Studies concerning drugs of abuse have made major contributions in defining the circuitry, as well as cellular and molecular substrates that underlie certain behaviors. Opiate drugs for example, have revealed important insights concerning pain perception and reward. Up to the late 1960s, opiate drugs were suspected to work by mysteriously perturbing lipid membrane structure. We now know the following: the sequence and neuroanatomy of the G-protein coupled receptors that mediate opiate effects; that many proteins interact with opioid receptors such as G-protein sub-unit combinations, G-protein receptor kinases, arrestins and calmodulin; that many signaling molecules are modulated by opioid receptors, including ion channels, kinase cascades and adenyl cyclase. More than 20 different peptides, excised from three precursor proteins by specific proteases, have been shown to be endogenous ligands for opioid receptors. Revealing the molecules of the endogenous opioid system has inspired efforts for developing new opioid analgesics with the hope of minimizing abuse potential. This article will detail the current rationale for searching for less-addictive opiate analgesics and speculate on the future of drug abuse research in furthering our understanding of neural plasticity and the underpinnings of addictive behavior.
"Later, interest focused on the intracellular effectors that mediate the activation of signaling cascades. It has been suggested that these post-transductional mechanisms are closely linked to the development of opiate tolerance and dependence on opiate drugs, mainly through the same plasticity mechanisms that produce adaptive changes in neural circuitries, for example, in memory and learning (Evans, 2004). After more than 40 years of intense research on opiates, scientists now partly understand their mechanism of action on receptors. "
[Show abstract][Hide abstract] ABSTRACT: When we talk about drug addiction, we are really dealing with an extremely complex system in which there still remain many unknowns and where many empty spaces or missing links are still present. Recent studies have identified changes in the expression profiles of several specific miRNAs which affect the interactions between these molecules and their targets in various illnesses, including addiction, and which may serve as valuable targets for more efficient therapies. In this review, we summarize results which clearly demonstrate that several morphine-related miRNAs have roles in the mechanisms that define addiction. In this regard, morphine has been shown to have an important role in the regulation of different miRNAs, such as miR-let-7 [which works as a mediator of the movement of the mu opioid receptor (MOR) mRNA into P-bodies, leading to translational repression], miR-23b (involved in linking MOR expression and morphine treatment at the post-transcriptional level), and miR-190 (a key post-transcriptional repressor of neurogenic differentiation, NeuroD). Fentanyl increases NeuroD levels by reducing the amount of miR-190, but morphine does not affect the levels of NeuroD. We also discuss the relationship between morphine, miRNAs, and the immune system, based on the discovery that morphine treatment of monocytes led to a decrease in several anti-HIV miRNAs (mir-28, 125b, 150, and 382). This review is centered on miR-133b and its possible involvement in addiction through the effects of morphine. We establish the importance of miR-133b as a regulatory factor by summarizing its activity in different pathological processes, especially cancer. Using the zebrafish as a research model, we discuss the relationship between mir-133b, the dopaminergic system, and morphine, considering: (1) that morphine modulates the expression of miR-133b and of its target transcript Pitx3, (2) the role of the zebrafish mu opioid receptor (zfMOR) in morphine-induced regulation of miR-133b, which depends on ERK1/2, (3) that morphine regulates miR-133b in hippocampal neurons, and (4) the role of delta opioid receptors in morphine-induced regulation of miR-133b. We conclude that the control of miR-133b levels may be a mechanism for the development of addiction to morphine, or other drugs of abuse that increase dopaminergic levels in the extracellular space. These results show that miR-133b is a possible new target for the design of new treatments against addictive disorders.
Frontiers in Genetics 11/2012; 3:223. DOI:10.3389/fgene.2012.00223
"Partial correlation controlling the group difference and moderator analysis indicated that this association is not due to sample pooling. It was proposed that lipids have functions related to drug abuse, including neuromodulator action in the synaptic plasticity and involvement in phenotypic alterations (Hillard, 2005), perturbing the membrane structure (Evans, 2004), and their effect on the circulating serotonin levels and fatty acid changes (Buydens-Branchey and Branchey, 2003). However, the blood-brain barrier is impermeable to plasma lipoproteins and so any changes in dietary cholesterol alter the plasma but not brain cholesterol (Edmond et al., 1991). "
[Show abstract][Hide abstract] ABSTRACT: Objective:
Lipids may play some roles in the central nervous system functions that are associated with drug addiction. To date, cholesterol is known to influence relapse of cocaine use. However, the relationship between cholesterol and heroin craving is unclear. This study examined the concurrent association between cholesterol and craving.
The serum lipid levels of 70 heroin users who were undergoing or had undergone a methadone maintenance therapy were measured. Their craving and demographic data were assessed.
Total cholesterol and low-density lipoprotein cholesterol are negatively associated with craving before (r = -0.33, P < 0.01, and r = -0.36, P < 0.01, respectively) and after controlling for the effects of potential confounders (β = -0.38, P < 0.01, and β = -0.42, P < 0.01, respectively).
Cholesterol could be associated with the cognitive aspect of craving and may be a potential marker to predict risk of drug relapse.
Journal of Addiction Medicine 08/2012; 6(4). DOI:10.1097/ADM.0b013e318262a9a1 · 1.76 Impact Factor
"One of the initial observations was found in cell lines containing the delta opioid receptor whereby treatment with several opioid peptides and alkaloid agonists but not morphine induced loss of surface opioid binding (Von Zastrow et al., 1993). Subsequently, many agonist-selective receptor-mediated effects have been documented, including receptor phosphorylation, receptor trafficking, receptor signaling and receptor desensitization (Evans, 2004). Research indicating that the same drug can induce different complexes in different environments is less well documented, but has been implicated in a study of mu receptor trafficking in dendrites and cell bodies. "
[Show abstract][Hide abstract] ABSTRACT: There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.
Drug and alcohol dependence 02/2010; 108(3):156-65. DOI:10.1016/j.drugalcdep.2010.01.001 · 3.42 Impact Factor
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