heroin and Body-Weight

Topics: Adult; Aged; Blood Pressure; Body Temperature; Body Weight; Cardiovascular Diseases; Female; Gastrointestinal Diseases; Heroin; Humans; Liver Diseases; Lung Diseases; Lymphatic Diseases; Male; Middle Aged; Morphine Dependence; Pulse; Skin Diseases; Splenic Diseases; Substance-Related Disorders; Urologic Diseases

In this prospective, randomised, double-blind study, we compared the effects of two dosage regimens. Pregnant patients at term were randomly assigned to two groups to be given diamorphine 0.4 mg in hyperbaric bupivacaine 0.5% 2.4 ml or diamorphine 0.4 mg in a volume of hyperbaric bupivacaine 0.5% adjusted according to the patient's height and weight. Adequate anaesthesia was provided in all patients in both groups. The onset of the sensory block for cold and pinprick was faster with the fixed dose regimen (p = 0.01). There were more spinal blocks to above the first thoracic dermatome in the fixed dose group (17.1% vs. 2.2%, p = 0.022). Hypotension occurred in 71.7% vs. 50.0% of patients in the fixed dose and adjusted dose groups respectively (p = 0.035). In the fixed dose group, more patients required ephedrine to treat hypotension (79.5% vs. 56.8%, p = 0.022) and a larger median dose was administered (9 mg vs. 6 mg, p = 0.042). The decrease in mean (SD) arterial pressure was less in the adjusted group (35.0 (16.4) mmHg vs. 28.0 (13.5) mmHg, p = 0.036).

Topics: Adult; Anesthesia, Obstetrical; Anesthesia, Spinal; Anesthetics, Local; Body Height; Body Weight; Bupivacaine; Cesarean Section; Double-Blind Method; Drug Administration Schedule; Ephedrine; Female; Heroin; Humans; Hypotension; Pregnancy; Prospective Studies; Vasoconstrictor Agents

The single nucleotide polymorphism of the μ-opioid receptor, OPRM1 A118G, has been associated with greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present studies, we employed a 'humanized' mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in a model of heroin-induced devaluation of an otherwise palatable saccharin cue when repeated saccharin-heroin pairings occurred every 24h (Experiment 1) or every 48h (Experiment 2). The results showed that, while both the 118AA and 118GG mice demonstrated robust avoidance of the heroin-paired saccharin cue following daily taste-drug pairings, only the 118AA mice suppressed intake of the heroin-paired saccharin cue when 48h elapsed between each taste-drug pairing. Humanized 118GG mice, then, defend their intake of the sweet cue despite saccharin-heroin pairings and this effect is illuminated by the use of spaced, rather than massed, trials. Given that this pattern of strain difference is not evident with saccharin-cocaine pairings (Freet et al., 2015), reduced avoidance of the heroin-paired saccharin cue by the 118GG mice may be due to an interaction between the opiate and the subjects' drive for the sweet or, alternatively, to differential downstream sensitivity to the aversive kappa mediated properties of the drug. These alternative hypotheses are addressed.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Association Learning; Avoidance Learning; Body Weight; Choice Behavior; Circadian Rhythm; Cues; Drinking; Heroin; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Polymorphism, Single Nucleotide; Receptors, Opioid, mu; Reward; Saccharin; Sweetening Agents; Taste

Whether social isolation of adult rats under standard laboratory conditions produces significant long-term alterations in behavior and physiology is unclear. In the present study, male Sprague-Dawley rats were singly or paired-housed for 10 wk. During this period, they were tested for acquisition, extinction, and reacquisition of heroin (0.3 mg/kg)-conditioned place preference. Fecal corticoid metabolite levels were analyzed several times throughout the period of housing, and food consumption and body weight were monitored. During place conditioning, heroin induced a significant increase in locomotor activity in both singly and pair housed rats, and the resulting place preference was similar in both groups. However, singly housed rats showed increased motor reactivity to heroin on reconditioning after extinction and displayed significant reacquisition of conditioned place preference, compared with pair-housed animals. Over the 10-wk period of the study, there were no differences in body weight or food consumption between groups. Mild significant increases in relative adrenal gland weight and decreases in relative brain weight were noted in singly housed animals compared with those paired. Significant decreases in nocturnal fecal corticoid metabolite output were noted in both groups, with loss of circadian variation in fecal corticoid levels over the course of the study. These data suggest that male Sprague-Dawley rats, irrespective of single or pair housing, develop reduced hypothalamic-pituitary-adrenal axis activity over time under standard laboratory housing conditions. Single housing can enhance both this effect and sensitivity to the stimulatory and rewarding actions of heroin after withdrawal.

