Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：(一社)日本小児神経学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions: These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.

DOI： 10.1186/s13229-018-0243-3

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：(一社)日本てんかん学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本アルコール・アディクション医学会  

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Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)   Publisher：(一社)日本神経精神薬理学会  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：FUTURE MEDICINE LTD  

Aim: The endogenous opioid system has been reportedly implicated in tobacco/nicotine dependence. Materials & methods: We examined the genetic effects of eight SNPs in opioid receptor-related genes on smoking status and smoking-related traits in Japanese. Results: The genotypic and allelic variations of the rs2229205 SNP in the OPRL1 gene were significantly associated with smoking status, but no significant differences were found in the genetic variations of any of the SNPs with regard to smoking-related traits. The rs2229205 SNP did not show high linkage disequilibrium with the other SNPs in the linkage disequilibrium block that contained the SNP. Conclusion: The rs2229205 SNP in the OPRL1 gene may be a genetic factor that contributes to individual differences in the vulnerability to smoking in Japanese individuals.

DOI： 10.2217/pgs.15.184

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Language：Japanese   Publisher：(一社)日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：(一社)日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：(一社)日本神経精神薬理学会  

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Authorship：Lead author   Language：English   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本生物学的精神医学会・日本神経精神薬理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.

DOI： 10.1038/npp.2014.295

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Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)   Publisher：(一社)日本神経精神薬理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORPORATION  

To clarify the potential role of variability within and around the AKT1 gene in smoking behaviors, we performed a single-nucleotide polymorphism (SNP) analysis of the AKT1 gene in an elderly Japanese cohort. Genotypes of the rs2498794 SNP, which is located in the fifth intron region of the AKT1 gene, were marginally but significantly associated with smoking duration in the total 999 samples of former and current smokers. Interestingly, this SNP had a marginally significant association with individual cancer history (past and current), especially in groups with a shorter smoking duration (<44 years) and fewer cigarettes per day (<20). These data suggest that the rs2498794 polymorphism of the AKT1 gene is associated with a long smoking duration and may be involved in the predisposition to cancer when the smoking duration is short or the cigarettes per day is rate low.

DOI： 10.1155/2015/316829

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BENTHAM SCIENCE PUBL LTD  

N-methyl-D-aspartate (NMDA) receptor plays important roles in learning and memory. NMDA receptors are a tetramer that consists of two glycine-binding subunits GluN1, two glutamate-binding subunits (i.e., GluN2A, GluN2B, GluN2C, and GluN2D), a combination of a GluN2 subunit and glycine-binding GluN3 subunit (i.e., GluN3A or GluN3B), or two GluN3 subunits. Recent studies revealed that the specific expression and distribution of each subunit are deeply involved in neural excitability, plasticity, and synaptic deficits. The present article summarizes reports on the dysfunction of NMDA receptors and responsible subunits in various neurological and psychiatric disorders, including schizophrenia, autoimmune-induced glutamatergic receptor dysfunction, mood disorders, and autism. A key role for the GluN2D subunit in NMDA receptor antagonist-induced psychosis has been recently revealed.

DOI： 10.2174/1566524015666150330142807

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed in many tissues and activated by several Gib, protein coupled receptors, such as opioid and dopamine receptors, and thus are known to be involved in the modulation of opioid-induced analgesia, pain, and reward. We focused on a GIRK-channel subunit that plays a pivotal role in the brain, GIRK2, and investigated the contribution of genetic variations of the GIRK2 (KCNJ6) gene to individual differences in the sensitivity to opioid analgesia. In our initial linkage disequilibrium analysis, a total of 27 single-nucleotide polymorphisms (SNPs) were selected within and around the regions of the KCNJ6 gene. Among them, the rs2835859 SNP, for which associations with analgesia and pain have not been previously reported, was selected in the exploratory study as a potent candidate SNP associated with opioid analgesic sensitivity. The results were corroborated in further confirmatory study. Interestingly, this SNP was also found to be associated with sensitivity to both cold and mechanical pain, susceptibility to nicotine dependence, and successful smoking cessation. The results indicate that this SNP could serve as a marker that predicts sensitivity to analgesic and pain and susceptibility to nicotine dependence.

