Opioid receptor and peptide gene polymorphisms: potential implications for addictions
Introduction
Many individuals are self-exposed to alcohol and drugs of abuse, and many continue to use alcohol or illicit drugs on an occasional, or even regular, basis; however, only some individuals develop specific addictions. For example, the latest report from the 1999 National Household Survey on Drug Abuse indicate that over 3 million persons in the United States have used heroin at some time in their life (SAMHSA, 2000); current estimates of heroin addicts in that country range from 0.8 to 1.2 million. Why do some become addicted following self-exposure while others do not?
Differences in individual variability to develop specific addictions have both an environmental and a heritable basis. Early twin and adoption studies established a role for heritability in alcoholism (e.g. Kaij, 1960, Partanen et al., 1966, Goodwin et al., 1973, Cloninger et al., 1981, Hrubec and Omenn, 1981, Cadoret et al., 1985). Heterogeneity of inheritance patterns in alcohol abuse disorders have been defined, with the highest heritability estimates for males Cloninger et al., 1981, Pickens et al., 1991. More recently, family, twin, and adoption studies have demonstrated that other substance abuse disorders also have, at least in part, a genetic basis (e.g. Cadoret et al., 1986, Grove et al., 1990, Tsuang et al., 1996, Bierut et al., 1998, Merikangas et al., 1998, Kendler and Prescott, 1998, Tsuang et al., 1998, Kendler et al., 1999). In a recent study of 3372 twin pairs, for example, evidence was found for a shared or common vulnerability for abuse of several types of drugs, with influences of genetic, family environmental, and non-family environmental factors. This shared vulnerability influenced susceptibility to abuse for different drugs to a different extent. In addition to the shared vulnerability, each drug had heritable influences specific to itself. Heroin abuse or dependence was found to have the highest genetic variance (54%), and also the highest degree of unique genetic influence, with 38% of the genetic variance specific to that drug (Tsuang et al., 1998).
Although a heritable basis for addictions has been established, the specific genes involved in the etiology of these disorders has not been well defined. Researchers have hypothesized that specific combinations of alleles of specific genes may result in innate differences in phenotypic expression of cellular or physiological systems known to be important in mediating the responses of drugs of abuse and alcohol; other studies have shown that opiates, cocaine, other drugs of abuse and alcohol profoundly alter physiological and cellular systems (see Kreek, 1996a, Kreek, 1996b, Kreek and Koob, 1998, Kreek, 2000). These changes are specific for the route and pattern of administration and length of time of exposure. Some of the induced alterations may be long lasting or even permanent. Therefore, cellular or physiological systems which show alterations in response to drugs of abuse and alcohol, and which might respond differently in individuals due to innate genetic differences that result from polymorphisms of any type, may also underlie the development of these disorders. One such system, the endogenous opioid system, is central in mediating the neurobiological and physiological responses to drugs of abuse and alcohol. Individual genetic differences that lead to functional differences in the endogenous opioid system may therefore be of interest as subjects for genetic studies of vulnerability to specific addictions. Human chromosomal locations for the identified endogenous opioid system genes (for the mu (μ-), delta (δ-), and kappa (κ-) opioid receptors and proopioimelanocortin (POMC), proenkephalin, and prodynorphin), are shown in Table 1. (For recent reviews of the endogenous opioid system and its functions, see Kreek, 1996b, Nestler and Aghajanian, 1997, Standifer and Pasternak, 1997, Akil et al., 1997, Massotte and Kieffer, 1998, Shippenberg and Elmer, 1998, Connor and Christie, 1999, Law and Loh, 1999.)
Section snippets
Polymorphisms in the human μ-opioid receptor gene
Because of the physiological significance of the μ-opioid receptor, particularly with respect to its role in mediating the analgesic and rewarding effects of opiate drugs, and also because of the evidence from quantitative trait locus (QTL) and knockout studies in mice (e.g. Belknap and Crabbe, 1992, Belknap et al., 1995, Berrettini et al., 1994, Matthes et al., 1996, Roberts et al., 2000), investigators have focused attention on this gene as a candidate in studies of polymorphism and potential
Population distributions of human opioid system gene alleles
Allelic frequencies of specific single nucleotide polymorphisms and other polymorphisms of the human opioid system genes have been shown to vary across populations. This is not an unexpected finding, since it is well know that specific allele frequencies often vary in different populations (e.g. Lin et al., 1994, Chu et al., 1998, Cargill et al., 1999, Halushka et al., 1999). Studies in diverse populations and ethnic groups have been described for specific common alleles of two of the opioid
μ-Opioid receptor gene polymorphisms and addictions
The human μ-opioid receptor gene has been a primary focus of studies of the potential association of endogenous opioid system genes with alcohol and drug abuse or dependence. With one exception (Bergen et al., 1997), all studies reported to date have used a classical case control association study design.
Berrettini et al. (1997) studied individuals with either opioid or cocaine dependence and matched control subjects. Research diagnostic criteria (RDC) diagnoses of opioid or cocaine dependence
Potential functional polymorphisms in the human μ-opioid receptor gene
The effects of polymorphisms in the human μ-opioid gene on receptor function has been studied in both in vitro assay systems and in clinical association studies with specific aspects of physiology that may have importance in addictions and other diseases.
In the first such study, we investigated the most frequent coding region variant identified to date, the A118G single nucleotide polymorphism, which results in the substitution of the amino acid asparagine to aspartic acid at amino acid
Discussion and conclusions
The terms “pharmacogenetics” and “pharmacogenomics” have come into common usage to describe genetic or genomic influences on individual variability in responses to medications used in the treatment of specific medical disorders. We have proposed the terms “physiogenetics” and “physiogenomics” to refer to the related concept of genetic or genomic influences on individual variability in physiological responses to endogenous substances such as neuropeptides or hormones Kreek, 2000, LaForge et al.,
Acknowledgements
The authors would like to thank S. Russo, S. Fung-Ho, B. Seides, and D. Nikaj for their assistance in the preparation of the manuscript, and A. Ho for critical reading. This work was supported in part by research grants from the United States National Institutes of Health: DA00049, DA05130, DA09444, DA12848 and RR00102.