Topics: Adrenal Glands; Animals; Body Weight; Conditioning, Psychological; Heroin; Housing, Animal; Hypothalamo-Hypophyseal System; Male; Motor Activity; Pituitary-Adrenal System; Random Allocation; Rats; Rats, Sprague-Dawley; Social Isolation

Early onset of heroin use during adolescence might increase chances of later drug addiction. Prior work from our laboratory suggests, however, that adolescent male rats are actually less sensitive than adults to some enduring effects of heroin self-administration. In the present study, we tested two likely correlates of sensitivity to behavioral reinforcement in rats: physical withdrawal and locomotor sensitization.. Adolescent (35 days old at start) and adult (79 days old) male Sprague-Dawley rats were administered escalating doses of heroin, increasing from 1.0 to 8.0 mg/kg (i.p.) every 12 h, across 13 days. Somatic signs of spontaneous withdrawal were scored 12 and 24 h after the last injection, and then every 24 h for 5 days; locomotion was recorded concurrently. Challenge injections of heroin (1 mg/kg i.p.) were given at four points: as the first of the escalating doses (day 1), at days 7 and 13 during the escalating regimen, and after 12 days of forced abstinence. Body mass and food intake were measured throughout experimentation.. A heroin withdrawal syndrome was not observed among adolescents as it was among adults, including somatic signs as well as reduced locomotion, body mass, and food intake. On the other hand, heroin-induced locomotor sensitization did not differ across ages.. Reduced withdrawal is consistent with the attenuated reinforcing effects of heroin among adolescent male rats that we reported previously. Thus, it is possible that adolescent rats could reveal important neuroprotective factors for use in treatment of heroin dependence.

Topics: Aging; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Heroin; Heroin Dependence; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome

To study the expression of phosphorylated-ERK1/2(p-ERK1/2)MAPK in the prefrontal lobe cortex (PFC), hippocampus (HP) and nucleus accumbens (Acb) in mice exposed to heroin in the uterus, and elucidate whether ERK MAPK signal transduction pathway participates in neurobehavioral teratogenicity induced by maternal heroin abuse.. Animal model was established by subcutaneous administration of diacetylmorphine (10 mg/kg.d) to pregnant BALB/c mice on embryonic days 9-18, and their offspring were assigned to heroin and normal saline groups according to the maternal treatment. P-ERK1/2 expression in the PFC, HP and Acb were detected by RT-PCR and Western blot.. The heroin group had body weights similar to the normal saline group after birth. There were no significant differences in the p-ERK1/2 expression in the PFC, HP and Acb between the two groups.. Prenatal exposure to 10 mg/kg heroin altered neither the body weight nor the general development in mice. The ERK1/2 MAPK signal pathway might not be involved in the neurobehavioral teratogenicity induced by prenatal heroin exposure.

Topics: Animals; Body Weight; Extracellular Signal-Regulated MAP Kinases; Female; Fetus; Heroin; Hippocampus; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Nucleus Accumbens; Prefrontal Cortex

