Review
The endogenous opioid system: A common substrate in drug addiction

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Abstract

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.

Introduction

Drug addiction is a chronic brain disorder characterized by the compulsive use of drugs in spite of their adverse consequences, loss of control over drug taking and relapse even after long periods of drug abstinence. Drug addiction can be viewed as the result of a series of transitions from voluntary use in search of a hedonic experience, to loss of control over this behavior, and ultimately to habitual and compulsive behavior (see Everitt et al., 2008 for review). There are various risk factors that determine whether an individual will become addicted to drugs. Thus, vulnerability to addiction is influenced by genetic and environmental factors, as well as by the developmental stage of a person or by comorbid mental disorders (see Volkow and Li, 2005 for review). Research into the neurobiological mechanisms involved in drug addiction is crucial for developing new treatment strategies for the management of this chronic and relapsing brain disorder.

Section snippets

Mesolimbic system and addiction theories

The mesolimbic dopamine (DA) system has been implicated in the reinforcing properties of most drugs of abuse. Indeed, the main prototypical drugs that are self-administered by experimental animals and humans such as alcohol, nicotine, opioids, cannabinoids and psychostimulants increase DA activity and extracellular levels predominantly in the shell portion of the nucleus accumbens (Nacc) (see Di Chiara et al., 2004 for review), which has been related to their reinforcing effects. There is

The endogenous opioid system

Opioid receptors and their endogenous peptide ligands are largely distributed through the CNS and peripheral tissues. This wide distribution is related to the important role that the opioid system plays in the control of several physiological responses including nociception, emotional behavior, learning and memory and regulation of reward circuits (see Bodnar, 2008 for review). The existence of membrane receptors in the brain for opiate drugs was shown for the first time in 1973 by three

Endogenous opioid system in opioid addiction

The exogenous administration of classical opioid compounds, such as morphine, activates the mesolimbic reward system mainly by stimulating opioid receptors in the VTA and Nacc (Bozarth, 1987) (Fig. 1). More specifically, opioids facilitate DA release by activating μ- and δ-opioid receptors in the Nacc (Hirose et al., 2005, Murakawa et al., 2004, Okutsu et al., 2006, Yoshida et al., 1999), and by decreasing GABA-inhibition via μ-opioid receptors in the VTA (Bonci and Williams, 1997, Johnson and

Endogenous opioid system in alcohol addiction

Ethanol shares with other drugs of abuse the ability to increase extracellular levels of DA in the Nacc, and this effect is modulated by the EOS. Indeed, the administration of μ- and δ-opioid antagonists such as naltrexone and naltrindole decreases the ethanol-induced enhancement of DA extracellular levels in the Nacc in rats (Acquas et al., 1993, Benjamin et al., 1993, Gonzales and Weiss, 1998, Lee et al., 2005). On the other hand, the reinforcing effects of ethanol were abolished in mice

Endogenous opioid system in nicotine addiction

Pharmacological studies have described that nicotine administration enhances the release of endogenous opioids at central and peripheral levels. Nicotine increases plasma concentrations of β-endorphin in rats (Conte-Devolx et al., 1981), and humans (Backon, 1989, del Arbol et al., 2000). However, changes at peripheral levels of β-endorphin do not seem directly related to the central activity of the EOS, and have been more likely related to a peripheral response to stress (Rasmussen and Farr,

Endogenous opioid system in addiction to psychostimulants

Psychostimulants directly affect mesolimbic DA activity by binding to monoamine transporters and blocking reuptake mechanisms (Tanda et al., 2000), and their reinforcing properties are primarily dependent on the activation of this system (Di Chiara et al., 2004). However, recent evidence highlights the relevance of other neurotransmitters that converge with the dopaminergic system to mediate the rewarding properties of psychostimulants, including the EOS (Boutrel, 2008). It has been well

Endogenous opioid system in cannabinoid addiction

The addictive properties of cannabinoids are directly related to the activation of CB1 receptors, which are extensively expressed in the CNS, including the reward circuits (see Maldonado et al., 2006 for review). Anatomical studies have found an overlapping distribution of CB1 and μ-opioid receptors in the limbic system, where functional coupling and bidirectional interactions between these two systems have been reported (Pickel et al., 2004, Rodríguez et al., 2001, Salio et al., 2001). The EOS

Concluding remarks

The EOS plays a crucial role in several aspects of the addictive process induced by prototypical drugs of abuse. Exposure to these drugs modifies the activity of the EOS, and produces adaptive changes that play an important role in the development of addiction. The μ-opioid receptor is the primary mediator of the rewarding properties of opioid compounds and also of their capability to produce physical dependence. These μ-opioid receptors are also critically involved in the rewarding properties

Role of funding source

This work was supported by the Spanish “Ministerio de Ciencia e Innovación” (#SAF2007-64062) and “Instituto de Salud Carlos III” (#RD06/001/001 to R.M., PI070709 to P.R., PI070559 to F.B.), the Catalan Government (SGR2009-00131), the ICREA Foundation (ICREA Academia-2008) and the DG Research of the European Commission (NEWMOOD LSHM-CT-2004-503474; GENADDICT, #LSHM-CT-2004-05166; and PHECOMP, #LSHM-CT-2007-037669). Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Catalan

Conflict of interest

R.M. has been external advisor from Sanofi-Aventis, and Dr Esteve laboratories, and has received grants Sanofi-Aventis, Dr Esteve laboratories and Ferrer laboratories. All the other authors declare that they have no conflicts of interest.

Contributors

J.M.T. managed the literature searches for Sections 2 Mesolimbic system and addiction theories, 4 Endogenous opioid system in opioid addiction, 5 Endogenous opioid system in alcohol addiction, 8 Endogenous opioid system in cannabinoid addiction, and contributed to write and organize the first draft of the manuscript. E.M. managed the literature searches for Sections 3 The endogenous opioid system, 6 Endogenous opioid system in nicotine addiction, 8 Endogenous opioid system in cannabinoid

Acknowledgements

J.M.T. and E.M. are post-doctoral fellows of Instituto de Salud Carlos III “Contratos posdoctorales de perfeccionamiento Sara Borrell”. We would like to thank Neus Morgui for her excellent assistance in preparation of the manuscript.

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