References (97)
- et al.
Molecular and neuroanatomical properties of the endogenous opioid system: implications for treatment of opiate addiction
Semin. Neurosci.
(1997) - et al.
Expression of two variants of the human μ-opioid receptor mRNA in SK-N-SH cells and human brain
FEBS Lett.
(1994) - et al.
Chromosomal localization of the delta opioid receptor gene to human 1p34.3–p36.1 and mouse 4D bands by in situ hybridization
Genomics
(1994) - et al.
Localization to chromosome 10 of a locus influencing morphine analgesia in crosses derived from C57BL/6 and DBA/2 strains
Life Sci.
(1995) - et al.
μ opioid receptor: role for the amino terminus as a determinant of ligand binding affinity
Mol. Brain Res.
(2000) - et al.
Hypothalamic–pituitary adrenal axis hypersensitivity to naloxone in opioid dependence: a case of naloxone-induced withdrawal
Metabolism
(1997) - et al.
Characterization of human prodynorphin gene transcripts
Biochem. Biophys. Res. Commun.
(1995) - et al.
Population studies of polymorphisms at loci of neuropsychiatric interest (tryptophan hydroxylase (TPH), dopamine transporter protein (SLC6A3), D3 dopamine receptor (DRD3), apolipoprotein E (APOE), ( opioid receptor (OPRM1), and ciliary neurotrophic factor (CNTF))
Genomics
(1998) - et al.
Heritability of substance abuse and antisocial behavior: a study of monozygotic twins reared apart
Biol. Psychiatry
(1990) - et al.
Drug dependence: stress and dysregulation of brain reward pathways
Drug Alcohol Depend.
(1998)
Effects of chronic exogenous opioid administration on levels of one endogenous opioid (beta-endorphin) in man
Genetic variation of the human μ-opioid receptor and susceptibility to idiopathic absence epilepsy
Epilepsy Res.
μ-opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal
Psychoneuroendocrinology
G proteins and opioid receptor-mediated signalling
Cell. Signalling
Isolation and structural organization of the human corticotropin-β-lipotropin precursor gene
FEBS Lett.
Human μ opiate receptor: cDNA and genomic clones, pharmacologic characterization and chromosomal assignment
FEBS Lett.
Localization of the kappa opioid receptor gene to human chromosome band 8q11.2
Genomics
Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations
Eur. J. Clin. Pharmacol.
Chromosome mapping of gene loci affecting morphine and amphetamine responses in BXD recombinant inbred mice
Ann. N. Y. Acad. Sci.
μ opioid receptor gene variants: lack of association with alcohol dependence
Mol. Psychiatry
Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains
Nat. Genet.
Human mu opioid receptor gene polymorphisms and vulnerability to substance abuse
Addict. Biol.
Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking
Arch. Gen. Psychiatry
Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction
Proc. Natl. Acad. Sci. U. S. A.
Alcoholism and antisocial personality
Arch. Gen. Psychiatry
An adoption study of genetic and environmental factors in drug abuse
Arch. Gen. Psychiatry
Characterization of single-nucleotide polymorphisms in coding regions of human genes
Nat. Genet.
Allele frequencies of the preproenkephalin A (PENK) gene CA repeat in Asians, African-Americans, and Caucasians: lack of evidence for different allele frequencies in alcoholics
Alcohol Clin. Exp. Res.
Genetic relationship of populations in China
Proc. Natl. Acad. Sci. U. S. A.
Inheritance of alcohol abuse: cross-fostering analysis of adopted men
Arch. Gen. Psychiatry
Primary structure of the human proenkephalin gene
DNA
The proenkephalin gene (PENK) and opioid dependence
NeuroReport
Opioid receptor signalling mechanisms
Clin. Exp. Pharmacol. Physiol.
Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity
Int. J. Obes.
Evidence of selection on silent site base composition in mammals: potential implications for the evolution of isochores and junk DNA
Genetics
A DNA polymorphism in close physical linkage with the proopiomelanocortin gene
Am. J. Hum. Genet.
DNA restriction fragment analysis of the proopiomelanocortin gene in schizophrenia and bipolar disorders
Am. J. Hum. Genet.
Human δ-opioid receptor gene and susceptibility to heroin and alcohol dependence
Neuropsychiatr. Genet.
Prodynorphin allelic distribution in Scandinavian chronic alcoholics
Alcohol Clin. Exp. Res.
Genetics of two μ opioid receptor gene (OPRM1) exon 1 polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects
Mol. Psychiatry
Alcohol problems in adoptees raised apart from alcoholic biological parents
Arch. Gen. Psychiatry
“Cryptic” repeating triplets of purines and pyrimidines (cRRY(i)) are frequent and polymorphic: analysis of coding cRRY(i) in the proopiomelanocortin (POMC) and TATA-binding protein (TBP) genes
Am. J. Hum. Genet.
Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis
Nat. Genet.
Systematic mutation screening of the pro-opiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes
J. Clin. Endocrinol. Metab.
Normal variation in leptin levels is associated with polymorphisms in the proopiomelanocortin gene, POMC
J. Clin. Endocrinol. Metab.
Isolation and structural organization of the human preproenkephalin B gene
Nature
Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans
Alcohol Clin. Exp. Res.
SSCP analysis: a blind sensitivity trial
Hum. Mutat.
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