Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies.

BACKGROUND: Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects. RESULTS: The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter. CONCLUSIONS: Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population.

Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements.

An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements.

[Shivering associated with general anesthesia using remifentanil].

General anesthesia using remifentanil is accompanied with post-operative shivering at a high incidence. Post-operative shivering can be divided into thermoregulatory and non-thermoregulatory. Hypothermia causes thermoregulatory shivering. The interthreshold range is defined as the difference between the sweating threshold and the vasoconstriction threshold. Generally, the interthreshold range is shifted to higher temperatures immediately after surgery under general anesthesia. Thus, thermoregulatory shivering can be exaggerated in patients without hypothermia. The application of patient warming devices and the administration of non-steroidal anti-inflammatory drugs are considered as effective treatments for the prevention of thermoregulatory shivering. Remifentanil is an ultra-short acting agent. Pharmacological effects of remifentanil quickly disappear just after the discontinuing of remifentanil infusion, leading to a kind of opioid withdrawal syndrome resulting in non-thermoregulatory shivering. In addition, postoperative pain shifts the shivering threshold to higher temperatures, resulting in non-thermoregulatory shivering. Thus, opioid transition using fentanyl and/or morphine during anesthetic management is essential for the prevention of non-thermoregulatory shivering. It is also reported that magnesium, ketamine and pethidine have preventive effects on non-thermoregulatory shivering. The mechanism underlying post-operative shivering associated with general anesthesia using remifentanil is very complicated; therefore, we speculate that multimodal approach is required for its prevention.

[Anesthetic management of laparoscopic cholecystectomy for a patient with Churg-Strauss syndrome: a case report].

Churg-Strauss syndrome (CSS) is an uncommon disease characterized by bronchial asthma, eosinophilia and systemic vasculitis. Many patients with CSS are suffering from cardiovascular disorders, neurological disorders and/or renal disorders which are associated with systemic vasculitis. Cardiac diseases are considered as the main cause of the death in patients with CSS. Steroid administration is the standard pharmacological therapy for CSS. There are very few clinical reports concerning anesthetic management for the patients with CSS. We suppose that precise perioperative managements are required for the patients with CSS, including the appropriate control of bronchial asthma and the careful treatments of disorders in cardiovascular system, neurological system and/or kidney. In addition, we believe that the steroid cover should be considered during the perioperative period of the patients with CSS. Here, we describe an anesthetic management of a 28-year-old man with CSS undergoing laparoscopic cholecystectomy. General anesthesia was induced with midazolam and fentanyl. Rocuronium was administered to facilitate tracheal intubation. After tracheal intubation, anesthesia was maintained with sevoflurane and remifentanil. Prior to the surgery, 100 mg of hydrocortisone was administered for the steroid cover. The surgery was uneventful. The patient emerged from general anesthesia smoothly, and was extubated safely.

[Desflurane anesthesia without muscle relaxant for a patient with myasthenia gravis undergoing laparoscopic high anterior resection: a case report].

Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular junction, which is characterized by fluctuating muscle weakness and abnormal fatigability. The use of muscle relaxants is major concern in anesthetic management for patients with MG. Muscle relaxant is a practical tool to assure immobilization during surgery under general anesthesia Anesthetic management without muscle relaxants for patients with MG is challenging, because it is difficult to assure immobilization. However, pharmacological effects of muscle relaxants can be prolonged in patients with MG, resulting in the increased incidence of postoperative respiratory support. We, here, describe an anesthetic management of an 82-year-old man with MG undergoing laparoscopic surgery. Anesthesia was induced with propofol and remifentanil Desflurane was administered via a face mask, and the patient was manually ventilated for 10 min, and the trachea was intubated safely without muscle relaxants. Anesthesia was maintained with desflurane and remifentanil. We did not administer muscle relaxants to the patient during surgery. Throughout laparoscopic procedures, no movements of the patient were observed, and there were no problems concerning the laparoscopic view of the operation filed. The surgery was uneventful. The patient emerged from anesthesia smoothly, and was extubated safely. The postoperative course of the patient was also uneventful.

[A case of acute renal failure following compartment syndrome after the surgery for femoral neck fracture].