DOI： 10.1254/jphs.14189FP

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)   Publisher：日本アルコール・アディクション医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The predictors of postoperative pain and analgesic consumption were previously found to include preoperative pain, anxiety, age, type of surgery, and genotype, but remaining unclear was whether intraoperative factors could predict postoperative pain. In the present study, we investigated the time-course of fentanyl consumption using intravenous patient-controlled analgesia records from patients who underwent orthognathic surgery for mandibular prognathism and analyzed the influence of anesthesia methods and surgical methods together with sex on the time course. A significant difference in the time course of fentanyl administration was found (P<0.001). No significant difference in the time course of fentanyl administration was found between males and females (P = 0.653), with no interaction between time course and sex (P = 0.567). No significant difference in the time course of fentanyl administration was found among anesthesia methods, such as fentanyl induction followed by fentanyl maintenance, fentanyl induction followed by remifentanil maintenance, and remifentanil induction followed by remifentanil maintenance (P = 0.512), but an interaction between time course and anesthesia method was observed (P = 0.004). A significant difference in the time course of fentanyl administration was found between surgical methods, such as bilateral mandibular sagittal split ramus osteotomy (BSSRO) and BSSRO combined with Le Fort I osteotomy (bimaxillary; P = 0.008), with no interaction between time course and surgical method (P = 0.535). Total postoperative 24 h consumption associated with the bimaxillary procedure was significantly higher than with BSSRO (P = 0.008). The present results indicate that administration patterns and total 24 h consumption were different among the three groups of anesthesia methods and between the two groups of surgical methods, respectively. Although more research on patient-controlled analgesia patterns and consumption is necessary, the present study will contribute to adequately relieving individual patients from postoperative pain.

DOI： 10.1371/journal.pone.0098548

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：(一社)日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, lead to different proper doses of fentanyl, which can hamper effective pain treatment. Voltage-activated Ca2+ channels (VACCs) play a crucial role in the nervous system by controlling membrane excitability and calcium signaling. Ca(v)2.3 (R-type) VACCs have been especially thought to play critical roles in pain pathways and the analgesic effects of opioids. However, unknown is whether single-nucleotide polymorphisms (SNPs) of the human CACNA1E (calcium channel, voltage-dependent, R type, alpha 1E subunit) gene that encodes Ca(v)2.3 VACCs influence the analgesic effects of opioids. Thus, the present study examined associations between fentanyl sensitivity and SNPs in the human CACNA1E gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. We first conducted linkage disequilibrium (LD) analyses of 223 SNPs in a region that contains the CACNA1E gene using genomic samples from 100 patients, and a total of 13 LD blocks with 42 Tag SNPs were observed within and around the CACNA1E gene region. In the preliminary study using the same 100 genomic samples, only the rs3845446 A/G SNP was significantly associated with perioperative fentanyl use among these 42 Tag SNPs. In a confirmatory study using the other 255 genomic samples, this SNP was also significantly associated with perioperative fentanyl use. Thus, we further analyzed associations between genotypes of this SNP and all of the clinical data using a total of 355 samples. The rs3845446 A/G SNP was associated with intraoperative fentanyl use, 24 h postoperative fentanyl requirements, and perioperative fentanyl use. Subjects who carried the minor G allele required significantly less fentanyl for pain control compared with subjects who did not carry this allele. Although further validation is needed, the present findings show the possibility of the involvement of CACNA1E gene polymorphisms in fentanyl sensitivity.

DOI： 10.1371/journal.pone.0070694

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

CXBH mice, known as an "opioid receptor-rich" strain, are a recombinant inbred mouse strain established by crossing the C57BL/6By and BALB/cBy strains. In the present study, we investigated nociceptive and antinociceptive sensitivity in CXBH mice and elucidated the underlying molecular mechanisms. CXBH mice exhibited slightly higher morphine-induced antinociception compared with C57BL/6J and BALB/cBy mice in the hot-plate test but not tail-flick test. CXBH mice exhibited a marked reduction of nociceptive sensitivity, regardless of the type of nociceptive stimulus, with the exception of tail stimulation. Changes in gene expression that corresponded to reduced nociceptive sensitivity in the brains of CXBH mice were observed in 62 transcripts, including pain-and analgesia-related transcripts, in a whole-genome expression assay. The total mRNA expression of opioid receptors was higher in CXBH mice than in C57BL/6J and BALB/cBy mice. However, the expression levels of MOR-1 mRNA, a major transcript of the mu opioid receptor gene, were not different among the C57BL/6J, BALB/cBy, and CXBH strains. In conclusion, supraspinal nociceptive responses were reduced in the CXBH mouse strain, and the expression levels of transcripts were altered in the brain of this strain.
Perspective: This article presents the nociceptive and antinociceptive properties of CXBH recombinant inbred mice and gene expression differences that may underlie nociceptive tolerance in the strain. The CXBH mouse strain may be a useful animal model to investigate the molecular basis of individual differences in supraspinal pain sensitivity. (C) 2013 Published by Elsevier Inc. on behalf of the American Pain Society.

