Yasukazu Ogai

Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype

AIMS The association between SNPs of the human OPRM1 gene encoding the micro-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.

Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery

ABSTRACT Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the μ‐opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor‐induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost–PPLpre]: 12 s) compared with subjects not carrying this allele (PPLpost–PPLpre: 15 s, p = 0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3′ untranslated region, was associated with 24‐h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24‐h postoperative pain control (median: 1.5 μg/kg) compared with subjects not carrying this allele (median: 2.5 μg/kg, p = 0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3′ untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl.

Association between KCNJ6 (GIRK2) Gene Polymorphisms and Postoperative Analgesic Requirements after Major Abdominal Surgery

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.

Fluoxetine as a potential pharmacotherapy for methamphetamine dependence: studies in mice.

Abstract:  The monoamine transporters are the main targets of psychostimulant drugs, including methamphetamine (METH) and cocaine. Interestingly, the rewarding effects of cocaine are retained in dopamine transporter (DAT) knockout (KO) mice, while serotonin transporter (SERT) and DAT double KO mice do not exhibit conditioned place preference (CPP) to cocaine. These data suggest that SERT inhibition decreases the rewarding effects of psychostimulants. To further test this hypothesis, in the present study, we investigated the effects of intraperitoneal (i.p.) injections of 20 mg/kg fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on 2 mg/kg METH (i.p.) CPP and locomotor sensitization to 1 mg/kg METH (i.p.) in C57BL/6J mice. Fluoxetine treatment before both the conditioning and preference tests abolished METH CPP. A two‐way analysis of variance (ANOVA) revealed that METH CPP tended to be lower in mice pretreated with fluoxetine before the preference test than in control mice pretreated with saline before the preference test. Furthermore, pretreatment with fluoxetine had inhibitory effects on METH‐induced locomotor sensitization. These results suggest that fluoxetine, a widely used medication for depression, may be also a useful tool for treating METH dependence.

G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants.

Antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been widely used for the treatment of not only depression but also other psychiatric disorders, although the molecular mechanisms of the drug effects have not yet been sufficiently revealed. Here, we investigated the in vivo effects of these antidepressants on G protein-activated inwardly rectifying K+ (GIRK) channels, which are important for regulating the excitability of various cells, by using weaver (wv) mice, which have mutant GIRK channels and show abnormal neuronal cell death and motor disturbances. First, we found that a widely used SSRI fluoxetine (also known as Prozac) effectively inhibited wv GIRK2 channels like wild-type GIRK channels, expressed in Xenopus oocytes. Next, we found that weaver motor disturbances were remarkably alleviated by chronic treatment with fluoxetine or desipramine. Furthermore, the chronic fluoxetine treatment substantially suppressed the abnormal neuronal cell death in the weaver mouse cerebellum and pontine nuclei. These results suggest that continuous inhibition of wv GIRK2 channels by a group of antidepressants caused substantial suppression of the neuronal cell death and resulted in improvement of motor abilities in weaver mice. These results provide evidence for in vivo GIRK channel inhibition by a group of antidepressants.

A novel SNP detection technique utilizing a multiple primer extension (MPEX) on a phospholipid polymer-coated surface

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 PrimeSurface 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 micro opioid receptor gene. We immobilized 20 allele-specific oligonucleotides on this substrate, and substantially reproduced the results previously obtained by other methods.

Association between 5-hydroxytryptamine 2A receptor gene polymorphism and postoperative analgesic requirements after major abdominal surgery

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.

Verification of the addiction severity index Japanese version (ASI-J) as a treatment-customization, prediction, and comparison tool for alcohol-dependent individuals.

Objective: To demonstrate the usefulness of the Addiction Severity Index Japanese Version (ASI-J) in Japanese alcohol-dependent individuals. The ASI is a frequently used clinical and research instrument that measures severities in seven functional domains in people with substance abuse disorders. Methods: A total of 370 male inpatients with a history of alcohol dependence participated in the study. Forty-nine participants were excluded in the final analysis due to lack of reliability (i.e., patient misrepresentation or inability to understand). We used the ASI-J and a series of indexes that determined patient states during and post-treatment. Results: The correlations between ASI Composite Scores (CSs), which were calculated through a weighted formula and indicated the severity of each problem area, were significant but low in eight relations and not significant in 13 relations, indicating substantial independence of the problem areas. Significant differences were found in Family/Social CSs between abstinent and relapsed alcohol-dependent individuals. The questions of undesirable attitude were significantly related to the CSs of Employment, Drug use, Family/Social, and Psychiatric sections. Significant differences were observed in patient demographics, CS, and ASI Severity Rating (SR) and interviewer’s subjective scoring between alcohol-dependent individuals and drug abusers. CSs in Japanese alcohol-dependent individuals were generally similar to corresponding CSs in individuals from other countries, with the exception of The Netherlands. Conclusions: This study demonstrated that the ASI-J is useful for understanding individual profiles of problems for each patient and planning customized treatment. The ASI-J served as a predictive tool for relapse and compliance to treatment afterward and was shown to be useful as a comparison tool in clarifying similarities and differences between substance abuser groups.

Family Dysfunction Differentially Affects Alcohol and Methamphetamine Dependence: A View from the Addiction Severity Index in Japan

We investigated the differential influence of family dysfunction on alcohol and methamphetamine dependence in Japan using the Addiction Severity Index (ASI), a useful instrument that multilaterally measures the severity of substance dependence. The participants in this study were 321 male patients with alcohol dependence and 68 male patients with methamphetamine dependence. We conducted semi-structured interviews with each patient using the ASI, which is designed to assess problem severity in seven functional domains: Medical, Employment/Support, Alcohol use, Drug use, Legal, Family/Social relationships, and Psychiatric. In patients with alcohol dependence, bad relationships with parents, brothers and sisters, and friends in their lives were related to current severe psychiatric problems. Bad relationships with brothers and sisters and partners in their lives were related to current severe employment/support problems, and bad relationships with partners in their lives were related to current severe family/social problems. The current severity of psychiatric problems was related to the current severity of drug use and family/social problems in patients with alcohol dependence. Patients with methamphetamine dependence had difficulty developing good relationships with their father. Furthermore, the current severity of psychiatric problems was related to the current severity of medical, employment/support, and family/social problems in patients with methamphetamine dependence. The results of this study suggest that family dysfunction differentially affects alcohol and methamphetamine dependence. Additionally, family relationships may be particularly related to psychiatric problems in these patients, although the ASI was developed to independently evaluate each of seven problem areas.

Parental Post-Traumatic Stress Symptoms as Predictors of Psychosocial Problems in Children Treated for Cancer

The purpose of this study was to explore the association between psychosocial functioning of children treated for cancer and that of their parents. Factors associated with psychosocial functioning were also examined. The present study was a cross-sectional survey of 33 mothers and one father (mean age: 37.9), each of whom had a child that had been treated for cancer. The participants answered a package of questionnaires consisting of the Impact of Event Scale-Revised (IES-R), the Parent Experience of Child Illness (PECI), and the Child Behavior Checklist (CBCL). Information about the children’s illnesses was collected from medical records. The CBCL total problems T score was correlated with the parental IES-R total scores. Intensity of treatment independently predicted the variance of parental long-term uncertainty. In conclusion, psychosocial problems of children with cancer were associated with parental post-traumatic stress symptoms (PTSS). Provision of early, adequate support to parents who are vulnerable to PTSS will help not only the parents, but also their children with cancer.