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Volume 122 (2003)
- Issue 6 Pages 473-
- Issue 5 Pages 367-
- Issue 4 Pages 34A-
- Issue 3 Pages 192-
- Issue 2 Pages 111-
- Issue 1 Pages 5-
Volume 122, Issue 3
Displaying 1-8 of 8 articles from this issue
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Reviews: Contribution of Pharmacology and Physiology to QOL
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-morphine-tolerance and morphine-resistant neuropathic painHiroshi UEDAArticle type: Reviews
2003 Volume 122 Issue 3 Pages 192-200
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSMorphine is now said to have no problematic side effects such as analgesic tolerance and physical dependence for cancer pain patients in clinic, as far as it is appropriately used. However, sub-sensitivity to morphine might be developed when higher doses of morphine are used for terminal cancer pain patients. Along with the severity of cancer, the nature of pain becomes changed to neuropathic pain, which is resistant to morphine or NSAIDS. In order to safely use morphine in the clinic, we need to know how morphine tolerance and neuropathic pain are developed and what adjuvants could be used to completely suppress the pain. Here I overview the proposed mechanisms for morphine tolerance and neuropathic pain in relation to the availability of analgesic adjuvants.
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Yasuo MORI, Chiyoko INAGAKI, Miyuki KUNO, Ryuji INOUE, Yasunobu OKADA, ...Article type: Reviews
2003 Volume 122 Issue 3 Pages 201-214
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSIon channels and transporters act as major components that regulate membrane excitability in neurons, muscles, and some secretory glands, but may also contribute to the regulation of proliferation, differentiation, and death in a greater variety of cells including non-excitable ones. The molecular basis of ionic mechanisms underlying the later regulation has been partly identified in the last several years and is a hot issue now. In this short review, some of the molecular mechanisms underlying these regulations and novel compounds acting on the mechanisms were introduced as exciting topics in this area. Several types of transient receptor potential (TRP), identified as Ca2+-permeable, non-selective cation channels, may play obligatory roles in functional complexes, which regulate multiple signal transduction pathways triggering proliferation, differentiation, or death of many cell types. In addition, the relation between Cl− pump activity and the induction of β-amyloid protein toxicity for neuronal cell death in Alzheimer disease was described. Unique functions of H+ channel and pump in osteoclasts in bone mineral homeostasis and remodeling were also discussed. Finally, topics about activation of specific types of Cl− channels and K+ channels, which are responsible for the induction of apoptosis or proliferation in several types of cells, were introduced.
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Masashi SASA, Akinori NISHI, Kazuto KOBAYASHI, Hiromi SANO, Toshihiko ...Article type: Reviews
2003 Volume 122 Issue 3 Pages 215-225
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESS(1)The basal ganglia circuitry mediates a wide rage of brain functions such as motor control, behavioral planning, and reward prediction. Dopamine (DA) transmission plays an essential role in the regulation of these brain functions. DA action not only regulates the firing activity of target neurons but also is involved in the pattern formation of their firing. The striatopallidal neurons containing dopamine D2 receptor plays a dual role in motor coordination dependent on DA transmission. (2)Activation of presynaptic D2-like receptors on GABAergic terminals onto striatal cholinergic interneurons selectively blocks N-type Ca2+ channels, thereby inhibiting GABA release. In addition, contribution of N-type channels and D2-like receptor-mediated presynaptic inhibition decreases in parallel with development, implying some relationship between basal ganglia-related function or dysfunction and age. (3)As an approach to determine dopamine neuronal activity, we monitored neuronal activities by measuring cytosolic Ca2+ concentration in VTA dopamine neurons. The present study indicates that VTA dopamine neurons are the direct targets of orexin-A and psychostimulants, and the [Ca2+]i signaling is thought to play a significant role in the regulation of dopamine neuronal activity. (4)The excitability of neostriatal neurons is regulated by a balance of glutamatergic and dopaminergic inputs. Glutamate has been shown to modulate dopaminergic signaling. Studies on the regulation of DARPP-32 phosphorylation by glutamate provide a molecular basis for both the synergistic and antagonistic effects of glutamate on dopaminergic signaling. (5) Impairment of function of stem/progenitor cells may be implicated in the pathogenesis of schizophrenia. To test this hypothesis, several experiments are currently ongoing in our laboratory, and the preliminary results obtained are described here.
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Ichiro NIKIArticle type: Reviews
2003 Volume 122 Issue 3 Pages 228-235
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSDiabetes mellitus is a very common life-style-related disease. Both genetic and environmental factors are strongly involved in its etiology and pathogenesis, and patients suffering from this disease are rapidly increasing in number. Since the discoveries of insulin in the 1920s and of antidiabetic sulphonylureas in the 1950s, these agents have been widely used for the treatment of diabetes mellitus. For the use of insulin, however, diabetic patients are imposed to inject insulin daily, and long-term use of sulphonylureas is suggested to impair pancreatic B cell functions. In order to overcome these problems and to achieve the fine control of blood glucose levels, many attempts for novel antidiabetic treatments are currently ongoing, and versatile therapeutic strategies for the treatment are expected to prevent the progression of this disease and resultant diabetic complications that severely affect the individuals' QOL. This paper overviews what diabetic research has done for its treatment and what it will do in the future.
