Heroin and its metabolites: relevance to heroin use disorder.

Heroin is an opioid agonist commonly abused for its rewarding effects. Since its synthesis at the end of the nineteenth century, its popularity as a recreational drug has ebbed and flowed. In the last three decades, heroin use has increased again, and yet the pharmacology of heroin is still poorly understood. After entering the body, heroin is rapidly deacetylated to 6-monoacetylmorphine (6-MAM), which is then deacetylated to morphine. Thus, drug addiction literature has long settled on the notion that heroin is little more than a pro-drug. In contrast to these former views, we will argue for a more complex interplay among heroin and its active metabolites: 6-MAM, morphine, and morphine-6-glucuronide (M6G). In particular, we propose that the complex temporal pattern of heroin effects results from the sequential, only partially overlapping, actions not only of 6-MAM, morphine, and M6G, but also of heroin per se, which, therefore, should not be seen as a mere brain-delivery system for its active metabolites. We will first review the literature concerning the pharmacokinetics and pharmacodynamics of heroin and its metabolites, then examine their neural and behavioral effects, and finally discuss the possible implications of these data for a better understanding of opioid reward and heroin addiction. By so doing we hope to highlight research topics to be investigated by future clinical and pre-clinical studies.

The Affective and Neural Correlates of Heroin versus Cocaine Use in Addiction Are Influenced by Environmental Setting But in Opposite Directions.

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values <0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes.SIGNIFICANCE STATEMENT The rewarding effects of addictive drugs are often thought to depend on shared substrates. Yet, environmental influences can unmask striking differences between psychostimulants and opiates. Here we used emotional tasks and fMRI to explore the influence of setting on the response to heroin versus cocaine in individuals with addiction. Simply moving from one setting to another significantly decreased heroin pleasure but increased cocaine pleasure, and vice versa. Similar double dissociation was observed in the activity of the fronto-striatal-cerebellar network. These findings suggest that the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates and that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use.

Cardiovascular and Hepatic Toxicity of Cocaine: Potential Beneficial Effects of Modulators of Oxidative Stress.

Oxidative stress (OS) is thought to play an important role in the pharmacological and toxic effects of various drugs of abuse. Herein we review the literature on the mechanisms responsible for the cardiovascular and hepatic toxicity of cocaine with special focus on OS-related mechanisms. We also review the preclinical and clinical literature concerning the putative therapeutic effects of OS modulators (such as N-acetylcysteine, superoxide dismutase mimetics, nitroxides and nitrones, NADPH oxidase inhibitors, xanthine oxidase inhibitors, and mitochondriotropic antioxidants) for the treatment of cocaine toxicity. We conclude that available OS modulators do not appear to have clinical efficacy.

Tobacco smoking and cannabis use in a longitudinal birth cohort: evidence of reciprocal causal relationships.

BACKGROUND: There is evidence of associations between tobacco and cannabis use that are consistent with both a classical stepping-stone scenario that posits the transition from tobacco use to cannabis use ('gateway' effect of tobacco) and with the reverse process leading from cannabis use to tobacco abuse ('reverse gateway' effect of cannabis). The evidence of direct causal relationships between the two disorders is still missing. METHODS: We analysed data from the Christchurch Health and Development Study (CHDS) longitudinal birth cohort using advanced statistical modelling to control for fixed sources of confounding and to explore causal pathways. The data were analysed using both: (a) conditional fixed effects logistic regression modelling; and (b) a systematic structural equation modelling approach previously developed to investigate psychiatric co-morbidities in the same cohort. RESULTS: We found significant (p<0.05) associations between the extent of cannabis use and tobacco smoking and vice versa, after controlling for non-observed fixed confounding factors and for a number of time-dynamic covariate factors (major depression, alcohol use disorder, anxiety disorder, stressful life events, deviant peer affiliations). Furthermore, increasing levels of tobacco smoking were associated with increasing cannabis use (p=0.02) and vice versa (p<0.001) over time. CONCLUSIONS: Our results lend support to the notion of both of 'gateway' and 'reverse gateway' effects. That is, the association between tobacco and cannabis use arises from a reciprocal feedback loop involving simultaneous causation between tobacco use disorder and cannabis use disorder.

