title: Single-nucleotide polymorphism (A118G) in exon 1 of OPRM1 gene causes alteration in downstream signaling by mu-opioid receptor and may contribute to the genetic risk for addiction.
abstract: The opioid receptor mu1 (OPRM1) mediates the action of morphine. Although genetic background plays an important role in the susceptibility toward abuse of drugs as evident from familial, adoption and twin studies, association of specific single-nucleotide polymorphisms of OPRM1 gene with narcotic addiction is to be established. Here, we demonstrate the involvement of A118G polymorphism of exon1 of human OPRM1 gene (hOPRM1), with heroin and alcohol addiction, in a population in eastern India. Statistical analysis exhibited a significant association of G allele with both heroin and alcohol addiction with a risk factor of P(trend) < 0.05. The functional significance of G allele in A118G single-nucleotide polymorphisms was evaluated by studying the regulation of protein kinase A (PKA), pCREB, and pERK1/2 by morphine in Neuro 2A cells, stably transfected with either wild type or A118G mutant hOPRM1. Unlike acute morphine treatment, both chronic morphine exposure and withdrawal precipitated by naloxone were differentially regulated by A118 and G118 receptor isoforms when both PKA and pERK1/2 activities were compared. Results suggest that the association of A118G polymorphism to heroin and alcohol addiction may be because of the altered regulation of PKA and pERK1/2 during opioid and alcohol exposures.
authors.affiliation: Neurobiology Division, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Ishani
authors.initials: I
authors.lastname: Deb
authors.forename: Japashish
authors.initials: J
authors.lastname: Chakraborty
authors.forename: Prasanta Kumar
authors.initials: PK
authors.lastname: Gangopadhyay
authors.forename: Susanta Roy
authors.initials: SR
authors.lastname: Choudhury
authors.forename: Sumantra
authors.initials: S
authors.lastname: Das
mesh_terms: D000328:Adult; D000818:Animals; D016001:Confidence Intervals; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D009447:Neuroblastoma; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011869:Radioligand Assay / Q000379:methods; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D019966:Substance-Related Disorders / Q000145:classification / Q000209:etiology* / Q000235:genetics*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases