Daisuke Nishizawa

Association of μ-Opioid Receptor Gene Polymorphism A118G with Alcohol Dependence in a Japanese Population

Ethanol is considered to activate the brain reward system by increasing the release of an endogenous opioid receptor ligand, β-endorphin. The polymorphism A118G in the µ-opioid receptor gene (OPRM1) causes the amino acid change Asn40Asp and has been reported to affect the affinity of the ligand for the receptor. The association of this polymorphism with the vulnerability to alcohol dependence has been studied in many populations, but not yet in Japanese people. In the present study, we compared the frequencies of the polymorphism OPRM1 A118G between patients with alcohol dependence and healthy control subjects living in a Japanese provincial prefecture. We also genotyped a polymorphism, G1510A, in the acetaldehyde dehydrogenase 2 gene (ALDH2), in which the A allele causes poor metabolism of acetaldehyde, a major metabolite of alcohol. Both OPRM1 118G and ALDH2 1510G were significantly associated with alcohol dependence. These results suggest that OPRM1 118G in addition to ALDH2 1510G might be one of the risk factors for alcohol dependence in Japanese people.

Identification of Selective Agonists and Antagonists to G Protein-Activated Inwardly Rectifying Potassium Channels: Candidate Medicines for Drug Dependence and Pain

G protein-activated inwardly rectifying K+ (GIRK) channels have been known to play a key role in the rewarding and analgesic effects of opioids. To identify potent agonists and antagonists to GIRK channels, we examined various compounds for their ability to activate or inhibit GIRK channels. A total of 503 possible compounds with low molecular weight were selected from a list of fluoxetine derivatives at Pfizer Japan Inc. We screened these compounds by a Xenopus oocyte expression system. GIRK1/2 and GIRK1/4 heteromeric channels were expressed on Xenopus laevis oocytes at Stage V or VI. A mouse IRK2 channel, which is another member of inwardly rectifying potassium channels with similarity to GIRK channels, was expressed on the oocytes to examine the selectivity of the identified compounds to GIRK channels. For electrophysiological analyses, a two-electrode voltage clamp method was used. Among the 503 compounds tested, one compound and three compounds were identified as the most effective agonist and antagonists, respectively. All of these compounds induced only negligible current responses in the oocytes expressing the IRK2 channel, suggesting that these compounds were selective to GIRK channels. These effective and GIRK-selective compounds may be useful possible therapeutics for drug dependence and pain.

A pharmacogenetics approach to pain management

Opioid analgesics are widely used as effective analgesics for the treatment of moderate‐to‐severe pain. However, the analgesic efficacy of opioids is well known to vary widely among individuals, and effective pain treatment is hampered by vast individual differences. Although these differences in opioid requirements have been attributed to various factors, genetic factors are becoming increasingly relevant to the development of genome science.

Association between rs2275913 single-nucleotide polymorphism of the interleukin-17A gene and perioperative analgesic use in cosmetic orthognathic surgery

Interleukin‐17A (IL‐17A) plays an essential role in tissue inflammation by inducing proinflammatory cytokine and chemokine production and is related to innate immune reactions. IL‐17A also contributes to neuroinflammation, neuropathic pain, and mechanical hypersensitivity after peripheral nerve injury in rodents. To clarify the contribution of IL‐17A to pain‐related phenotypes in humans, we investigated the association between pain‐related phenotypes and the rs2275913 single‐nucleotide polymorphism (SNP) of the IL‐17A gene, which has been reported to be associated with rheumatoid arthritis, ulcerative colitis, and some cancers.

Gamma-aminobutyric acid transaminase genetic polymorphism is a candidate locus for responsiveness to opioid analgesics in patients with cancer pain: An exploratory study

Cancer pain impairs not only physical functions but also social functions and roles. Consequently, the overall health‐related quality of life of patients with cancer pain deteriorates. Opioid analgesics are recommended for treating moderate to strong cancer pain. Advances in human genome research have fueled a growing interest to understand individual differences in responsiveness to opioid analgesics. This study aimed to explore and identify novel loci for genes predisposing an individual to opioid analgesic responsiveness.

Association between the rs7583431 single nucleotide polymorphism close to the activating transcription factor 2 gene and the analgesic effect of fentanyl in the cold pain test

Activating transcription factor 2 (ATF2) is a member of the leucine zipper family of DNA binding proteins and is widely distributed in tissues. Several recent studies have demonstrated that this protein is involved in mechanisms that are related to pain and inflammation. However, unclear is whether polymorphisms of the ATF2 gene, which encodes the human ATF2 protein, influence pain or analgesic sensitivity. This study examined associations between the analgesic effect of fentanyl in the cold pressor‐induced pain test and polymorphisms in the ATF2 gene in 355 Japanese subjects.