RESUMEN
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 2/genética , Metilasas de Modificación del ADN/genética , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/etiología , Escalas de Valoración Psiquiátrica , Procedimientos de Cirugía Plástica/efectos adversos , Trastornos Relacionados con Sustancias/genética , Adulto JovenRESUMEN
Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover.
Asunto(s)
Trastornos Relacionados con Anfetaminas/genética , Anorexia/genética , Proteínas del Citoesqueleto/genética , Dopamina/metabolismo , Neuropéptidos/genética , Serotonina/metabolismo , Edad de Inicio , Analgésicos Opioides/uso terapéutico , Fentanilo/uso terapéutico , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Células HEK293 , Humanos , Intrones , Cirugía Ortognática , Polimorfismo de Nucleótido SimpleRESUMEN
Most investigations into the negative effects of viewing stereoscopic 3D content on human health have addressed 3D visual fatigue and visually induced motion sickness (VIMS). Very few, however, have looked into changes in autonomic balance and heart rhythm, which are homeostatic factors that ought to be taken into consideration when assessing the overall impact of 3D video viewing on human health. In this study, 30 participants were randomly assigned to two groups: one group watching a 2D video, (2D-group) and the other watching a 3D video (3D-group). The subjects in the 3D-group showed significantly increased heart rates (HR), indicating arousal, and an increased VLF/HF (Very Low Frequency/High Frequency) ratio (a measure of autonomic balance), compared to those in the 2D-group, indicating that autonomic balance was not stable in the 3D-group. Additionally, a more disordered heart rhythm pattern and increasing heart rate (as determined by the R-peak to R-peak (RR) interval) was observed among subjects in the 3D-group compared to subjects in the 2D-group, further indicating that 3D viewing induces lasting activation of the sympathetic nervous system and interrupts autonomic balance.