Polydrug abuse by intravenous use of heroin and tropicamide-containing eyedrops.

BACKGROUND: Drug abuse is rarely limited to a single substance; polydrug use is the norm rather than the exception. In many cases, the misuse of potentially psychoactive substances can lead to serious intoxications and results in addictive behavior. CASE DESCRIPTION: A 22-year-old heroin-addicted woman presented in our clinic reporting a 2-year history of intravenous injection of an eyedrop solution containing 1% tropicamide, an antimuscarinic agent. She reported injecting tropicamide because it attenuated symptoms and signs of opiate withdrawal and it also has hallucinogenic and euphorigenic effects. Despite the large amounts (up to 1.5 g), the rapidity of injection, and the long-term use, tropicamide was relatively well tolerated, without life-threatening consequences.An outpatient detoxification program was performed without any sign or symptom caused by discontinuing tropicamide. CONCLUSIONS: The present case claims a role for pharmacological interactions, in addition to rewarding effects, in influencing drug association in polyabuse pattern. Moreover, this case underlines the need for physicians to be aware of the potential emergence of tropicamide as a drug of misuse, to prevent further harm.

Role of environmental factors in cocaine addiction.

Decades of experimentation with a variety of pharmacological treatments have identified some effective therapies for heroin addiction but not for cocaine addiction. This may be due, at least in part, to our incomplete understanding of the factors involved in the differential vulnerability to these addictions, which are often considered mere variations of the same disorder. Indeed, the preference for one drug or another has been variously attributed to factors such as drug availability or price, to the addict's lifestyle, or even to chance. Yet, there is evidence of substance-specific influences on drug taking. Data from twin registries, for example, suggest that a sizeable portion of the variability in the susceptibility to drug abuse is due to environmental factors that are unique to opiates or to psychostimulants. Very little is known about the nature of these environmental influences. We report here original data, based on retrospective reports in human addicts, indicating that the setting of drug taking exerts a differential influence on heroin versus cocaine use. We also review additional clinical and pre-clinical data pointing to fundamental differences in the way in which the environment interacts with cocaine relative to heroin and other addictive drugs. These findings - as well as other evidence, including the lack of pharmacological treatments effective for both cocaine and heroin addiction - support the notion that much is to be gained by taking into account the substance-specific aspects of drug addiction. At a therapeutic level, for example, it appears reasonable to propose that cognitive-behavioral approaches should be tailored in a substance-specific manner in order to allow the addict to anticipate, and cope with, the risks associated to the various environmental settings of drug use.

Drug context differently regulates cocaine versus heroin self-administration and cocaine- versus heroin-induced Fos mRNA expression in the rat.

RATIONALE: We have previously reported that cocaine self-administration is facilitated in male rats not residing in the test chambers (Non Resident rats) relative to rats living in the test chambers at all times (Resident rats). Surprisingly, the opposite was found for heroin. MATERIALS AND METHODS: We predicted that, when given access to both cocaine and heroin on alternate days, Non Resident rats would take more cocaine relative to heroin than Resident rats. Heroin (25.0 microg/kg) and cocaine (400 microg/kg), were made alternately available for 14 self-administration sessions, on a fixed ratio (FR) schedule that was progressively increased from FR1 to FR5. Next, some rats underwent a progressive-ratio procedure for heroin and cocaine. The other rats continued to alternate heroin and cocaine self-administration for 12 additional sessions, during which the FR schedule was progressively increased from FR10 to FR100. The second aim of the study was to investigate Fos mRNA expression in Resident and Non Resident rats treated with non-contingent intravenous infusion of "self-administration doses" of heroin (25.0 microg/kg) and cocaine (400 microg/kg). RESULTS: We found that: (1) drug-taking context differentially modulates intravenous cocaine versus heroin self-administration; (2) very low doses of cocaine and heroin are sufficient to induce Fos mRNA expression in the posterior caudate; (3) drug-administration context differentially modulates cocaine- versus heroin-induced Fos mRNA expression. CONCLUSIONS: Our study indicates that the context of drug taking can play a powerful role in modulating cocaine versus heroin intake in the laboratory rat.

In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat.