Compartment syndrome is known to develop after a prolonged surgery in the lithotomy position. We experienced acute renal failure following compartment syndrome after the surgery in hemilithotomy position. A 62-year-old man underwent a left hip fixation for femoral neck fracture. The surgical leg was placed into traction in a foot piece and the intact leg was placed in the hemilithotomy position. Because of the difficulty in repositioning and the trouble with fluoroscope, the surgery took over 5 hours. He suffered acute pain, swelling and spasm in his intact leg placed into hemilithotomy after the surgery. Creatine kinase, blood urea nitrogen and creatinine markedly increased and myoglobinuria was recognized. We diagnosed an acute renal failure following compartment syndrome and treated him in the ICU on close monitoring. In spite of the treatment with massive transfusion and diuretics, he needed hemodialysis twice and then his renal function improved. Prevention is most essential for compartment syndrome after a prolonged surgery in the lithotomy position. Risk factors should be recognized before surgery and appropriate action should be taken such as using Allen stirrups and avoiding hypotension, hypovolemia and the prolonged lithotomy position with exaggerated elevation of legs.

Effects of acetaldehyde on action potentials and Ca2+ currents in single atrial myocytes from the bullfrog.

AIM: The purpose of the present study was to examine the effects of acetaldehyde on the contractile force and membrane potentials and currents in the bullfrog heart. METHODS: Contractile force was recorded using right atrial tissues, and membrane potentials and currents were measured by using whole cell patch clamp methods in right atrial myocytes. RESULTS: Acetaldehyde at 500 µmol/l and 1 mmol/l increased the contractile force significantly. Acetaldehyde at 300 and 500 µmol/l increased the overshoot and the plateau of electrically induced action potentials in a concentration-dependent and reversible manner, while the resting membrane potential did not change. The duration of the action potential (APD(90)) measured at the 90% repolarization level was shortened. The L-type Ca(2+) current (I(Ca)) increased significantly when 300 and 500 µmol/l were applied. The fast transient inward current, the inward rectifying potassium current and the outward delayed-rectifier potassium current were not changed following acetaldehyde application (500 µmol/l or 1 mmol/l). CONCLUSION: These results suggest that acetaldehyde increased the I(Ca), thereby increased the contractile force, the overshoot and the plateau of action potentials. The shortening of APD(90) may be due to the acceleration of the current decay during the I(Ca) inactivation phase.

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.

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

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 mu-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]: 12s) compared with subjects not carrying this allele (PPLpost-PPLpre: 15s, 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: 1.5microg/kg) compared with subjects not carrying this allele (median: 2.5microg/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.

[Genetic polymorphisms and human sensitivity to pain and opioids].

It has been known widely that sensitivity to pain and opioid analgesics varies widely among individual subjects. Because of this variability, a dose of an opioid analgesic that can produce satisfactory pain relief without adverse effects in some patients might cause underdosing or overdosing in other patients, which is often problematic in the clinic. Individual differences can be attributed to both genetic and environmental factors, although the relative influence of each of these factors can be diverse. Numerous molecules have been identifled to be involved in the transduction, conduction, transmission and modulation of pain, as well as pharmacological effects of opioids. Further, many technologies of genotyping polymorphisms, most often single nucleotide polymorphisms (SNPs), have been developed and advanced, leading to accelerated understanding of many associations between various genetic polymorphisms and sensitivity to pain and opioids. In this article, we review the evidence of these associations accumulated thus far.

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.

Hypotensive and hypertensive effects of acetaldehyde on blood pressure in rats.

Intravenous injection of acetaldehyde produced hypotensive actions in pentobarbital-anaesthetised whole rats, but hypertensive actions in pithed rats. The hypotensive effects of acetaldehyde in whole rats were abolished by pre-treatment with yohimbine. In pithed rats, the hypertensive effects of acetaldehyde were significantly attenuated by prazosin and phentolamine, and in rats that had been pre-treated with reserpine. Our results suggest that the hypertensive actions of acetaldehyde in pithed rats are due to the release of catecholamines, which subsequently leads to vasoconstriction. In whole rats the hypotensive actions of acetaldehyde may be due to alpha2-adrenoceptor stimulation in the central nervous or peripheral system.

[Selection of drugs suitable for the treatment of intractable chronic pain patients by using drug challenge tests].

