Publications (117) View all
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Article: Reduced Supraspinal Nociceptive Responses and Distinct Gene Expression Profile in CXBH Recombinant Inbred Mice.
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ABSTRACT: 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 μ 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.The journal of pain: official journal of the American Pain Society 04/2013; · 3.78 Impact Factor -
Article: Association between the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene and sensitivity to analgesics and pain in patients undergoing painful cosmetic surgery.
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ABSTRACT: To elucidate the mechanisms of individual differences in pain and analgesic sensitivity, we analyzed the variable number of tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene. Alleles that were less than four repeats long and four or more repeats long were considered Short and Long, respectively. We found that the Short/Short genotype group was significantly more sensitive to pain and less sensitive to analgesics than the Short/Long+Long/Long genotype group. Our data suggest that this polymorphism may predict individual differences in pain and analgesic sensitivity and help achieve adequate pain control in the future.Neuroscience Letters 02/2013; · 2.11 Impact Factor -
Article: Exclusive expression of VMAT2 in noradrenergic neurons increases viability of homozygous VMAT2 knockout mice.
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ABSTRACT: The vesicular monoamine transporter 2 (VMAT2) translocates monoamine neurotransmitters from the neuronal cytoplasm into synaptic vesicles. Since VMAT2-/- mice die within a few days of birth, it is difficult to analyze the detailed VMAT2 functions using these mice. In this study, we generated human VMAT2 transgenic mice that expressed VMAT2 in noradrenergic neurons with the aim to rescue the lethality of VMAT2 deletion. The expression of human VMAT2 in noradrenergic neurons extended the life of VMAT2-/- mice for up to three weeks, and these mice showed severe growth deficiency compared with VMAT2+/+ mice. These results may indicate that VMAT2 expressed in noradrenergic neurons has crucial roles in survival during the first several weeks after birth, and VMAT2 functions in other monoaminergic systems could be required for further extended survival. Although VMAT2 rescue in noradrenergic neurons did not eliminate the increased morbidity and lethality associated with VMAT2 deletion, the extension of the lifespan in VMAT2 transgenic mice will enable behavioral, pharmacological and pathophysiological studies of VMAT2 function.Biochemical and Biophysical Research Communications 02/2013; · 2.48 Impact Factor -
Article: Association Between Genetic Polymorphisms of the β(1)-Adrenergic Receptor and Sensitivity to Pain and Fentanyl in Patients Undergoing Painful Cosmetic Surgery.
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ABSTRACT: 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.Journal of Pharmacological Sciences 12/2012; · 2.08 Impact Factor -
Article: Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex.
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ABSTRACT: 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.Nature Communications 12/2012; 3:1292. · 7.40 Impact Factor