We have previously found that repeated exposure to heroin reduces liver synthesis of morphine-3-glucuronide (M3G) and increases the production of morphine-6-glucuronide (M6G), which normally is not formed in the rat. By contrast repeated exposure to naltrexone does not activate M6G synthesis but increases the V(max) of M3G formation. M3G synthesis depends on the activity of two isoforms of the UDP-glucuronosyltransferase (UGT), UGT1A1 and UGT2B1. These isozymes also activate the formation of estradiol-3-glucuronide (E3G) and estradiol-17-glucuronide (E17G), respectively. The goal of the present study was to investigate the role of UGT1A1 and UGT2B1 in the effects of heroin and naltrexone by determining their influence on the synthesis of E3G and E17G. Estradiol glucuronidation was performed using microsomes of rats treated daily, for 10 days, with saline, heroin (10mg/kg, i.p.), or naltrexone (40mg/kg, i.p.). Moreover, liver expression of both UGT1A1 and UGT2B1 was studied in the same experimental conditions by polymerase chain reaction analysis. Kinetic analysis showed that the V(max) for E3G formation was significantly reduced by both heroin (168.82+/-9.73nmol/mg/min) and naltrexone (194.60+/-16.6) relative to saline (624.60+/-17.6). Moreover, homotropic kinetic of E3G formation (Hill coefficient: 1.8) was transformed in Michaelis-Menten kinetic by both heroin (0.88) and naltrexone (1.15). The synthesis of E17G was not affected by either opioid. The expression of liver UGT1A1 and UGT2B1 did not differ across groups. The present results suggest that heroin and naltrexone can reduce estradiol glucuronidation via a specific interaction with UGT1A1 isoform.

Opposite environmental regulation of heroin and amphetamine self-administration in the rat.

RATIONALE: The circumstances of drug taking are thought to play a role in drug abuse but the evidence of it is anecdotal. Previous studies have shown that the intravenous self-administration of cocaine is facilitated in rats non-residing in the test chambers relative to rats that live in the test chambers at all times. We investigated here whether environmental context could exert its modulatory influence on heroin and amphetamine self-administration as well. MATERIALS AND METHODS: Independent groups of rats were given the possibility to self-administer different doses of heroin or amphetamine (12.5, 25.0, or 50.0 microg/kg). Some animals were housed in the self-administration chambers (resident groups) whereas other rats were transported to the self-administration chambers only for the test sessions (non-resident groups). RESULTS: Amphetamine-reinforcing effects were more pronounced in non-resident rats than in resident rats, as previously reported for cocaine. Quite unexpectedly, the opposite was found for heroin. Because of this surprising dissociation, some of the rats trained to self-administer amphetamine were later given the opportunity to self-administer heroin. Also in this case, resident rats took more heroin than non-resident rats. CONCLUSIONS: These findings suggest an unforeseen dissociation between opioid and psychostimulant reward and demonstrate that even in the laboratory rat some contexts are associated with the propensity to self-administer more opioid than psychostimulant drugs and vice versa, thus indicating that drug taking is influenced not only by economical or cultural factors but also can be modulated at a much more basic level by the setting in which drugs are experienced.

Modeling the role of environment in addiction.

The aim of this review is to provide an overview of the main types of animal models used to investigate the modulatory role of environment on drug addiction. The environment can alter the responsiveness to addictive drugs in at least three major ways. First, adverse life experiences can make an individual more vulnerable to develop drug addiction or to relapse into drug seeking. Second, neutral environmental cues can acquire, through Pavlovian conditioning, the ability to trigger drug seeking even after long periods of abstinence. Third, the environment immediately surrounding drug taking can alter the behavioral, subjective, and rewarding effects of a given drug, thus influencing the propensity to use the same drug again. We have focused in particular on the results obtained using an animal model we have developed to study the latter type of drug-environment interaction.

Modulatory effect of environmental context and drug history on heroin-induced psychomotor activity and fos protein expression in the rat brain.