DOI： 10.1016/j.jpain.2013.01.773

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. The adrenergic system is reportedly involved in the mechanisms of pain and analgesia. Here, we focused on one of the adrenergic receptor genes, ADRB1, and analyzed the influence of single-nucleotide polymorphisms (SNPs) in the ADRB1 gene on individual differences in pain and analgesic sensitivity. We examined associations between pain and fentanyl sensitivity and the two SNPs, A145G and G1165C, in the human ADRB1 gene in 216 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. The patients who carried the A-allele of the A145G SNP were more sensitive to cold pressor -induced pain than those who did not carry this allele, especially in male patients. The analgesic effect was significantly less in females who carried the G-allele of the G1165C SNP than the females who did not carry the G-allele. The haplotype analysis revealed a significant decrease in 24-h postoperative fentanyl use in female 145A/1165C haplotype carriers. These results suggest that SNPs in the ADRB1 gene are associated with individual differences in pain and analgesic sensitivity, and analyzing these SNPs may promote personalized pain treatment in the future.

DOI： 10.1254/jphs.12159FP

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Impairment of reciprocal social interaction is a core symptom of autism spectrum disorder. Genetic disorders frequently accompany autism spectrum disorder, such as tuberous sclerosis complex caused by haploinsufficiency of the TSC1 and TSC2 genes. Accumulating evidence implicates a relationship between autism spectrum disorder and signal transduction that involves tuberous sclerosis complex 1, tuberous sclerosis complex 2 and mammalian target of rapamycin. Here we show behavioural abnormalities relevant to autism spectrum disorder and their recovery by the mammalian target of rapamycin inhibitor rapamycin in mouse models of tuberous sclerosis complex. In Tsc2(+/-) mice, we find enhanced transcription of multiple genes involved in mammalian target of rapamycin signalling, which is dependent on activated mammalian target of rapamycin signalling with a minimal influence of Akt. The findings indicate a crucial role of mammalian target of rapamycin signalling in deficient social behaviour in mouse models of tuberous sclerosis complex, supporting the notion that mammalian target of rapamycin inhibitors may be useful for the pharmacological treatment of autism spectrum disorder associated with tuberous sclerosis complex and other conditions that result from dysregulated mammalian target of rapamycin signalling.

DOI： 10.1038/ncomms2295

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本神経精神薬理学会  

β-アドレナリン受容体(β-AR)遺伝子多型と自己式記入質問紙のTCI(Temperament and Character Inventory)の関連性について調査を行った。健常者192名(男性121名、女性71名)を対象にTCIを実施し、ゲノムDNAを解析した。全体では、ADRB1の49Ser/GlyがTCIのSelf-directedness(SD)、389Arg/GlyがPersistence(P)、ADBR2の27Gnl/GluがSelf-transcendence(ST)の人格特性と関連していた。男性は、ADRB1 49Ser/GlyがSTと、女性はADRB1 49Ser/GlyがSDと関連しているなどの差異があった。β-AR遺伝子型とTCIの下位次元との間には関連があり、その関連には性差もあることが示唆された。

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本臨床精神神経薬理学会・日本神経精神薬理学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：FUTURE MEDICINE LTD  

The mu-opioid receptor is a primary target for clinically important opioid analgesics, including morphine, fentanyl and methadone. Many genetic variations have been identified in the human mu-opioid receptor MOP gene (OPRM1), and their implications have been reported in the effects of opioid drugs and susceptibility to drug dependence. Interestingly, agonistic and antagonistic opioid effects are inversely associated with the A118G polymorphism genotype. The A118G polymorphism may also be associated with substance dependence and susceptibility to other disorders, including epilepsy and schizophrenia. The IVS1+A21573G, IVS1-T17286C, and TAA+A5359G polymorphisms in the OPRM1 gene may be associated with alcohol, opioid and tobacco dependence, respectively. However, some studies have failed to confirm the correlations between the polymorphisms and opioid effects and substance dependence. Further studies are needed to elucidate the molecular mechanisms underlying the effects of OPRM1 polymorphisms.