In the accompanying paper, we described incubation of heroin-seeking behavior in rats following 14 days of abstinence. To gain an understanding of genomic changes that accompany this behavioral observation, we measured the expression of genes previously reported to respond to drugs of abuse. Specifically, after 1 or 14 days of abstinence, mRNA expression was measured for 11 genes in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) immediately following a single 90 min extinction session. Additionally, the role of contingency was examined in control rats that received yoked, response-independent heroin administration. Gene expression was quantified by real-time quantitative PCR. Expression of five genes (Arc, EGR1, EGR2, Fos, and Homer1b/c) was changed in the mPFC. EGR1 and EGR2 expression was increased following the 90 min extinction session in a contingency-specific manner and this increase persisted through the 14 days of abstinence. Fos expression was also increased after 1 and 14 days of abstinence, but at 14 days this increase was response-independent (i.e., it occurred in both the rats with a history of heroin self-administration and in the yoked controls). Arc expression increased following the extinction session only in rats with a history of heroin self-administration and only when tested following 1, but not 14, days of abstinence. Homer 1 b/c decreased after 14 days of enforced abstinence in rats that received non-contingent heroin. Expression of only a single gene (EGR2) was increased in the NAc. These data demonstrate that behavioral incubation is coincident with altered levels of specific transcripts and that this response is contingently-specific. Moreover, EGR1 and EGR2 are specifically upregulated in self-administering rats following extinction and this finding persists through 14 days of abstinence, suggesting that these genes are particularly associated with the incubation phenomenon. These latter observations of persistent changes in gene expression following abstinence may reflect molecular correlates of relapse liability.

Topics: Animals; Behavior, Animal; Body Weight; Central Nervous System; Cues; Drinking; Extinction, Psychological; Gene Expression; Heroin; Heroin Dependence; Male; Narcotics; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA; Substance Withdrawal Syndrome

Increased drug availability can precipitate a rapid transition to compulsive drug use in both vulnerable humans and laboratory animals. Recent studies have shown that despite equivalent levels of psychomotor sensitization, only rats with prolonged, but not limited, access to cocaine self-administration respond to the priming effects of cocaine on drug seeking, as measured in a within-session reinstatement model of drug craving. In this model, drug seeking is first extinguished and then reinstated by non-contingent presentations of the drug alone in the absence of response-contingent stimuli. Here, we assessed the generality of this observation in rats with daily short (1 h, ShA) vs long access (6 h, LgA) to i.v. heroin self-administration. As expected, heroin intake by LgA rats (n=24) increased over time to become excessive compared to heroin intake by ShA rats (n=24). After escalation, LgA rats tended to be less sensitive to heroin-induced locomotion (7.5-30 microg, i.v.) than ShA rats. In contrast, only LgA rats, not ShA rats, responded to the priming effects of heroin, as measured by the ability of heroin alone (7.5-30 microg, i.v.) to reinstate extinguished drug-seeking behavior. Finally, during the course of heroin intake escalation, a large proportion of LgA rats developed self-injury (mostly targeting the nails and digit tips of the forepaws), a negative consequence not seen in ShA rats. This study reproduces and extends previous research on compulsive cocaine use by showing that heroin-induced reinstatement is also specific to compulsive drug use and dissociable from heroin-induced reward and psychomotor sensitization.

Topics: Animals; Behavior, Addictive; Behavior, Animal; Body Weight; Conditioning, Operant; Dose-Response Relationship, Drug; Extinction, Psychological; Heroin; Locomotion; Male; Narcotics; Rats; Rats, Wistar; Reward; Self Administration

The goal of the present study was to develop and validate an animal model of unlimited access to intravenous heroin self-administration combined with responding for food and water to characterize the transition to drug dependence. Male Wistar rats were allowed to lever press for heroin (60 microg/kg/0.1 ml infusion/s; fixed ratio 1; 20-s time out) and nosepoke for food and water in consecutive, daily 23-h sessions. Daily heroin intake increased over days, reaching significance by Day 14. Drug-taking increased across the circadian cycle, reflected as increases in both the nocturnal peak and diurnal nadir of heroin intake. Changes in the circadian pattern of food intake and meal patterning preceded and paralleled the changes in heroin intake. By Day 7, the circadian amplitude of feeding was blunted. Nocturnal intake decreased because rats consumed smaller and briefer meals. Diurnal intake increased due to increased meal frequency, whereas total daily food intake decreased. To control for time or experience in the self-administration boxes as a possible confound, rats with saline (no drug) tethers were tested and did not display significant changes in food intake pattern. Body weight gain slowed slightly in heroin rats relative to saline controls. Separate groups of rats revealed that significant physical dependence as measured by physical signs of opiate withdrawal following a naloxone injection (1.0 mg/kg, subcutaneous (s.c.)) was reached by Day 14. Significant increases in heroin intake could be produced using low doses of naloxone (0.003-0.03 mg/kg, s.c.) on days 28-31 of heroin access. After 6 weeks of heroin self-administration, rats injected with buprenorphine (0, 0.01, 0.04, and 0.2 mg/kg, s.c.) showed a dose-dependent reduction in heroin intake. Changes in the pattern of drug and food intake in the present unlimited heroin access model may serve as independent motivational markers for the transition to a drug-dependent state.