The goal of the present study was to investigate the role of environmental context and drug history in modulating the effects of heroin on locomotor activity and Fos protein expression in the neocortex and striatal complex of the rat. It was found that (1) repeated i.p. administrations of a relatively low dose of heroin (1 mg/kg, i.p.) induced psychomotor sensitization only when the treatment was administered in a relatively 'novel' environment (ie, a unique test environment distinct from the home cage) but not when the same treatment was administered in the home cage; (2) environmental novelty facilitated heroin-induced Fos expression in the caudate, particularly in its most caudal regions; (3) environmental context also modulated heroin-induced Fos expression in the nucleus accumbens and in the neocortex; (4) repeated exposures to heroin dramatically altered its effects on Fos expression in the caudate and in the neocortex; and (5) Fos protein levels in the postero-dorsal caudate, in the shell of the nucleus accumbens, and in the barrel field cortex predicted most of the variance in heroin-induced activity scores, as shown by multiple regression analysis. The present report demonstrates that environment and drug history powerfully interact in shaping the neurobehavioral response to heroin, as previously shown for amphetamine and cocaine. Thus, a full understanding of the mechanisms responsible for the neurobehavioral adaptations produced by addictive drugs will also require taking into due consideration the environment in which drugs are experienced.

Effect of repeated administrations of heroin, naltrexone, methadone, and alcohol on morphine glucuronidation in the rat.

RATIONALE: Heroin is rapidly metabolized to morphine that in turn is transformed in morphine-3-glucuronide (M3G), an inactive metabolite, and morphine-6-glucuronide (M6G), a potent mu-opioid receptor (MOR) agonist. We have found that heroin addicts exhibit higher M6G/M3G ratios relative to morphine-treated control subjects. We have also shown that heroin-treated rats exhibit measurable levels of M6G (which is usually undetectable in this species) and reduced levels of M3G. OBJECTIVE: We investigated the role of MOR in these effects of heroin, by examining the effects of methadone, a MOR agonist, and of naltrexone, a MOR antagonist, on morphine glucuronidation. We also investigated the effects of alcohol, which is known to alter drug metabolism and is frequently coabused by heroin addicts. METHODS: Morphine glucuronidation was studied in liver microsomes obtained from rats exposed daily for 10 days to saline, heroin (10 mg/kg, i.p.), naltrexone (20-40 mg/kg, i.p.), heroin + naltrexone (10 mg/kg+20-40 mg/kg, i.p.), methadone (5-20 mg/kg, i.p.), or 10% ethanol. RESULTS: Heroin induced the synthesis of M6G and decreased the synthesis of M3G. Naltrexone exhibited intrinsic modulatory activity on morphine glucuronidation, increasing the synthesis of M3G via a low-affinity/high-capacity reaction characterized by positive cooperativity. The rate of M3G synthesis in the heroin + naltrexone groups was not different from that of the naltrexone groups. Methadone and ethanol induced a modest increase in M3G synthesis and had no effect on M6G synthesis. CONCLUSION: The effects of heroin on morphine glucuronidation are not shared by methadone or alcohol (two drugs that figure prominently in the natural history of heroin addiction) and do not appear to depend on the activation of MOR.

Repeated exposures to heroin and/or cadmium alter the rate of formation of morphine glucuronides in the rat.

After absorption, heroin is transformed into mono-acetyl-morphine and then into morphine. Morphine, in turn, is metabolized to morphine-3-glucuronide (M3G), an inactive compound, and morphine-6-glucuronide (M6G), a potent opioid agonist. Thus, changes in the rate of formation of M6G may alter the pharmacological consequences of a treatment with heroin or morphine. In this study, we investigate the effect of repeated exposures (10 daily i.p. injections) to heroin, morphine, cadmium (which has been previously shown to inhibit M3G formation in vitro), or heroin + cadmium on morphine glucuronidation both in vivo and ex vivo (i.e., microsomal preparation obtained from rats treated in vivo). Repeated heroin (2.5, 5.0, and 10 mg/kg) increased plasma levels of M6G (which was undetectable in all other groups) and reduced those of M3G. Also, the microsomal preparations obtained from the liver of repeated heroin rats, when incubated with morphine, yielded significant amounts of M6G (which was undetectable in all other groups) and decreased levels of M3G relative to the control groups. These effects were reversible upon discontinuation of heroin administration. In contrast, repeated morphine (10, 20, and 40 mg/kg) only slightly reduced M3G formation at the dose of 40 mg/kg. Repeated cadmium (5, 15, and 45 microg/kg) reduced the rate of M3G formation without inducing M6G synthesis. The effects of the repeated coadministration of heroin (10 mg/kg) and cadmium (15 microg/kg) were virtually identical to those of repeated heroin alone. In summary, repeated exposure of rats to heroin can shift morphine glucuronidation toward the formation of the active metabolite M6G.