DOI： 10.2217/PGS.11.68

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)   Publisher：日本アルコール・アディクション医学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本アルコール・アディクション医学会  

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：(NPO)日本緩和医療学会  

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：(一社)日本神経精神薬理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BENTHAM SCIENCE PUBL LTD  

MDMA (3,4-methylenedioxymethamphetamine) is reportedly severely toxic to both dopamine (DA) and serotonin neurons. MDMA significantly reduces the number of DA neurons in the substantia nigra, but not in the nucleus accumbens, indicating that MDMA causes selective destruction of DA neurons in the nigrostriatal pathway, sparing the mesolimbic pathway. Parkinson's disease (PD) is a neurodegenerative disorder of multifactorial origin. The pathological hallmark of PD is the degeneration of DA neurons in the nigrostriatal pathway. Mutations in the parkin gene are frequently observed in autosomal recessive parkinsonism in humans. Parkin is hypothesized to protect against neurotoxic insult, and we attempted to clarify the role of parkin in MDMA-induced hyperthermia, one of the causal factors of neuronal damage, using parkin knockout mice. Body temperature was measured rectally before and 15, 30, 45, and 60 min after intraperitoneal injection of MDMA (30 mg/kg) at an ambient temperature of 22 +/- 2 degrees C. Significantly enhanced hyperthermia after MDMA injection was observed in heterozygous and homozygous parkin knockout mice compared with wildtype mice, suggesting that parkin plays a protective role in MDMA neurotoxicity.

DOI： 10.2174/157015911795016985

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BENTHAM SCIENCE PUBL LTD  

Increasing evidence suggests that mu opioid receptor (MOP) expression is altered during the development of and withdrawal from substance dependence. Although anti-MOP antibodies have been hypothesized to be useful for estimating MOP expression levels, inconsistent MOP molecular weights (MWs) have been reported in studies using anti-MOP antibodies. In the present study, we generated a new anti-MOP antibody (N38) against the 1-38 amino acid sequence of the mouse MOP N-terminus and conducted Western blot analysis with wildtype and MOP knockout brain lysates to determine the MWs of intrinsic MOP. The N38 antibody detected migrating bands with relative MWs of 60-67 kDa in the plasma membrane fraction isolated from wildtype brain, but not from the MOP knockout brain. These migrating bands exhibited semi-linear density in the range of 3-30 mu g membrane proteins/lane. The N38 antibody may be useful for quantitatively detecting MOP.

DOI： 10.2174/157015911795016921

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Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, increases locomotor activity in rodents and causes schizophrenia-like symptoms in humans. Although activation of the dopamine (DA) pathway is hypothesized to mediate these effects of PCP, the precise mechanisms by which PCP induces its effects remain to be elucidated. The present study investigated the effect of PCP on extracellular levels of DA (DA(ex)) in the striatum and prefrontal cortex (PFC) using in vivo microdialysis in mice lacking the NMDA receptor channel epsilon 1 or epsilon 4 subunit (GluR epsilon 1 [GluN2A] or GluR epsilon 4 [GluN2D]) and locomotor activity. PCP significantly increased DA(ex) in wildtype and GluR epsilon 1 knockout mice, but not in GluR epsilon 4 knockout mice, in the striatum and PFC. Acute and repeated administration of PCP did not increase locomotor activity in GluR epsilon 4 knockout mice. The present results suggest that PCP enhances dopaminergic transmission and increases locomotor activity by acting at GluR epsilon 4.