Topics: Analgesics, Opioid; Animals; Biomarkers; Body Weight; Brain; Buprenorphine; Circadian Rhythm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Eating; Feeding Behavior; Heroin; Injections, Intravenous; Male; Motivation; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Rats; Rats, Wistar; Self Administration; Substance Withdrawal Syndrome

We investigated immune, endocrine, and somatic alterations using two animal models of human heroin administration. In a heroin self-administration paradigm, we observed changes in immune function which suggest that the cycle of intermittent drug use is actually a stressor, which in turn not only exacerbates craving and drug-seeking behavior but also collaterally causes suppression of immune function and therefore susceptibility to disease. In another model of rats made physically dependent to heroin, we show that immune function is more broadly compromised, leading to evidence of infection, followed by chronic activation of innate immune function, cachexia, and weight loss.

Topics: Animals; Behavior, Animal; Body Weight; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Heroin; Heroin Dependence; Immune System; Neurosecretory Systems; Rats; Self Administration

Developmental lead exposure has been found to produce differential patterns of drug self-administration in adult animals.. The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult patterns of heroin self-administration.. Female rats were gavaged daily with 0 mg or 16 mg lead for 30 days prior to breeding with non-exposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning [postnatal day 21 (PND 21)]. Animals born to control or lead-exposed dams received indwelling jugular catheters as adults and were randomly assigned to one of two studies. In experiment 1, animals were tested on a FR-2 schedule in an effort to examine differential sensitivity to heroin in an intravenous self-administration paradigm. Seven doses of heroin were selected ranging from 0.56 microg/kg to 36 microg/kg per infusion. In experiment 2, littermates were tested on a progressive ratio (PR) schedule in order to more explicitly determine the nature of the change in sensitivity to the drug.. In experiment 1, lead-exposed animals responded for heroin at significantly lower rates across most doses as evidenced by a downward shift in the inverted-U dose-effect curve. Congruent with these findings, lead-exposed animals in experiment 2 exhibited a decrease in progressive ratio responding (lower breaking points) across all heroin doses, further suggesting that perinatal lead exposure attenuates opiate self-administration in adult animals by altering the rewarding efficacy of the drug. In experiment 2, it was determined further that lead-exposed animals had lower latencies to make the initial lever press for heroin.. These results support previous literature suggesting that perinatal exposure to inorganic lead attenuates the effectiveness of opiates as a reinforcer when animals are tested in the adult life cycle.

Topics: Animals; Body Weight; Conditioning, Operant; Female; Heroin; Infusions, Intravenous; Lead; Male; Maternal-Fetal Exchange; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Self Administration

A wide variety of otherwise unrelated neuroteratogens elicit a common set of behavioral defects centering around cholinergic contributions to cognitive function. We utilized the developing chick to overcome confounds related to maternal effects and compared the actions of nicotine, chlorpyrifos, and heroin on cholinergic signaling in the intermedial part of the hyperstriatum ventrale (IMHV), which controls imprinting behavior. Chicken eggs were injected with nicotine (10 mg/kg of egg), chlorpyrifos (10 mg/kg of egg), or heroin (20 mg/kg of egg; all doses below the threshold for dysmorphology) on incubation days (ID) 0 and 5, and then tests were conducted posthatching. All three compounds elicited significant deficits in imprinting behavior. We also found defects in cholinergic synaptic signaling specifically involving the muscarinic receptor-mediated membrane translocation of protein kinase C (PKC)-gamma and in the basal levels of both PKCgamma and PKCbetaII, the two isoforms known to be relevant to behavioral performance. In contrast, there were no alterations in the response of PKCalpha, an isoform that does not contribute to the behavior, nor were cytosolic levels of any of the isoforms affected. Taken together with similar results obtained in rodents, our findings suggest that disparate neuroteratogens all involve signaling defects centering on the ability of cholinergic receptors to elicit PKCgamma translocation/activation and that this effect is direct, i.e., not mediated by maternal confounds. The chick thus provides a suitable model for the rapid screening of neuroteratogens and elucidation of the mechanisms underlying behavioral anomalies.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Biological Transport; Blotting, Western; Body Weight; Chick Embryo; Chickens; Chlorpyrifos; Cholinergic Agents; Corpus Striatum; Dose-Response Relationship, Drug; Female; Heroin; Imprinting, Psychological; Models, Animal; Motor Activity; Narcotics; Nicotine; Protein Kinase C; Signal Transduction; Time Factors

