Opioid abuse and brain gene expression

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Abstract

Opiate addiction is a central nervous system disorder of unknown mechanism. Neuronal basis of positive reinforcement, which is essential to the action of opioids, relies on activation of dopaminergic neurons resulting in an increased dopamine release in the mesolimbic brain structures. Certain aspects of opioid dependence and withdrawal syndrome are also related to the activity of noradrenergic and serotonergic systems, as well as to both excitatory and inhibitory amino acid and peptidergic systems. The latter pathways have been recently proven to be involved both in the development of dependence and in counteracting the states related to relapse. An important role in neurochemical mechanisms of opioid reward, dependence and vulnerability to addiction has been ascribed to endogenous opioid peptides, particularly those acting via the mu- and kappa-opioid receptors. Opiate abuse leads to adaptive reactions in the nervous system which occur at the cellular and molecular levels. Recent research indicates that intracellular mechanisms of signal transmission—from the receptor, through G proteins, cyclic AMP, MAP kinases to transcription factors—also play an important role in opioid tolerance and dependence. The latter link in this chain of reactions may modify synthesis of target genes and in this manner, it may be responsible for opiate-induced long-lasting neural plasticity.

Introduction

Addiction to drugs, including opiates, is a brain disease resulting in a loss of control over drug-taking or in compulsive drug-seeking, despite noxious consequences (Nestler, 2000). It is a serious social burden and has destructive influence on health and standard of living of an inflicted person. Costs of drug dependence are high both to an individual and to the society. Society bears partial or total costs of healthcare but a price paid by an addict is incomparably higher. He or she pays with devastated health on the one hand and on the other, with difficult to measure deterioration of their adaptive abilities.

Opioid dependence makes permanent physiological and psychological alterations leading to dramatic relapses of the disease. Uncontrollable compulsion to take the drug and anxiety of craving and relapse are characteristics of the use of opiates. Efficient treatment methods curing of the disease and fending off relapses and preventive measures counteracting development of dependence are not yet accessible. The present clinical treatment permits efficient detoxification, i.e. the removal of an addictive substances from the organism and liberation of a person from negative symptoms of drug withdrawal. In the case of opiate addiction, very high percentage of patient backslides to the drug use. Thus, the understanding of opioid addiction is critical for development of efficient pharmacological therapy. Addiction to morphine, heroin and other compounds acting via opioid receptors is a disease of unknown mechanisms. Numerous studies are based on animal models of various stages of addictive behavior since they well imitate phases of the development of the disease in humans. The results of animal behavioral experiments, correlated with molecular and clinical genetic studies, may lead to better understanding the disease. Many years of research led us to better understanding of a brain substrate and molecular mechanisms of opioid dependence. The main objective of investigations carried out by many research teams worldwide is to discover neuronal and molecular mechanisms of the disease. These adaptive changes underlie neuronal and molecular alterations that manifest themselves as behavioral syndromes, such as opioid dependence. Recent research has focused on a role of gene expression in mediating long-lasting opioid-induced neuronal plasticity. Understanding the molecular and genetic mechanisms of opioid abuse is critical to creation of a novel efficient therapy.

Section snippets

Neuronal bases of opioid dependence

The brain network mediating the rewarding properties of drugs and craving phenomena and the reinforcing properties of addictive drugs of abuse has been identified (Wise and Bozarth, 1987, Koob, 1992, Samson and Harris, 1992). The system was shown to involve such structures as the nucleus accumbens, ventral tegmental area, prefrontal cortex and limbic structures, in particular the so-called “extended” amygdala.

The mesolimbic system consists of dopaminergic neurons found in the ventral tegmental

Endogenous opioid systems and reward

The endogenous opioid systems play a key role in modulating reward, mood and regulate the brain hedonic homeostasis (Koob and Le Moal, 1997). Alterations of the endogenous systems following exposure to drugs of abuse appear to contribute to the dysregulation of the reward processes which may participate in the development of addiction (Przewlocka et al., 1996, Koob and Le Moal, 1997, Herz, 1997, Turchan et al., 1997, Turchan et al., 1999, Van Ree et al., 2000, Gianoulakis, 2004).