DOI： 10.1371/journal.pone.0013722

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Although the serotonin (5-hydroxytryptamine (5-HT)) 2A receptor has been reported to be associated with pain, no relationship has been found between single nucleotide polymorphisms in the 5-HT2A receptor gene and analgesic requirements. To clarify the mechanism of individual differences in analgesic requirements, we investigated the relationship between the 5-HT2A 102T/C gene polymorphism and analgesic requirements in 135 patients who underwent major open abdominal surgery and were managed with continuous epidural analgesia with opioids after surgery. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. We found that the 102T/C polymorphism had significant main effects with regard to analgesic requirements. In addition, significant interaction effects were found between the 102T/C polymorphism and sex in terms of analgesic requirements. Among female subjects, patients with the T/T genotype of the 102T/C polymorphism had more analgesic requirements than those with the other genotypes. This finding suggests that the linkage disequilibrium block, which includes the 102T/C polymorphism of the 5-HT2A receptor gene, is involved in individual differences in analgesic requirements in women. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2010.05.024

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Authorship：Lead author   Language：English   Publishing type：(MISC) Summary of the papers read (international conference)   Publisher：CAMBRIDGE UNIV PRESS  

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Opioids are commonly used as effective analgesics for the treatment of acute and chronic pain. However, considerable individual differences have been widely observed in sensitivity to opioid analgesics. We focused on a G-protein-activated inwardly rectifying potassium (GIRK) channel subunit, GIRK2, that is an important molecule in opioid transmission. In our initial polymorphism search, a total of nine single-nucleotide polymorphisms (SNPs) were identified in the whole exon, 5'-flanking, and exon-intron boundary regions of the KCNJ6 gene encoding GIRK2. Among them, G-1250A and A1032G were selected as representative SNPs for further association studies. In an association study of 129 subjects who underwent major open abdominal surgery, the A/A genotype in the A1032G SNP and -1250G/1032A haplotype were significantly associated with increased postoperative analgesic requirements compared with other genotypes and haplotypes. The total dose (mean +/- SEM) of rescue analgesics converted to equivalent oral morphine doses was 20.45 +/- 9.27 mg, 10.84 +/- 2.24 mg, and 13.07 +/- 2.39 mg for the A/A, A/G, and G/G genotypes in the A1032G SNP, respectively. Additionally, KCNJ6 gene expression levels in the 1032A/A subjects were significantly decreased compared with the 1032A/G and 1032G/G subjects in a real-time quantitative PCR analysis using human brain tissues, suggesting that the 1032A/A subjects required more analgesics because of lower KCNJ6 gene expression levels and consequently insufficient analgesic effects. The results indicate that the A1032G SNP and G-1250A/A1032G haplotype could serve as markers that predict increased analgesic requirements. Our findings will provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

DOI： 10.1371/journal.pone.0007060

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(株)星和書店  

疼痛と関連が報告されているセロトニン2A受容体について、その遺伝子多型である102T/C多型および-1438A/G多型が鎮痛薬感受性に与える影響について解析を行った。外科開腹手術を受け、術後にオピオイドを用いた持続硬膜外麻酔によって疼痛管理を行った患者のDNAから、制限酵素断片長多型解析法を用いて5-HT2A受容体遺伝子多型を判定した。両多型とも性別との交互作用において鎮痛薬投与回数および投与量との間に関連性が認められ、102T/C多型がT/T型(-1438A/G多型がA/A型)の女性は術後鎮痛薬必要量が有意に多かった。本研究により5-HT2A受容体遺伝子の102T/C多型がT/T型(-1438A/G多型がA/A型)の女性では術後鎮痛薬を多く必要とし、5-HT2A受容体遺伝子のプロモーター領域からエキソン1にまたがる連鎖不平衡ブロック(連鎖不平衡が強い領域)が女性における術後鎮痛薬感受性の個人差に関与することが示唆された。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FUTURE MEDICINE LTD  

The association between SNPs of the human OPRM1 gene encoding the P-opioid receptor and postoperative analgesic requirements in surgical patients remains controversial. Here, we evaluate whether any of the five tag SNPs (A118G, IVS2+G691C, IVS3+G5953A, IVS3+A8449G and TAA+A2109G) representing the four linkage disequilibrium blocks of the OPRM1 gene influences postoperative analgesic requirements. Materials & methods: We studied 138 adult Japanese patients who underwent major open abdominal surgery under combined general and epidural anesthesia and received continuous postoperative epidural analgesia with opioids. Results: The 118G homozygous (GG) patients required 24-h postoperative analgesics more than 118A homozygous (AA) and heterozygous (AG) patients. Tag SNP haplotypes also were associated with 24-h postoperative analgesic requirements. Conclusions: These results suggest that OPRM1 gene tag SNP genotypes and haplotypes can primarily contribute to prediction of postoperative analgesic requirements in individual patients undergoing major open abdominal surgery.