Administration of heroin to pregnant mice evokes neurochemical and behavioral deficits consequent to disruption of septohippocampal cholinergic innervation, notably involving desensitization of the ability of cholinergic receptors to activate PKC activity. The present study further evaluates whether desensitization occurs specifically for the PKCgamma isoform, the behaviorally relevant subtype, as compared to PKCalpha. Mice were exposed transplacentally to heroin on gestational days (GD) 9-18 via s.c. maternal injections (10 mg/kg per day). In young adulthood (50 days old), control offspring showed an increase in hippocampal cell membrane PKCgamma after incubation with the muscarinic cholinergic receptor agonist, carbachol, indicative of translocation from the cytosol. Prenatal exposure to heroin eliminated this response, whereas basal PKCgamma levels were unchanged. In contrast, PKCalpha, which is not related to heroin-induced behavioral deficits, did not show a loss of response. The present findings strongly point to abnormalities in the responsiveness of PKCgamma as a mechanism underlying the neurobehavioral teratogenicity of heroin.

Topics: Animals; Behavior, Animal; Body Weight; Carbachol; Cell Membrane; Enzyme Activation; Feeding Behavior; Female; Heroin; Hippocampus; Maternal Behavior; Mice; Models, Animal; Posture; Pregnancy; Prenatal Exposure Delayed Effects; Protein Kinase C; Reflex; Reflex, Startle; Signal Transduction

We investigated whether chronic exposure to heroin alters responses to cocaine in ways that might explain the use of cocaine by opioid addicts. To this end, the effects of cocaine (5 and 20 mg/kg) were assessed on locomotor activity of rats chronically exposed to heroin (0.0, 3.5, 7.0, and 14.0 mg/kg/day, over 14 days, via osmotic mini-pumps), or withdrawn from heroin (1 day, acute withdrawal, and 14 days, protracted withdrawal). Chronic heroin exposure, in itself, dose dependently increased locomotion and acute cocaine administration further elevated locomotor activity in a dose-dependent and additive manner. During acute withdrawal, there was a dose-dependent decrease in locomotion that was reversed by cocaine in a dose-dependent manner. During protracted withdrawal, spontaneous locomotion normalized, but rats previously exposed to heroin displayed cross-sensitization to cocaine as indicated by small, but significant, enhanced locomotor response to 5 mg/kg of cocaine, and enhanced intravenous self-administration of low doses of cocaine (0.13 mg/kg/infusion). In a separate study, we measured extracellular dopamine (DA) in the nucleus accumbens (Acb) using in vivo microdialysis before and after acute withdrawal from heroin. During chronic exposure to heroin, basal extracellular DA was elevated dose dependently, whereas in acute withdrawal, levels were not different from those in vehicle-treated rats. In response to cocaine, however, DA activity in the Acb was significantly lower in rats withdrawn from the highest dose of heroin.

Topics: Analysis of Variance; Animals; Behavior, Animal; Body Weight; Cocaine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Heroin; Heroin Dependence; Infusion Pumps; Male; Microdialysis; Motor Activity; Narcotics; Nucleus Accumbens; Rats; Rats, Long-Evans; Self Administration; Time Factors