Dissociation in the modulatory effects of environmental novelty on the locomotor, analgesic, and eating response to acute and repeated morphine in the rat.

RATIONALE: We have previously shown that environmental novelty can potentiate the activating effects of morphine and the development of sensitization to this effect. OBJECTIVES. Our main goal was to determine whether environmental novelty can also modulate the prophagic (time spent eating and food intake; experiment 1) and/or the analgesic (tail-flick test; experiments 2 and 3) effect of morphine, as well as the development of tolerance or sensitization to these effects. METHODS: In experiment 1, two groups of rats were administered seven intraperitoneal (i.p.) injections of either saline or morphine (4.0 mg/kg) either in their home cages (home groups) or in a distinct environment (novelty groups). After 7 days of withdrawal, both groups underwent a morphine challenge (4.0 mg/kg, i.p.). In experiment 2, home and novelty rats were administered four doses of morphine (0.0, 2.0, 4.0, and 8.0 mg/kg, i.p.) following a counterbalanced order. In experiment 3, home and novelty rats were administered eight intraperitoneal (i.p.) injections of either saline or morphine (8.0 mg/kg) and then given a morphine challenge (4.0 mg/kg). RESULTS: Environmental novelty enhanced the locomotor activating effect of morphine and the expression of sensitization to this effect (even after a period of withdrawal). Environmental novelty had relatively little effect on morphine-induced eating, and no effect on morphine-induced analgesia. CONCLUSIONS: Environmental context can have very different consequences on distinct drug effects as well as on distinct neurobehavioral adaptations to the same drug treatment (e.g., psychomotor sensitization versus analgesic tolerance).

A 6-hydroxydopamine lesion of the mesostriatal dopamine system decreases the expression of corticotropin releasing hormone and neurotensin mRNAs in the amygdala and bed nucleus of the stria terminalis.

The mesostriatal dopamine (DA) system is known to play a vital role in extrapyramidal motor responses, and animals with a unilateral 6-hydroxydopamine (6-OHDA) lesion of this system have proved useful in studying the behavioral and neurobiological effects of DA depletion. Less is known about the role of this system in modulating emotional responses, although a number of lines of evidence suggest that dopamine influences emotional behavior. During the course of a study involving rats that had a unilateral 6-OHDA lesion, we discovered a hemispheric asymmetry in the levels of corticotropin releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA). The present study was performed in order to determine (1) if the lesion resulted in a decrease in CRH mRNA, and/or if there was upregulation on the intact side, (2) if a similar imbalance in CRH mRNA was observed in other brain regions and (3) if levels of other neuropeptide mRNAs were affected by the lesion. Adult male Sprague-Dawley rats were left unoperated or were pretreated with desipramine and then injected unilaterally with 6-OHDA into the medial forebrain bundle to lesion the ascending mesostriatal DA neurons. Animals were killed 15-31 days following surgery and brain sections processed for CRH, neurotensin and enkephalin mRNAs by in situ hybridization. Levels of CRH and neurotensin mRNAs were decreased on the lesioned side in the CEA and oval nucleus of the BST (BSTov) relative to the intact side and to unoperated controls. Levels of enkephalin mRNA in these regions were not affected by the lesion. These effects appeared specific, because the lesion did not alter CRH mRNA expression in the ventral BST, paraventricular nucleus of the hypothalamus or cortex or neurotensin mRNA expression in the CA1 region of the hippocampus. In contrast, and consistent with previous reports, levels of neurotensin and enkephalin mRNAs were upregulated on the lesioned side of the striatum. This study provides evidence that the mesostriatal DA system regulates CRH and neurotensin mRNA in the BSTov and CEA, suggesting that dopamine may be an important modulator of CRH and neurotensin function within these nuclei. Although the precise mechanisms are not clear, and the involvement of noradrenergic systems cannot be precluded, data are consistent with the idea that dopamine, released in response to a stressful experience for example, interacts with CRH and neurotensin in the extended amygdala to affect emotional responsiveness.