DOI： 10.2217/14622416.9.11.1605

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective Genetic factors are hypothesized to be involved in interindividual differences in opioid sensitivity. Inbred mouse strains that are genetically different and isogenic within each strain are useful for elucidating the genetic mechanisms underlying the interindividual differences in opioid-induced analgesia.
Methods We examined the effects of morphine in 10 inbred mouse strains, including wild-derived strains that have a wide range of genetic diversity, including BLG2, CHD, KJR, MSM, NA, PGN2, and SWN. We also performed full sequencing of the 5' flanking region and exons of the mouse p opioid receptor gene Oprm1 and analyzed the association between genotypes and phenotypes in these mice.
Results The effects of morphine on locomotor activation and antinociception varied among the inbred strains. The nucleotide differences that cause amino acid substitutions were not found in the Oprm1 gene in the inbred strains analyzed in this study. In the 5' flanking region and 3' untranslated region of the Oprm1 gene, four highly variable regions containing novel short tandem repeat polymorphisms (GA, T, TA, and CA/CT) were identified. The GA, T, and TA repeat numbers were significantly associated with morphine-induced antinociception.
Conclusion These results suggest that the short tandem repeats in the 5' flanking and 3' untranslated regions of the It opioid receptor gene are involved in interstrain differences in opioid sensitivity in mice. Wild-derived inbred mouse strains with different numbers of these repeats may be useful models for examining interindividual differences in opioid sensitivity. Pharmacogenetics and Genomics 18:927-936 (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/FPC.0b013e32830d0b9e

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (commerce magazine)   Publisher：真興交易(株)医書出版部  

オピオイド関連分子の遺伝子や遺伝子改変動物の解析により、モルヒネの鎮痛作用や副作用、およびモルヒネ感受性個人差のメカニズムが明らかになりつつある。また、近年におけるヒトゲノムデータベースの公開や国際ハップマップ計画により、ヒトゲノムの遺伝子特性について網羅的な解析も可能になった。これらの研究結果は、依存や耐性といった副作用の解決や各個人に最適な疼痛治療法の確立に寄与すると期待される。(著者抄録)

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. Studies using gene knockout mice have revealed that genes encoding some metabolic enzymes, opioid transporters, and opioid system signal transduction mediators may be candidate genes to predict appropriate kinds and doses of opioids for individuals. Recently, various databases on knockout mice, pharmacogenetics, and gene polymorphisms have been rapidly consolidated. Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.

DOI： 10.1007/s00210-007-0205-3

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本外科系連合学会  

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (commerce magazine)   Publisher：(株)メディカル・サイエンス・インターナショナル  

2007年4月に「がん対策基本法」が施行されたことも含めて、疼痛治療の重要性は近年ますます高まっている。しかしながら、患者個々で鎮痛薬の感受性が異なることが疼痛治療を難しくしている。この個人差にはさまざまな原因が考えられ、その一つに遺伝要因もある。ここでは、最近明らかになりつつある鎮痛薬感受性個人差の遺伝子メカニズムを紹介し、テーラーメイド疼痛治療の可能性について述べたい。(著者抄録)

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Language：Japanese   Publishing type：(MISC) Introduction and explanation (commerce magazine)  

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)   Publisher：(公社)日本薬理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Conventional methods for detecting single nucleotide polymorphisms (SNPs), including direct DNA sequencing, pyrosequencing, and melting curve analysis, are to a great extent limited by their requirement for particular detection instruments. To overcome this limitation, we established a novel SNP detection technique utilizing multiple primer extension (MPEX) on a phospholipid polymer- coated surface. This technique is based on the development of a new plastic S-BIO (R) PrimeSurface (R) with a biocompatible polymer; its surface chemistry offers extraordinarily stable thermal properties, as well as chemical properties advantageous for enzymatic reactions on the surface. To visualize allele- specific PCR products on the surface, biotin-dUTP was incorporated into newly synthesized PCR products during the extension reaction. The products were ultimately detected by carrying out a colorimetric reaction with substrate solution containing 4-nitro-blue tetrazolium chloride (NBT) and 5-bromo-4-chloro-3-indolyl phosphate (BCIP). We demonstrated the significance of this novel SNP detection technique by analyzing representative SNPs on 4 LD blocks of the mu opioid receptor gene. We immobilized 20 allele-specific oligonucleotides on this substrate, and substantially reproduced the results previously obtained by other methods.