Rats selectively bred for high intake of a sweet saccharin solution (HiS) consume more ethanol than their low-saccharin intake (LoS) counterparts. The HiS phenotype may be a predictor of abuse of other drugs via other routes of administration.. HiS and LoS, male and female rats were tested for acquisition of IV cocaine and heroin self-administration under a fixed-ratio 1 (FR1) schedule, and cocaine-reinforced behavior was examined under a progressive-ratio (PR) schedule.. Four groups of rats (HiS males and females and LoS males and females) were trained to self-administer IV cocaine (0.2 mg/kg), and another four groups were trained to self-administer heroin (0.015 mg/kg) using an automated autoshaping procedure. Rats were allowed 30 days to reach a criterion whereby a mean of 100 (cocaine) or 20 (heroin) infusions were self-administered during 6-h sessions over 5 consecutive days.. The HiS female rats acquired cocaine self-administration significantly more rapidly than the LoS rats, and females of both phenotypes met the acquisition criteria more rapidly than males. In both HiS and LoS cocaine groups a greater percentage of females (compared with males) met the acquisition criteria within 30 days. The only cocaine group in which 100% met the criterion was the HiS females. The female (compared with male) heroin groups showed a more rapid rate of acquisition, but there was no difference due to saccharin phenotype. In each of the four heroin groups 100% of all rats met the criteria within 30 days. Results of the PR schedule in the HiS females and males and LoS females indicated significantly higher break points in the HiS females (compared with HiS males), but there were no differences in females due to phenotype.. Female rats selectively bred for higher saccharin intake show more rapid and successful acquisition of IV self-administration of a low dose of cocaine than those bred for low saccharin intake. Female rats (compared with males) consistently showed accelerated rates of acquisition and maintenance (PR) of cocaine self-administration and acquisition of heroin self-administration.

Topics: Analysis of Variance; Animals; Body Weight; Cocaine; Conditioning, Operant; Drinking; Eating; Female; Heroin; Infusions, Intravenous; Male; Phenotype; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Saccharin; Self Administration; Sex Factors; Time Factors

Rats suppress intake of a saccharin conditioned stimulus (CS) when paired with an aversive unconditioned stimulus such as lithium chloride. This phenomenon is referred to as a conditioned taste aversion (CTA). Rats also suppress intake of a saccharin CS when paired with a rewarding sucrose solution and when paired with a drug of abuse. Although the suppressive effects of drugs of abuse have long been interpreted as CTAs, evidence suggests that rats may suppress intake of the saccharin CS following taste-drug pairings because they are anticipating the rewarding rather than the aversive properties of the drug. Oddly, however, while all other drugs of abuse tested suppress intake of a gustatory CS, the highly reinforcing drug, heroin, is reportedly ineffective. The present study reexamined this issue in both water-deprived and water-replete rats using procedures that sustain both morphine- and cocaine-induced suppression of CS intake. The results showed that heroin greatly reduced CS intake following saccharin-heroin pairings and that this effect was less variable when assessed in water-replete subjects. When taken with other reports, these data suggest that rats suppress intake of a saccharin CS in anticipation of the availability of all drugs of abuse tested.

Topics: Analysis of Variance; Animals; Body Weight; Drinking Behavior; Eating; Heroin; Male; Narcotics; Rats; Rats, Sprague-Dawley; Reward; Saccharin; Taste; Water Deprivation

Drug addicts are prone to infection with viruses including hepatitis-B and HIV. Besides indirect effects as a consequence of lifestyle, heroin and methadone may also enhance the risk of infections by a direct immunotoxic effect affecting resistance. In addition to general toxicological screening, we therefore performed a screening for potential immunotoxicity of morphine and methadone. Rats treated orally with different dosages of morphine or methadone for 6 weeks showed only a minor effect of overt toxicity on liver and spleen at the high dose, whereas at lower doses an increase in the relative weight of the mesenteric lymph nodes and an increase in cell density in the medullary cords were observed histopathologically, indicating a specific effect on humoral immunity. This specific immunotoxic effect was corroborated by an increased IgG concentration in serum (significant for the methadone-treated group). Further immunotoxicological research is needed aimed at revealing the potential risk of opiate use with respect to immune function. In conclusion, the present paper showed the toxicological profile of morphine and methadone in an extended 28 day subchronic study. Specific immunotoxicological effects were observed at doses where no effects were seen in routine toxicological evaluation, suggesting that the immune system is sensitive to opiates.