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Takeshi SAKURAIArticle type: Reviews
2003 Volume 122 Issue 3 Pages 236-242
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSThe mechanisms for regulating food intake involve a complicated interplay between peripheral systems (including gastrointestinal peptide secretion, leptin, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. Many hypothalamic neuropeptides are involved in the regulation of energy homeostasis and feeding behavior, including melanocortins, Agouti-related peptide, neuropeptide-Y, cocain, and amphetamine-regulated transcript, orexin, and melanine concentrating homone (MCH) as well as monamines (serotonin, dopamine, norepinephrine). Many of these systems are regulated by peripheral metabolic cues including plasma leptin levels. This review summarizes roles of neuropeptides in the regulatory mechanism of feeding and energy homeostasis.
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Haruaki NAKAYA, Takashi MIKI, Susumu SEINO, Katsuya YAMADA, Nobuya INA ...Article type: Reviews
2003 Volume 122 Issue 3 Pages 243-250
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSATP-sensitive K+ (KATP) channels comprise the pore-forming subunit (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptors (SUR1 or SUR2). KATP channels with different combinations of these subunits are present in various tissues and regulate cellular functions. From the analysis of mouse models with targeted deletion of the gene encoding the pore-forming subunit Kir6.1 or Kir6.2, functional roles of KATP channels in various organs have been clarified. Kir6.1−/− mice showed sudden death associated with ST elevation and atrioventricular block in ECG, a phenotype resembling Prinzmetal angina in humans. Kir6.2−/− mice were more susceptible to generalized seizure during hypoxia than wild-type (WT) mice, suggesting that neuronal KATP channels, probably composed of Kir6.2 and SUR1, play a crucial role for the protection of the brain against lethal damage due to seizure. In Kir6.2−/− mice lacking the sarcolemmal KATP channel activity in cardiac cells, ischemic preconditioning failed to reduce the infarct size, suggesting that sarcolemmal KATP channels play an important role in cardioprotection against ischemia/reperfusion injuries in the heart. Mitochondrial KATP channels have been also proposed to play a crucial role in cardioprotection, although the molecular identity of the channel has not been established. Nicorandil and minoxidil, K+ channel openers activating mitochondrial KATP channels, decreased the mitochondrial membrane potential, thereby preventing the Ca2+ overload in the mitochondria of guinea-pig ventricular cells. SURs are the receptors for K+ channel openers and the activating effects on sarcolemmal KATP channels in cardiovascular tissues could be modulated by the interaction of nucleotides. Due to the molecular diversity of the accessory and pore subunits of KATP channels, there would be considerable differences in the tissue selectivity of KATP channel-acting drugs. Studies of Kir6.1 and Kir6.2 knockout mice indicate that KATP channels are involved in the mechanisms of the protection against metabolic stress. Further clarification of physiological as well as pathophysilogical roles of KATP channels may lead to a new therapeutic strategy to improve the quality of life.
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Review
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Yasushi SHIGERI, Keiko SHIMAMOTOArticle type: Review
2003 Volume 122 Issue 3 Pages 253-264
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSL-Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS). It contributes not only to fast synaptic neurotransmission but also to complex physiological processes like plasticity, learning, and memory. Glutamate is synthesized in the cytoplasm and stored in synaptic vesicles by a proton gradient-dependent uptake system (VGLUTs). Following its exocytotic release, glutamate activates different kinds of glutamate receptors and mediates excitatory neurotransmission. To terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels, glutamate is quickly removed by Na+-dependent glutamate transporters (EAATs). Recently, three vesicular glutamate transporters (VGLUT1-3) and five Na+-dependent glutamate transporters (EAAT1-5) were identified. VGLUTs and EAATs are thought to play important roles in neuronal disorders, such as amyotrophic lateral sclerosis, Alzheimer's disease, cerebral ischemia, and Huntington's disease. In this review, the development of new compounds to regulate the function of VGLUTs and EAATs will be described.
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Review on New Drug
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Kojiro OGURIArticle type: Review on New Drug
2003 Volume 122 Issue 3 Pages 265-270
Published: 2003
Released on J-STAGE: August 26, 2003
JOURNAL FREE ACCESSPrevious systemic β2 agonists such as procatrol tablets and tulobuterol patch were developed in Japan to address nocturnal symptoms and maintenance of lung function in asthmatic patients. Salmeterol, a potent and highly selective in β2 adrenocepter agonist with a duration of action greater than 12 h, was developed to provide long duration of bronchodilation with binding to a non-active site in the β2-adrenocepter. Salmeterol is administrated via dry power inhalation and clinical studies have showed it has a good efficacy and a good safety profile, similar to inhaled steroids. Indeed, many clinical studies showed that salmeterol demonstrated better efficacy than long-acting β2-agonist oral bronchodilators, theophyllines, and leukotriene-receptor antagonists in asthmatic patients and anticholinergic agents and theophyllines in COPD patients. Salmeterol will provide clinical benefits for Japanese asthma and COPD patients.
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