DOI： 10.1039/b701645j

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Embryonic patterning and germ-cell specification in mice are regulative and depend on zygotic gene activities. However, there are mouse homologues of Drosophila maternal eff ect genes, including vasa and tudor, that function in posterior and germ-cell determination. We report here that a targeted mutation in Tudor domain containing 11mouse tudor repeat 1 (Tdrd1/Mtr- 1), a tudor-related gene in mice, leads to male sterility because of postnatal spermatogenic defects. TDRDl/MTR-1 predominantly localizes to nuage/ germinal granules, an evolutionarily conserved structure in the germ line, and its intracellular localization is downstream of mouse vasal homologuelbEAD box polypeptide 4 (MMID&4), similar to Drosophiia vasa-tudor. TdrdlIMtr-1 mutants lack, and MvhlDdx4 mutants show, strong reduction of intermitochondrial cement, a form of nuage in both male and female germ cells, whereas chromatoid bodies, another specialized form of nuage in spermatogenic cells, are observed in TdrdlIMtr-1 mutants. Hence, intermitochondrial cement is not a direct prerequisite for oocyte development and fertility in mice, indicating differing requirements for nuage and/or its components between male and female germ cells. The result also proposes that chromatoid bodies likely have an origin independent of or additional to intermitochondrial cement. The analogy between Mvh-Tdrdl in mouse spermatogenic cells and vasa-tudor in Drosophila oocytes suggests that this molecular pathway retains an essential role(s) that functions in divergent species and in different stages/sexes of the germ line.

DOI： 10.1073/pnas.0601878103

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Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本神経化学会  

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (commerce magazine)   Publisher：真興交易(株)医書出版部  

オピオイド関連分子の遺伝子や遺伝子改変動物の解析により,モルヒネの鎮痛作用や副作用,およびモルヒネ感受性個人差のメカニズムが明らかになりつつある.また,近年におけるヒトゲノムデータベースの公開や国際ハップマップ計画により,ヒトゲノムの遺伝子特性について網羅的な解析も可能になった.これらの研究結果は,依存や耐性といった副作用の解決や各個人に最適な疼痛治療法の確立に寄与すると期待される(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives CXBK mice, recombinant inbred mice derived from C57BL/6By and BALB/cBy progenitors, display reduced morphine-induced analgesia. Earlier we reported that CXBK mice expressed a reduced amount of the major transcript, MOR-1 mRNA, of the mu-opioid receptor gene. The CXBK MOR-1 mRNA contains a normal coding region and an abnormally long untranslated region.
Methods and results To identify the nucleotide-sequence difference between the CXBK MOR-1 mRNA and that of the progenitors, we first characterized the 3' untranslated region of the MOR-1 mRNA, which was largely unknown. A 3' rapid amplification of cDNA ends-PCR analysis revealed that the 3' untranslated region of the C57BL/6By MOR-1 mRNA was 10 181 nuclecitides transcribed from an exon. Next, we compared the MOR-1 genes in C57BL/6By, CXBK, and BALB/cBy mice, and found a 5293 nucleotide insertion only in CXBK mice. The inserted sequence was a variant of the intracisternal A-particle elements that exist in the mouse genome at approximately 1000 sites. Reverse transcription-PCR analyses revealed that the intracisternal A-particle element was transcribed as a part of the CXBK MOR-1 mRNA. No other differences were found in the MOR-1 mRNA between CXBK and BALB/cBy mice, whereas 100 nucleotides differed between C57BL/6By and CXBK mice aside from the intracisternal A-particle insertion. Finally, CXBK mice displayed reduced morphine responses compared with BALB/cBy mice.
Conclusions Our data suggest that differences in the MOR-1 3' untranslated region appear to cause the CXBK phenotype. This genetic mechanism underlying the CXBK phenotype may provide good insight into the possible genetic mechanisms underlying individual differences in opioid sensitivity in humans. Pharmacogenetics (C) 2006 Lippincott Williams & Wilkins.