Topics: Animal Feed; Animals; Body Weight; Drug Administration Schedule; Drug Stability; Eating; Heroin; Immunoglobulins; Immunosuppressive Agents; Lymph Nodes; Male; Methadone; Organ Size; Rats; Rats, Wistar

Topics: Adult; Body Weight; CD4-Positive T-Lymphocytes; Cocaine; Female; Heroin; HIV Infections; Humans; Substance-Related Disorders

Topics: Adult; Body Weight; Bulimia; Female; Heroin; Heroin Dependence; Humans; Vomiting

Laboratory rats were given unlimited access to intravenous cocaine hydrochloride or heroin hydrochloride. Animals self-administering cocaine quickly developed a pattern of episodic drug intake, with periods of excessive cocaine self-administration alternating with brief periods of abstinence. Subjects allowed continuous access to intravenous heroin showed stable drug self-administration, with a gradual increase in daily heroin intake over the first two weeks of testing. The general health of the animals became markedly different: those self-administering heroin maintained grooming behavior, pretesting body weight, and a good state of general health; rats self-administering cocaine tended to cease grooming behavior, to lose up to 47% of their pretesting body weight, and to show a pronounced deterioration in general health. The mortality rate for 30 days of continuous testing was 36% for animals self-administering heroin and 90% for those self-administering cocaine. These results suggest that cocaine is a much more toxic compound than heroin when animals are given unlimited access to intravenous drug.

Topics: Animals; Body Weight; Cocaine; Grooming; Heroin; Heroin Dependence; Humans; Infusions, Parenteral; Male; Rats; Self Administration; Substance-Related Disorders

Experiment 1 reported the effects of the interaction of a fixed 1 min delivery schedule and body weight, using schedule-induced self-injection paradigm, in the rate of acquisition of methadone and heroin. Eighty-one rats were assigned to 100% and 80% reduced body weight conditions with and without a schedule. The findings show that: (a) voluntary heroin and methadone intake was enhanced when a schedule was introduced to animals at 80% but not at 100% body weight; (b) high intake of heroin and methadone was accompanied by increased levels of plasma 11-OHCS. Experiment 2 showed that the high rate of self-injection was due to the interaction of pharmacological properties of opiates and environmental variables rather than to a general increase in activity arising from the deprivation state or the effects of the schedule. The results are discussed in terms of a stress factor arising from an interaction between environmental and pharmacological factors.

Topics: Analgesics, Opioid; Animals; Body Weight; Conditioning, Operant; Corticosterone; Food; Heroin; Male; Methadone; Rats; Reinforcement Schedule; Self Administration

Topics: Analgesics, Opioid; Animals; Body Weight; Delayed-Action Preparations; Heroin; Hydrolyzable Tannins; Hydromorphone; Male; Pain; Rats; Solubility; Time Factors; Zinc

The effects of long-acting narcotic agonist preparations on the severe withdrawal syndrome following abrupt cessation of daily injections of codeine phosphate were studied in rats. Twelve hours after the last codeine injections, one injection of either a high or low dose of the zinc tannate salt of heroin, levo-alpha-acetylmethadol (LAAM) or hydromorphone in slow-release vehicle (SRV) was administered. Body weight, core temperature and hyperirritability scores (Teiger, 1974) were recorded every 6 h for the next 3 days. With the exception of the group that received the lower dose of heroin zinc tannate, all drug-treated groups lost significantly less weight than the SRV controls. All rats injected with either LAAM or hydromorphone zinc tannate exhibited prolonged marked hyperthermia, but the low, the high dose heroin groups and the SRV groups showed no significant differences in diurnal temperature patterns. Rats treated with the narcotic agonists were generally less irritable, as indicated by lower Teiger scores. These results indicate that a single injection of heroin, LAAM or hydromorphone zinc tannate can ameliorate the characteristic and intense signs of abstinence following withdrawal from codeine.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Codeine; Delayed-Action Preparations; Heroin; Humans; Hydromorphone; Male; Methadone; Methadyl Acetate; Opioid-Related Disorders; Rats; Substance Withdrawal Syndrome; Zinc

Topics: Adolescent; Adult; Age Factors; Appetite Depressants; Black or African American; Body Weight; Data Collection; Drug and Narcotic Control; Female; Heroin; Heroin Dependence; Humans; Injections, Intravenous; Male; Obesity; Phenmetrazine; Random Allocation; Sex Factors; Substance-Related Disorders; United States; White People

Experimental evidence has shown that an intermittent food delivery schedule interacts with the pharmacological properties of a variety of drugs to produce significant increases in self-injection rates. This self-infusion drug seeking behaviour is further strengthened when body weight reduction is introduced. This experiment studies the effect of the opiate antagonist naloxone upon a strongly established response pattern for heroin self-administration, using naive rats at 80% body weight which were made dependent upon the drug by the schedule-induced self-injection procedure. Results show a clear reversal in responding following naloxone treatment, suggesting that once an interaction between schedule-induced behaviour and a drug is established, blockage of the reinforcing effects of the drug extinguishes the behaviour altogether.

