Showing papers on "Opiate published in 2011"

The dopamine hypothesis of drug addiction and its potential therapeutic value.

Abstract: Dopamine (DA) transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid and other drug-dependent rats. Further, DA release in the Nacc is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS) thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the Medium Spiny Neuron (MSN) of the Nucleus accumbens (Nacc), post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin and alcohol-dependent subjects, thereby offering visual proof of the ‘dopamine-impoverished’ addicted human brain. The reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse and drug-seeking/taking). In theory, it may be achieved pharmacologically and/or with novel interventions such as Transcranial Magnetic Stimulation (TMS). Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts.

Opiate-receptor mediated changes in monoamine synthesis in rat brain.

Abstract: The effects of morphine, β-endorphin, naloxone and naltrexone on the rate of tyrosine and tryptophan hydroxylation were investigated in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan (5-HTP) in different brain regions of rats after inhibition of the aromatic L-amino acid decarboxylase. The cerebral concentrations of tyrosine and tryptophan were also measured. Morphine (3–30 mg kg−1) increased the accumulation of dopa dose-dependently (25–50%) in the dopamine-rich areas (limbic forebrain and corpus striatum). In the noradrenaline-predominant parts of the brain (containing hemispheres, diencephalon and lower brain stem) only the highest dose of morphine (30 mg kg−1) significantly increased dopa formation (47%). Similarly to morphine, intracerebroventricularly injected β-endorphin (5–10 βg per rat) increased the formation of dopa. This increase was doubled in limbic forebrain, corpus striatum and cerebral hemispheres. Doses of 10 to 20 μg of β-endorphin were needed to increase dopa accumulation in the diencephalon and the lower brain stem. Naloxone antagonized the β-endorphin-induced increases in dopa. But naloxone and naltrexone (10–100 mg kg−1) decreased the dopa formation in the dopamine-rich areas (about 20–25 %) but not in the noradrenaline-predominant areas. Morphine (30 mg kg−1) and β-endorphin (5 μg per rat) increased the accumulation of 5-HTP whereas naloxone and naltrexone (10 mg kg−1) tended to decrease its formation. Morphine and β-endorphine increased the concentrations of tyrosine and tryptophan, and naloxone decreased the cerebral tryptophan concentration. These results show that the effects of a narcotic agonist (morphine) and of pure narcotic antagonists (naloxone and naltrexone) on the synthesis of dopamine and 5-HT are opposite to each other. Furthermore, the effects of β-endorphine on brain monoamine synthesis are remarkably similar to those of morphine. Thus, it is probable that opiate receptors and their endogenous ligands are involved in the regulation of dopamine and 5-HT synthesis.

Identification of a Dopamine Receptor-Mediated Opiate Reward Memory Switch in the Basolateral Amygdala–Nucleus Accumbens Circuit

Abstract: The basolateral amygdala (BLA), ventral tegmental area (VTA), and nucleus accumbens (NAc) play central roles in the processing of opiate-related associative reward learning and memory. The BLA receives innervation from dopaminergic fibers originating in the VTA, and both dopamine (DA) D1 and D2 receptors are expressed in this region. Using a combination of in vivo single-unit extracellular recording in the NAc combined with behavioral pharmacology studies, we have identified a double dissociation in the functional roles of DA D1 versus D2 receptor transmission in the BLA, which depends on opiate exposure state; thus, in previously opiate-naive rats, blockade of intra-BLA D1, but not D2, receptor transmission blocked the acquisition of associative opiate reward memory, measured in an unbiased conditioned place preference procedure. In direct contrast, in rats made opiate dependent and conditioned in a state of withdrawal, intra-BLA D2, but not D1, receptor blockade blocked opiate reward encoding. This functional switch was dependent on cAMP signaling as comodulation of intra-BLA cAMP levels reversed or replicated the functional effects of intra-BLA D1 or D2 transmission during opiate reward processing. Single-unit in vivo extracellular recordings performed in neurons of the NAc confirmed an opiate-state-dependent role for BLA D1/D2 transmission in NAc neuronal response patterns to morphine. Our results characterize and identify a novel opiate addiction switching mechanism directly in the BLA that can control the processing of opiate reward information as a direct function of opiate exposure state via D1 or D2 receptor signaling substrates.

Powerful behavioral interactions between methamphetamine and morphine.

Abstract: Use of drugs of abuse in combination is common among recreational users and addicts. The combination of a psychomotor stimulant with an opiate, known as a 'speedball,' reportedly produces greater effects than either drug alone and has been responsible for numerous deaths. Historically, the most popular speedball combination is that of cocaine and heroin. However, with the growing popularity of methamphetamine in recent years, there has been increased use of this drug in combination with other drugs of abuse, including opiates. Despite this, relatively little research has examined interactions between methamphetamine and opiates. In the current research, behavioral interactions between methamphetamine and the prototypical opiate, morphine, were examined across a variety of dose combinations in Sprague-Dawley rats. The combination of methamphetamine and morphine produced stimulation of behavior that was dramatically higher than either drug alone; however, the magnitude of the interaction was dependent on the dose of the drugs and the specific behaviors examined. The results demonstrate complex behavioral interactions between these drugs, but are consistent with the idea that this combination is used because it produces a greater effect than either drug alone.

Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

Abstract: A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.

A Unique Role of RGS9-2 in the Striatum as a Positive or Negative Regulator of Opiate Analgesia

Abstract: The signaling molecule RGS9-2 is a potent modulator of G-protein-coupled receptor function in striatum. Our earlier work revealed a critical role for RGS9-2 in the actions of the μ-opioid receptor (MOR) agonist morphine. In this study, we demonstrate that RGS9-2 may act as a positive or negative modulator of MOR-mediated behavioral responses in mice depending on the agonist administered. Paralleling these findings we use coimmunoprecipitation assays to show that the signaling complexes formed between RGS9-2 and Gα subunits in striatum are determined by the MOR agonist, and we identify RGS9-2 containing complexes associated with analgesic tolerance. In striatum, MOR activation promotes the formation of complexes between RGS9-2 and several Gα subunits, but morphine uniquely promotes an association between RGS9-2 and Gαi3. In contrast, RGS9-2/Gαq complexes assemble after acute application of several MOR agonists but not after morphine application. Repeated morphine administration leads to the formation of distinct complexes, which contain RGS9-2, Gβ5, and Gαq. Finally, we use simple pharmacological manipulations to disrupt RGS9-2 complexes formed during repeated MOR activation to delay the development of analgesic tolerance to morphine. Our data provide a better understanding of the brain-region-specific signaling events associated with opiate analgesia and tolerance and point to pharmacological approaches that can be readily tested for improving chronic analgesic responsiveness.

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.

Abstract: Background:Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into mor

An Anatomical Basis for Opponent Process Mechanisms of Opiate Withdrawal

Abstract: Opponent process theory predicts that the first step in the induction of drug withdrawal is the activation of reward-related circuitry. Using the acoustic startle reflex as a model of anxiety-like behavior in rats, we show the emergence of a negative affective state during withdrawal after direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in opiate receptor stimulation in the VTA and can be relieved by administration of the dopamine receptor agonist apomorphine. Together, our results suggest that the emergence of anxiety during withdrawal from acute opiate exposure begins with activation of VTA mesolimbic dopamine circuitry, providing a mechanism for the opponent process view of withdrawal.

Opiate sensitization induces FosB/ΔFosB expression in prefrontal cortical, striatal and amygdala brain regions.

Abstract: Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/ΔFosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12) with either subcutaneous morphine (10 mg/kg) or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1), consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/ΔFosB, measured on day 16, in multiple brain regions including prelimbic (PL) and infralimbic (IL) cortex, nucleus accumbens (NAc) core, dorsomedial caudate-putamen (CPU), basolateral amygdala (BLA) and central nucleus of the amygdala (CNA) but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/ΔFosB plasticity in motivational pathways (NAc), motor outputs (CPU), and associative learning (PL, IL, BLA) and stress pathways (CNA).

Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997-2007.

Abstract: AIMS Although its effectiveness is somewhat controversial, it appears that dihydrocodeine (DHC) is still prescribed in the UK as an alternative to both methadone and buprenorphine for the treatment of opiate addiction.

Changing mechanisms of opiate tolerance and withdrawal during early development: animal models of the human experience.

Abstract: Human infants may be exposed to opiates through placental transfer from an opiate-using mother or through the direct administration of such drugs to relieve pain (e.g., due to illness or neonatal surgery). Infants of many species show physical dependence and tolerance to opiates. The magnitude of tolerance and the nature of withdrawal differ from those of the adult. Moreover, the mechanisms that contribute to the chronic effects of opiates are not well understood in the infant but include biological processes that are both common to and distinct from those of the adult. We review the animal research literature on the effects of chronic and acute opiate exposure in infants and identify mechanisms of withdrawal and tolerance that are similar to and different from those understood in adults. These mechanisms include opioid pharmacology, underlying neural substrates, and the involvement of other neurotransmitter systems. It appears that brain circuitry and opioid receptor types are similar but that NMDA receptor function is immature in the infant. Intracellular signaling cascades may differ but data are complicated by differences between the effects of chronic versus acute morphine treatment. Given the limited treatment options for the dependent infant patient, further study of the biological functions that are altered by chronic opiate treatment is necessary to guide evidenced-based treatment modalities.

