-lesioned and carbon monoxide (CO)-induced amnesia models and senescence-accelerated mouse (SAM). In addition, these sigma1-receptor agonists have good profiles for the central acetylcholine and dopamine systems. Moreover, they also have neuroprotective and anti-depressive effects. These evidence suggested that the sigma1-receptor agonists may be promising compounds for the treatment of dementing disorders such as Alzheimer's disease, senile dementia and vascular dementia. However, the sigma-receptor family is still considered to be enigmatic molecular targets. More molecular cloning and biochemical studies on the sigma-receptor family are needed.View full abstractDownload PDF (9472K) -
Junzo KAMEI1999 Volume 114 Issue 1 Pages 35-41
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThis paper provides an overview of our current understanding of the role of σ-receptors in the regulation of cough, gastrointestinal and retinal function. Systemic administration of N-(+)-allylnormetazocine ((+)SKF-10, 047), 1, 2-di-(2-toyl) guanidine (DTG) or pentazocine markedly reduced the number of coughs in a dose-dependent manner. The antitussive effect of these σ-receptor ligands was significantly reduced by pretreatment with haloperidol or rimcazol, a specific antagonist of σ-receptors. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that haloperidol-sensitive σ-receptors may be involved in the antitussive mechanism of nonnarcotic antitussive drugs. Selective σ-receptor ligands such as (+)SKF-10, 047, DTG and (+)pentazocine elicit a potent protection against gastric and duodenal ulcers. Ulcerprotective activity of σ-receptor ligands may be related to their stimulating effect on bicarbonate secretion through interaction with σ-receptors in the gastrointestinal mucosa. Activation of σ-receptors in retina protect retinal cells against glutamate-induced neurotoxicity. It is possible that σ-receptor ligands may be useful as therapeutic drugs against retinal disease with ischemia-induced neuronal cell death such as retinal artery occlusion, diabetes mellitus or glaucoma.View full abstractDownload PDF (7632K) -
Yukihiro NODA, Hiroyuki KAMEI, Toshitaka NABESHIMA1999 Volume 114 Issue 1 Pages 43-49
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma1-receptors have been shown to play an important role in antidepressive effects since selective sigma1-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma1-receptor agonists is antagonized by NE-100, a sigma1-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma2-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin-sensitive sigma1-receptor agonists such as (+)-SKF-10, 047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoinsensitive sigma1 receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma, receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma1-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.View full abstractDownload PDF (8905K) -
Hiroshi UEDA, Akira YOSHIDA1999 Volume 114 Issue 1 Pages 51-59
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSStudies on the sigma receptor and related compounds are becoming more attractive since they were found to be closely related to higher brain functions such as memory, learning, depression, anxiety, schizophrenia and neuroprotection. Along with these pharmacological findings, the single transmembrane-type, non-metabotropic sigma binding protein has been cloned, while the presence of metabotropic sigma receptor has been also claimed. Thus, various pharmacological findings are now ready to be characterized on the molecular basis of receptor mechanisms. On the other hand, neurosteroids have higher brain functions such as non-genomic fast actions, which are similar to the actions of sigma compounds. Indeed some neurosteroids were revealed to behave as sigma agonists while others behave like antagonists of metabotropic sigma receptors. Pharmacolgical studies to determine if sigma compounds can be used to cure various central symptoms related to neurosteroids or steroid hormones can be expected.View full abstractDownload PDF (10230K) -
Yoshihiro NAKATA, Atsuko INOUE, Sayori SUGITA1999 Volume 114 Issue 1 Pages 61-68
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSSigma (σ) receptors are expressed in the brain as well as endocrine and immune systems. Several antipsychotic drugs such as haloperidol and pentazocine can bind to the a receptor, which is believed to play important roles in the pathogenesis of schizophrenia by as yet unknown mechanisms. Two subtypes of σ receptors (σ1 and σ2) have been identified, and the σ1 receptor was cloned. The chronic administration of haloperidol to guinea pigs produced a marked inhibition of the binding to σ1 receptor, but did not change σ2-receptor binding. Scatchard analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. The treatment with haloperidol also did not affect σ1-receptor mRNA detected by the RNase protection assay. The treatment of rats with haloperidol inhibited σ1-receptor binding to a much lesser extent than that to guinea pigs. These finding suggest thathaloperidol or its metabolite, reduced haloperidol, which is produced in greater quantity in humans and guinea pigs than in rats and mice, might influence protein translation or modification of σ1-receptor without changing the transcriptional activity. The mechanisms through which σ receptors could be differently regulated in vivo by chronic treatment with haloperidol may contribute to the therapeutic efficacy of haloperidol.View full abstractDownload PDF (8995K) -
Kumatoshi ISHIHARA, Masashi SASA1999 Volume 114 Issue 1 Pages 69-76
Published: 1999
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe functions of sigma (σ) receptors were reviewed based on electrophysiological studies. Systemic administration of σ ligands reportedly produces a variety of effects on dopamine (DA) neurons. In the mesolimbic DA system, (+)SKF-10, 047 suppressed activities of the ventral tegmental area. In the substantia nigra, DTG also suppressed these activities, while BMY-14802 increased the activity of neurons. In the cerebellum, however, activities of Purkinje cells were suppressed by locally applied DTG, with probable involvement of the catecholaminergic system. This effect on Purkinje cells may explain the action of σ ligands on the motor system. In the hippocampus, neuronal activities were inhibited by SR31742A in vivo (CA3 region) and by (+)SKF10, 047 in vitro (CA1 region). DTG at high concentration (1 mM) completely suppressed population spikes (PS) in the CA1 region of hippocampal slice preparations. In our experiments, a novel σ ligand, OPC-24439, suppressed PS in CA1 at concentrations of 1-100 μM. However, NMDA-induced neuronal firings in CA3 in vivo were augmented by low doses of DTG in a haloperidolsensitive manner, but high doses were ineffective. In contrast, non-NMDA responses were not affected by DTG. In addition, several σ ligands having no effect on the NMDA response have been reported. In addition, endogenous ligands, neuropeptide Y and dehydroepiandrosterone, augmented the NMDA-induced firing. In whole-cell patch clamp recording, NMDA-induced currents were suppressed by a relatively higher concentration of DTG in a concentration-dependent manner, while non-NMDA responses were only slightly suppressed. These findings suggest that effects of σ ligands on NMDA receptor responses are biphasic, and σ ligands may modulate memory and learning and suppress neuronal death by anoxia. In addition, σligands are also reported to suppress Ca2+ channels in hippocampal culture neurons and induce current by closing α2 channels in NCB-20 cells. Thus, σ receptors may be involved in the modulation of a variety of neurons that relate to psychiatric function and plasticity.View full abstractDownload PDF (9067K)
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