Topics: Animals; Body Weight; Heroin; Male; Naloxone; Rats; Reinforcement Schedule; Self Administration

Complex zinc tannate salts of heroin, hydromorphone and l-alpha-acetylmethadol were synthesized and injected in a slow-release vehicle, into rats. One, 3, 7, 10 and 14 days after the drug was administered rats were injected with naloxone hydrochloride (10 mg/kg) and during the following 4 hours body weights, core temperature and behavioral signs such as diarrhea, writhing, teeth chattering and wet dog shakes were recorded. On every naloxone testing day the narcotic-treated groups presented behavioral signs of abstinence, but weight loss and temperature changes were much less consistent. Reduction of core temperature following naloxone administration seems to be an earlier indicator of physical dependence than weight loss. According to the parameters tested a level of physical dependence can persist for at least two weeks after a single injection of these narcotic salts.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Heroin; Heroin Dependence; Humans; Hydromorphone; Methadone; Methadyl Acetate; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

The effects on behaviour and growth of rats given heroin s.c. every 8-hr, and during withdrawal (saline q.8.h.) were studied. Performance of rats trained on one food-reinforcement schedule (FR-10 or VI-10) was tested every day after one of the injections of saline or heroin. Doses of 0.25 mg/kg/injection heroin hydrochloride were increased stepwise to 32 mg/kg as "behavioural tolerance" developed. Threshold doses which blocked feeding in the first 30 min of testing ranged from 0.75 to 4.0 mg/kg and "tolerance" to 32 mg/kg/injection required from 18-71 + days. Heroin interrupted growth in heavier rats; lighter rats gained like saline-treated controls. Within 48 hr of withdrawal bar-pressing increased but all rats lost weight, were hyperirritable, and had diarrhoea. Thereafter, performance and body weight rose steadily. Administration of heroin at regular intervals over a prolonged period, and withdrawal from it, cause a disruption in behaviour comparable to that reported for morphine.

Topics: Animals; Body Weight; Conditioning, Operant; Depression, Chemical; Drug Tolerance; Heroin; Humans; Male; Rats; Reinforcement Schedule; Stimulation, Chemical; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Cricetinae; Drug Combinations; Female; Heroin; Isoproterenol; Mescaline; Methadone; Morphine; Pregnancy; Trypan Blue; Vitamin A

Tests on 12 heroin addicts showed that their response to a glucose load differed from that in normal controls. Though the fasting blood sugar was normal, the rise in blood glucose after a standard 50-g oral glucose tolerance test was delayed and the rise smaller than in the controls. The heroin addicts had high resting insulin levels and a delayed peak response to an oral glucose load, and their growth hormone response was also abnormal.

Topics: Adolescent; Adult; Body Weight; Food Preferences; Glucose Tolerance Test; Growth Hormone; Heroin; Hormones; Humans; Hydrocortisone; Insulin; Liver Function Tests; Male; Substance-Related Disorders; Time Factors

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Embryonic and Fetal Development; Female; Fetal Diseases; Fetus; Growth Disorders; Heroin; Heroin Dependence; Humans; Injections, Intramuscular; Injections, Intraperitoneal; Injections, Intravenous; Lung; Pregnancy; Pregnancy Complications; Rabbits

Topics: Adult; Amino Acids; Body Weight; Catheterization; Diet Therapy; Female; Heroin; Humans; Hypertonic Solutions; Male; Methods; Morphine Dependence; Nitrogen; Parenteral Nutrition; Subclavian Vein; Tetanus

Topics: Animals; Blood-Brain Barrier; Body Weight; Brain; Dactinomycin; Female; Heroin; Lethal Dose 50; Male; Mice; Morphine; Permeability