Opioid Use Disorder __________________________________________________________________________
increasingly severe, withdrawal-induced negative affective state may reinforce continued drug taking and directly contribute to the development of dependence [82]. Molecular Basis The diverse biologic effects of opioids are manifested through specific opioid receptors distributed throughout the central and peripheral nervous system. Opioid receptors, upon the binding of opioid drugs (or endogenous opioid peptides), regu- late a multitude of intracellular signaling pathways. Involve- ment of opioid receptors in opioid dependence is unequivocal. This is reliably demonstrated by the rapid precipitation of withdrawal syndromes in opioid addicts by opioid receptor antagonists such as naloxone [83]. Repeated exposure to short-acting opioids can result in durable alterations in opioid receptor kinetics, transmembrane signaling, and postreceptor signal transduction [84]. Opioid dependence requires sustained activation of opioid receptors, and this chronic signaling process ultimately leads to changes in protein functions of gene transcription [83]. Opioid receptors are members of the G-protein receptor family, and each opioid receptor uses inhibitory G-proteins for signal transduction. Opioid receptors have the capacity to interact with five different forms of G-proteins, regulating a diverse spectrum of effectors ranging from adenylyl cyclases and ion channels to mitogen-activated protein kinases. These isoform-specific and differential regulations of various classes of effectors are combined into a sophisticated signaling net- work that mediates opioid actions. The enormous diversity in opioid signaling stems from the array of effectors and signaling molecules that functionally interact with the G-protein beta gamma complex [83]. Prolonged administration of opioids causes molecular and cellular adaptations that rapidly develop into tolerance and dependence. An upregulation of adenylyl cyclase responsive- ness, referred to as adenylyl cyclases superactivation, is a classic sign of this tissue adaptation [83]. G-protein signals lead to changes in gene expression, and opioid-induced, long-term functional alterations of the nervous system involve changes in gene expression. Many opioid-induced signals converge at the level of transcription factors, although little is known about the exact mechanisms of gene transcription in the development of opioid tolerance and dependence [83]. Mechanism of Reinforcement Drugs with an abuse liability have habit-forming actions that can be localized in a variety of brain regions. Drugs of abuse mimic or enhance the actions of endogenous chemical mes- sengers in the brain [85]. The mesolimbic dopamine system is the likely substrate upon which opioids act to produce their reinforcing effects. Both the positive (rewarding) and negative (aversive) reinforcement of opioid mu- and kappa-receptor agonists are mediated by the mesolimbic dopamine system [81].
PATHOPHYSIOLOGY
OPIOID TOLERANCE Tolerance refers to a decrease in effectiveness of a drug with repeated administration. Tolerance to opioid effects is encoun- tered in both the clinical use of opioids for pain relief and in recreational use of heroin [51]. Tolerance (as well as withdrawal and physiologic dependence) are expected responses to opioids and other controlled substances when given in sufficient doses over time and are not, by themselves, indicative of addiction [78; 79]. Acute tolerance stems from transient administration of opioids; sustained administration leads to the development of classical or chronic tolerance. Short-term receptor desensi- tization may underlie the development of tolerance, probably involving phosphorylation of the mu and delta receptors by protein kinase C, protein kinase A, and beta-adrenergic receptor kinase (beta ARK). Long-term tolerance is believed to be associated with increases in adenylyl cyclase activity, a counter-regulation to the decrease in cyclic adenosine mono- phosphate levels [9]. The degree of tolerance can be influenced by changes in the environment in which drug use occurs. In the presence of cues previously associated with drug ingestion, tolerance is markedly enhanced, compared to the tolerance observed in a novel environment. Thus, administration of an opioid in an environment not previously associated with administration of the drug will be associated with lower tolerance and therefore a higher risk of overdose [51]. OPIOID DEPENDENCE Opioid dependence is best described as a central nervous sys- tem disorder characterized by neurobiologic changes leading to compulsive drug-taking behaviors. As the result of chronic use, the cells producing endogenous opioids cease to function and degenerate, causing the user to become physically dependent on exogenous opioids [80]. According to the classical theory of addiction, opioid depen- dence results from the need to reduce distress, as withdrawal is a physical expression of distress. This is referred to as negatively reinforced behavior. This hypothesis has been challenged by the finding that the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Additionally, the motivational aspects of withdrawal are inde- pendent of the intensity and pattern of the physical symptoms of withdrawal [81]. Alternative hypotheses focus on the role of the mesocortico- limbic dopamine system, an anatomical pathway that origi- nates from the ventral tegmental area in the midbrain and projects to several forebrain regions, including the nucleus accumbens and medial prefrontal cortex [81]. Dependence on most drugs of abuse is characterized by an altered physiologic state inferred from the emergence of a withdrawal syndrome following cessation of drug administration. Alleviation of an
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MDRI2026
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