DOI： 10.1097/01.fpc.0000215072.36965.8d

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1440-1819.2006.01523.x-i1

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (commerce magazine)   Publisher：(株)先端医学社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The mu-opioid receptor (MOR) plays a mandatory role in the action of most opioid drugs, such as morphine, fentanyl, and heroin. it has been revealed that a deficiency in the MOR gene (Oprm 1) or a difference in the 3' noncoding region of the gene markedly affects the sensitivity of mice to opioids. As the 3' noncoding region of the human OPRM1 gene had not yet been characterized, in the present study we conducted 3'-rapid amplification of cDNA ends (3'RACE)-PCR and identified the 3' end of the human MOR-1 mRNA, the most abundant transcript among OPRM1 gene transcripts. The poly(A) signal was located at 13612-13617 nucleotides downstream from the stop codon in the OPRM1 gene. Reverse transcription PCR analyses showed that the region from the stop codon to the poly(A) signal was transcribed. In the 3' UTR, we identified 33 AU-rich regions and more than 300 putative transcription factor-binding sites. Furthermore, we compared the 3' noncoding regions of the human and mouse OPRM1/Oprm1] genes and found apparent homology. In Northern blotting with mouse brain mRNAs, a same-size band was detected by a probe for the MOR-1 coding region and by a probe for a mouse genome region corresponding to the human MOR-1 3'UTR. Since 3'UTRs affect gene expression, the present characterization of the 3' noncoding region in the human OPRM1 gene should lead to a better understanding of the mechanisms underlying OPRM1 gene regulation and individual differences in sensitivity to opioids. Published by Elsevier B.V.

DOI： 10.1016/j.gene.2005.05.040

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Introduction and explanation (scientific journal)   Publisher：(一社)日本神経精神薬理学会  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

In germ cells, the function of which is to form the next generation, apoptotic cell death occurs during development, as in the case of somatic cells. In this study, we show that Bcl-x knockout heterozygous (Bcl-(+/-)) mice exhibit severe defects in male germ cells during development. A substantial increase in apoptosis of male germ cells occurs at around embryonic day 13.5 (E13.5) in Bcl-x(+/-) embryos, leading to hypoplasia of postnatal testes and reduced fertility. On the other hand, female germ cells at the same stages do not show discernible differences between wild-type and Bcl-x(+/-) embryos. This phenotype of Bcl-x haploinsufficiency shows that regulation of apoptosis becomes different between the sexes at around the onset of sex differentiation. Through this study, we found that, in wild-type embryos, (1) apoptosis is much more frequent (approximately 10 times) in the male than in female germ cells, and (2) expression of Bcl-x, but not that of Bax, is higher in female than in male germ cells, at around E13.5. Male fetal germ cells, cultured with gonadal somatic cells in vitro, showed higher frequencies of apoptosis than those cultured without gonadal somatic cells. On the other hand, in the absence of gonadal somatic cells, both male and female fetal germ cells in vitro showed similar frequencies of apoptosis to female fetal germ cells in vivo. Therefore, male germ cell apoptosis, of which the default pathway is similar to that of the female, is likely to be influenced by male gonadal environments. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0012-1606(03)00400-7

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Authorship：Lead author   Language：Japanese   Publishing type：(MISC) Summary of the papers read (national conference and other science council)   Publisher：日本発生生物学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

To propose candidates for the prevention or treatment of osteoporosis, we have screened compounds naturally in food for their ability to regulate the differentiation and function of osteoclasts. One of the major green tea flavonoids, (-)-epigallocatechin-3-gallate (EGCG), was found to induce apoptotic cell death of osteoclast-like multinucleated cells after 24 h treatment in a dose-dependent manner (25-100 muM), whereas osteoblasts were not affected. In the present study, we report for the first time a novel cell-death-inducing mechanism triggered by EGCG. The induction of apoptosis by EGCG was suppressed by pretreatment of catalase or calcitonin. It was also suppressed by Fe(III) and Fe(II) chelators. Furthermore, EGCG promoted the reduction of Fe(III) into Fe(II), and the combination of EGCG/Fe(III)/H2O2 induced single-strand DNA breakage in a cell free system. These results indicate that the Fenton reaction is primarily involved in EGCG-induced osteoclastic cell death. (C) 2002 Elsevier Science (USA).

DOI： 10.1006/bbrc.2002.6622

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Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

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Language：Japanese   Presentation type：Symposium workshop panel(nominated)  

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Language：English   Presentation type：Oral presentation(invited, special)  

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