Opioid receptor and peptide gene polymorphisms: potential implications for addictions

Abstract

Addictions to drugs of abuse and alcohol have been shown by studies of genetic epidemiology to have both a heritable and an environmental basis, with these factors influencing addiction to different substances to a different extent. In the search for specific alleles of specific genes that may contribute to the development of the addictions, many researchers have focused on the endogenous opioid system, which mediates a diverse array of neurological, physiological, and behavioral functions. The endogenous opioid system is also centrally important in mediating the effects of drugs of abuse and alcohol. Polymorphisms, including single nucleotide polymorphisms, have been identified in genes of the endogenous opioid receptors and peptides. A number of recent genetic association studies and a few studies of potential function provide clues as to which genes and which alleles may have implications for human physiology and pathophysiology, including the 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.)