CRF2 mediates the increased noradrenergic activity in the hypothalamic paraventricular nucleus and the negative state of morphine withdrawal in rats

Abstract: BACKGROUND AND PURPOSE Recent evidence suggests that corticotropin-releasing factor (CRF) receptor signalling is involved in modulating the negative symptoms of opiate withdrawal. In this study, a series of experiments were performed to further characterize the role of CRF-type 2 receptor (CRF2) signalling in opiate withdrawal-induced physical signs of dependence, hypothalamus-pituitary-adrenal (HPA) axis activation, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation), as well as CRF2 expression in the nucleus of the solitary tract-A2 noradrenergic cell group (NTS-A2). EXPERIMENTAL APPROACH The contribution of CRF2 signalling in opiate withdrawal was assessed by i.c.v. infusion of the selective CRF2 antagonist, antisauvagine-30 (AS-30). Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with AS-30 or saline 10 min before naloxone and the physical signs of abstinence, the HPA axis activity, NA turnover, TH activation and CRF2 expression were measured using immunoblotting, RIA, HPLC and immunohistochemistry. KEY RESULTS Rats pretreated with AS-30 showed decreased levels of somatic signs of naloxone-induced opiate withdrawal, but the corticosterone response was not modified. AS-30 attenuated the increased production of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol, as well as the enhanced NA turnover observed in morphine-withdrawn rats. Finally, AS-30 antagonized the TH phosphorylation at Serine40 induced by morphine withdrawal. CONCLUSIONS AND IMPLICATIONS These results suggest that physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by CRF2 signalling. Furthermore, they indicate a marginal role for the HPA axis in CRF2-mediation of opiate withdrawal.

Age-dependent and strain-dependent influences of morphine on mouse social investigation behavior.

Abstract: Opioid-coded neural circuits play a substantial role in how individuals respond to drugs of abuse. Most individuals begin using such drugs during adolescence and within a social context. Several studies indicate that adolescent mice exhibit a heightened sensitivity to the effects of morphine, a prototypical opiate drug, but it is unclear whether these developmental differences are related to aspects of motivated behavior. Moreover, exposure to opioids within the rodent brain can alter the expression of social behavior, yet little is known about whether this relationship changes as a function of development or genetic variation. In this study, we conducted a series of experiments to characterize the relationship between genetic background, adolescent development and morphine-induced changes in mouse social investigation (SI). At two time points during adolescent development [postnatal days (PD) 25 and 45], social interactions of test mice of the gregarious C57BL/6J (B6) strain were more tolerant to the suppressive effects of morphine [effective dose 50 (ED50)=0.97 mg/kg and 2.17 mg/kg morphine, respectively] than test mice from the less social BALB/cJ (BALB) strain (ED50=0.61 mg/kg and 0.91 mg/kg morphine, respectively). By contrast, this strain-dependent difference was not evident among adult mice on PD 90 (ED50=1.07 mg/kg and 1.41 mg/kg morphine for BALB and B6 mice, respectively). An additional experiment showed that the ability of morphine to alter social responsiveness was not directly related to drug-induced changes in locomotor behavior. Finally, administration of morphine to stimulus mice on PD 25 reduced social investigation of test mice only when individuals were from the B6 genetic background. Overall, these results indicate that alterations in endogenous opioid systems are related to changes in SI that occur during adolescence, and that morphine administration may mimic rewarding aspects of social encounter.

Comparison of methadone and buprenorphine for opiate detoxification (LEEDS trial): a randomised controlled trial

Abstract: Background Many opiate users require prescribed medication to help them achieve abstinence, commonly taking the form of a detoxification regime. In UK prisons, drug users are nearly universally treated for their opiate use by primary care clinicians, and once released access GP services where 40% of practices now treat drug users. There is a paucity of evidence evaluating methadone and buprenorphine (the two most commonly prescribed agents in the UK) for opiate detoxification. Aim To evaluate whether buprenorphine or methadone help to achieve drug abstinence at completion of a reducing regimen for heroin users presenting to UK prison health care for detoxification. Design Open-label, pragmatic, randomised controlled trial in three prison primary healthcare departments in the north of England. Method Prisoners (n = 306) using illicit opiates were recruited and given daily sublingual buprenorphine or oral methadone, in the context of routine care, over a standard reduced regimen of not more than 20 days. The primary outcome measure was abstinence from illicit opiates at 8 days post detoxification, as indicated by urine test (self-report/clinical notes where urine sample was not feasible). Secondary outcomes were also recorded. Results Abstinence was ascertained for 73.7% at 8 days post detoxification (urine sample = 52.6%, self report = 15.2%, clinical notes = 5.9%). There was no statistically significant difference in the odds of achieving abstinence between methadone and buprenorphine (odds ratio [OR] = 1.69; 95% confidence interval [CI] = 0.81 to 3.51; P = 0.163). Abstinence was associated solely with whether or not the participant was still in prison at that time (15.22 times the odds; 95% CI = 4.19 to 55.28). The strongest association for lasting abstinence was abstinence at an earlier time point. Conclusion There is equal clinical effectiveness between methadone and buprenorphine in achieving abstinence from opiates at 8 days post detoxification within prison.