Intractable chronic pain is very difficult to treat. Nowadays, small amounts of drugs, that have different actions on the mechanism of pain relief are administered intravenously, and the effects of the test drugs on individual chronic pain patients are investigated by using the evaluation method of the visual analogue scale (VAS). This will enable elucidation of the mechanisms of pain in each chronic pain patient. Based on this information, drugs that are effective for the treatment of individual chronic pain patients can be prescribed. Drugs that are used for the drug challenge tests are phentolamine, barbiturate, morphine, lidocaine, ketamine, benzodiazepine, adenosine-3-phosphate (ATP), neurotropine, and prostaglandine E1. Phentolamine is effective for the management of sympathetically maintained pain. Barbiturate and morphine are effective for the treatment of deafferentation pain and nociceptive pain, respectively. Lidocaine is effective for the treatment of neuropathic pain; ketamine, for allodynia; and benzodiazepine, for anxiety-related pain. ATP exerts a positive effect in total pain management. Neurotropine and prostaglandine E1 are effective for the management of neuropathic pain and ischemic pain, respectively. These tests aid in the selection of drugs that maybe useful for the treatment of intractable chronic pain in patients.

[Preoperative evaluation and anesthetic management of a patient with Brugada syndrome-like ECG].

Brugada syndrome has been known as one of the causes of sudden death due to ventricular fibrillation. We experienced anesthetic management of seven patients with ECG showing Brugada syndrome before surgery, even though they had no symptoms nor family history. All of them showed no problems through-out the operation. Such patients are often untreated, but they have the risks of cardiac accidents such as ventricular fibrillation or sudden death. For preoperative evaluation of patients with Brugada syndrome-like ECG, it is important to ask them their experience of syncope and family history. Ultrasonic cardiography and Holter ECG recording should be done. External defibrillator should be prepared and parasympathetic dominant condition must be avoided during the anesthetic management.

[Effects of linear polarized light irradiation around the lumbar sympathetic ganglion area upon the skin temperature of lower extremities].

BACKGROUND: The effect of linear polarized light irradiation around the lumbar sympathetic ganglion area upon the skin temperature of legs may be similar to that of irradiation of near stellate ganglion area upon arms. METHODS: Linear polarized light irradiation was induced with SUPER LIZER (Tokyo Iken, Tokyo, Japan). The C probe of SUPER LIZER was placed on the left side of the supine at the level of L2. RESULTS: Seven-minute irradiation around the lumbar sympathetic ganglion area increased significantly the skin temperature of the irradiated side leg. CONCLUSIONS: These results suggest that linear polarized light irradiation around the lumbar sympathetic ganglion area might be useful and beneficial for clinical application.

Is there genetic polymorphism evidence for individual human sensitivity to opiates?

Opiate analgesics have been widely used for severe acute pain and chronic cancer-related pain. Individual differences in the effectiveness of opiates and their side effects limit the clinical benefits and increase risks of drug abuse. Genetic factors might affect variations of opiate sensitivity. The mu opioid peptide receptor (MOP) is the principal site of pharmacologic actions for most clinically important opiate drugs. Recent studies using various knockout mice and recombinant-inbred strain CXBK mice have indicated that the analgesic effect of morphine is dependent on the amount of the MOP. There are more than 100 polymorphisms identified in the human MOP (OPRM1) gene. These polymorphisms might be correlated with OPRM1 mRNA stability and opiate sensitivity, including opiate analgesia, tolerance, and dependence. More precise studies on the relationship between gene polymorphisms and opiate sensitivity will enable realization of personalized pain treatment by predicting opiate sensitivity and requirement for each patient.

Novel mutations in C-terminal channel region of the ryanodine receptor in malignant hyperthermia patients.

Malignant hyperthermia (MH) is a pharmacogenetical complication of general anesthesia resulting from abnormal Ca2+-induced Ca2+ release (CICR) via the type 1 ryanodine receptor (RyR1) in skeletal muscles. In this study, we analyzed the genomic DNAs prepared for determination of all the 106 exons of the RyR1 gene from blood samples donated by two MH patients with extremely high CICR rates in their biopsied skeletal muscles and a clear history of MH incidence. Two novel point mutations were found in the exons 96 and 101 with alterations in the coded amino acids within the C-terminal channel region, i.e., Pro4668 to Ser and Leu4838 to Val. The latter mutation was found in both MH patients. Rabbit RyR1 channels carrying corresponding mutations were expressed in CHO cells for functional assay. It was found that the L to V but not the P to S mutation of the RyR1 resulted in enhanced Ca2+ release activity. These results indicate that the L4838V mutation is responsible for the MH incidence. The L4838V mutation is unique because it is the mutation first found within a hydrophobic transmembrane segment of the channel region and should provide further information on the function of the RyR1 as well as for genetic diagnosis of MH.