A family of endogenous opioid peptides

Opioid peptides derive from three different precursor proteins: proopiomelanocortin (POMC), proenkephalin and prodynorphin. POMC is the precursor of endorphins (β-endorphin, α-endorphin) and a family of non-opioid peptides, melanocortins: α, β and γ melanocyte stimulating hormone (MSH) and adrenocorticotropin releasing hormone (ACTH). proenkephalin is a source of both enkephalins and several longer opioid peptides, such as Met-enkephalin-Arg-Phe. Dynorphin A, dynorphin B, α- and β-neoendorphin

Effect of morphine on opioid peptide systems in the brain reward circuit

Proenkephalin- and POMC-containing neurons localized within the ventral tegmental area dopamine system modulate activity of dopaminergic neurons. The increase of their activity may indirectly enhance dopamine release. The prolonged administration of exogenous opiates appears to inhibit the biosynthesis of the opioid peptides which in consequence may lead to the shortage of endogenous opioid peptide agonists at the mu-opioid receptors localized in the reward system and therefore inhibition of

Multiple opioid receptors

Three members of the opioid receptor family have been identified (Snyder and Pasternak, 2003) beginning with the delta-opioid receptor (Evans et al., 1992, Kieffer et al., 1992) and followed by cloning of mu-opioid receptor (Chen et al., 1993a, Chen et al., 1993b, Fukuda et al., 1993) and kappa-opioid receptor (Li et al., 1993, Meng et al., 1993, Minami et al., 1993, Nishi et al., 1993). In addition to the well-established three types of opioid receptors, an orphan opioid-like nociceptin

Effect of morphine on opioid receptors

Opioids may interact with opioid receptors causing alterations of receptor internalization (Burford et al., 1998, Koch et al., 1998), binding or postranslational modification and its biosynthesis (Buzas et al., 1996). Several authors have shown that after chronic treatment of rats with morphine or etorphine, mu-opioid receptors in some brain structures were down-regulated (Patel et al., 2002, Bhargava and Gulati, 1990, Tao et al., 1987, Tao et al., 1988, Bernstein and Welch, 1998) while the

Dopaminergic pathways

The principal neural effect of opiates consists in the stimulation dopaminergic neurons in the ventral tegmental area and an increase in the release of dopamine in the nucleus accumbens, which in result leads to a reward response (Herz, 1998, Xie et al., 1998, Piepponen et al., 1999). This effect can result from an indirect effect of opioids by modifying activity of certain populations of GABAergic interneurons that interact with dopaminergic ventral tegmental area neurons. The response to

Molecular basis of opioid addiction

For understanding of opioid addiction, it is important to characterize opioid-induced molecular and cellular adaptations in the specific neuronal network involved in the changes of behaviors associated with opioid addiction. Recent studies indicate that exposure to opiates leads to short- and long-term adaptive changes in the intracellular signaling pathways. Acute activation of opioid receptors inhibits cAMP signaling as well as alters voltage gated Ca2+ channel function and activates K+

Regulation of gene expression by opioids

Acute and chronic morphine administration leads to dynamic changes in the immediate-early gene expression in the nucleus accumbens, prefrontal cortex and in several additional forebrain regions, including portions of the extended amygdala. The altered expression of transcription factors resulted in adaptive changes in the expression of membrane receptors, channels, intracellular signaling proteins and plethora of target genes within the mesolimbic system (Przewlocka et al., 1994, Turchan et

Striatum

Loguinov et al. (2001) using Affymetrix microarrays (GMS 417; Affymetrix) analyzed a gene expression profile in the striatum of mice after a single injection of morphine. It was found that two groups of genes encoding proteins involved in mitochondrial respiration and cytoskeleton-related proteins were transiently down-regulated.

More recently, another study was concerned with the long-lasting changes in gene expression after intermittent exposure to morphine in the rat (Spijker et al., 2004).

Acknowledgement

This paper was supported by KBN, Warsaw, grant no. 6 P05A 107 20 and PBZ-KBN-033/P05/2000.

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