The effect of propranolol and midazolam on the reconsolidation of a morphine place preference in chronically treated rats

Abstract: A stable memory can be disrupted if amnestic treatment is applied in conjunction with memory reactivation. Recent findings in the conditioned place preference (CPP) model suggest that blocking reconsolidation attenuates the ability of environmental cues to induce craving and relapse in drug addicts, but the impact of prior physical dependence has not been described. We examined the effect of post-reactivation amnestic treatment on reconsolidation of a CPP for morphine, in animals naive to morphine, under chronic morphine experience or abstinent. Morphine experience was induced by escalating doses of morphine from 10 mg/kg/day (s.c.), and maintained on 30 mg/kg/day during the course of conditioning and reactivation procedures, or conditioning alone. Naive and morphine-experienced animals were trained in a 3-compartment apparatus by 4 morphine (5 mg/kg, s.c.) and 4 saline experiences paired with either of two large conditioning compartments. The memory was then reactivated by a CPP test, and immediately afterwards animals received an injection of the beta-adrenergic antagonist propranolol (10 mg/kg, s.c.), the GABAa agonist midazolam (1 mg/kg, i.p.), or saline. Morphine-naive rats received only a single reconsolidation blocking treatment (Exp 1), while chronic morphine rats were given 8 reactivation sessions each followed by amnestic treatment, either before (Exp 2) or after 10 days of withdrawal (Exp 3). Propranolol and midazolam disrupted reconsolidation in morphine- naive rats, but failed to disrupt the CPP when rats were trained under chronic morphine treatment, even if they were recovered from chronic opiate exposure before reactivation. In fact, propranolol increased the preference for the drug-paired context in animals trained while maintained on chronic morphine. Midazolam had little effect. Morphine experience may produce neurochemical changes which alter memory storage processes and reduce the impact of amnestic treatments on reconsolidation.

Pharmacological Treatment of Neonatal Opiate Withdrawal: Between the Devil and the Deep Blue Sea

Abstract: Illicit drug use with opiates in pregnancy is a major global health issue with neonatal withdrawal being a common complication. Morphine is the main pharmacological agent administered for the treatment of neonatal withdrawal. In the past, morphine has been considered by and large inert in terms of its long-term effects on the central nervous system. However, recent animal and clinical studies have demonstrated that opiates exhibit significant effects on the growing brain. This includes direct dose-dependent effects on reduction in brain size and weight, protein, DNA, RNA, and neurotransmitters—possibly as a direct consequence of a number of opiate-mediated systems that influence neural cell differentiation, proliferation, and apoptosis. At this stage, we are stuck between the devil and the deep blue sea. There are no real alternatives to pharmacological treatment with opiates and other drugs for neonatal opiate withdrawal and opiate addiction in pregnant women. However, pending further rigorous studies examining the potential harmful effects of opiate exposure in utero and the perinatal period, prolonged use of these agents in the neonatal period should be used judiciously, with caution, and avoided where possible.

Inhibition of morphine-induced cAMP overshoot: a cell-based assay model in a high-throughput format

Abstract: Opiates are not only potent analgesics but also drugs of abuse mainly because they produce euphoria. Chronic use of opiates results in the development of tolerance and dependence. Dr Marshall Nirenberg’s group at the National Institutes of Health (NIH) was the first to use a cellular model system of Neuroblastoma × Glioma hybrid cells (NG108-15) to study morphine addiction. They showed that opiates affect adenylyl cyclase (AC) by two opposing mechanisms mediated by the opiate receptor. Although the cellular mechanisms that cause addiction are not yet completely understood, the most observed correlative biochemical adaptation is the upregulation of AC. This model also provides the opportunity to look for compounds which could dissociate the acute effect of opiates from the delayed response, upregulation of AC, and thus lead to the discovery of non-addictive drugs. To identify small molecule compounds that can inhibit morphine-induced cAMP overshoot, we have validated and optimized a cell-based assay in a high throughput format that measures cellular cAMP production after morphine withdrawal. The assay performed well in the 1536-well plate format. The LOPAC library of 1,280 compounds was screened in this assay on a quantitative high-throughput screening (qHTS) platform. A group of compounds that can inhibit morphine-induced cAMP overshoot were identified. The most potent compounds are eight naloxone-related compounds, including levallorphan tartrate, naloxonazine dihydrochloride, naloxone hydrochloride, naltrexone hydrochloride, and naltriben methanesulfonate. The qHTS approach we used in this study will be useful in identifying novel inhibitors of morphine induced addiction from a larger scale screening.