[Therapy in heroin addiction]. / A heroinaddikció gyógyítása.

Heroin addiction is one of the most devastating and expensive of public health problems. The most effective treatment is opioid replacement therapy. Replacement of heroin, a short-acting euphoriant with methadone or other opioids that have significantly longer duration of action provides a number of therapeutic benefits. Opioid detoxification has a role in both preventing acute withdrawal and maintaining long-term abstinence. Opioid-based detoxification is based on the principle of cross-tolerance, in which one opioid is replaced with another one that is slowly tapered. For the treatment of heroin addicts a wide range of psychosocial and pharmacotherapeutic treatments are available; of these, methadone maintenance therapy has the most evidence of benefit. Methadone maintenance reduces and/or eliminates the use of heroin, reduces the death rate and criminality associated with heroin use, and allows patients to improve their health and social productivity. In addition, enrollment in methadone maintenance has the potential to reduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. There is growing interest in expanding treatment into primary care, allowing opioid addiction to be managed like other chronic illnesses. Buprenorphine which is a long-acting partial agonist was also approved as pharmacotherapy for opioid dependence. Opioid antagonists can reduce heroin self-administration and opioid craving in detoxified addicts. Naltrexone, which is a long-acting competitive antagonist at the opioid receptors, blocks the subjective and objective responses produced by intravenous opioids. Naltrexone is employed to accelerate opioid detoxification by displacing heroin and as a maintenance agent for detoxified formerly heroin-dependent patients who want to remain opioid-free.

New approach to the neurobiological mechanisms of addiction.

Much progress has been made in the last decade in the understanding the neural substrates of drug addiction, transmitters involved, epigenetic background and their relation to learning and memory but much remains to be elucidated and strong effort is necessary to integrate the rich information at the molecular, cellular systems, and behavioral levels to further clarify the mechanisms and therapy of this complex disease. The aim of this review is to collect and interpret the latest opinions in the development, the underlying mechanisms and therapy of addiction as a disease of central nervous system. The neurocircuitry, the transmitters and the epigenetics of addiction are discussed.

[Behavioural studies during the gestational-lactation period in morphine treated rats]. / Viselkedési vizsgálatok a gesztációs-laktációs idoszakban morfin-kezelt patkányon.

UNLABELLED: Opioids impair the maternal behaviour of experimental animals. The effect of morphine on maternal behaviour in rat dams treated chronically with morphine during the whole pregnancy and lactation has not been yet analysed systematically. OBJECTIVE: The aim of our work was to investigate the behavioural effects of moderate dose morphine administered constantly in the whole perinatal period in rats. METHODS: Nulliparous female rats were treated with 10 mg/kg morphine s.c. once daily, from the day of mating. Maternal behaviour was observed, the effects of acute morphine treatment on the maternal behaviour and whether this effect could be antagonised by naloxone were also investigated. Physical and other behavioural (anxiety-like signals in elevated plus maze, changes in locomotor activity) withdrawal signs precipitated by naloxone were registered. After weaning sensitivity to the rewarding effect of morphine was measured by conditioned place preference and to the aversive effect of naloxone by conditioned place aversion tests. Antinociceptive test on tail-flick apparatus was performed to investigate the changes in morphine antinociceptive effects due to chronic morphine treatment. RESULTS: Maternal behaviour was significantly impaired in morphine-treated dams. This effect of morphine lasted c.a. 2-3 hours a day, it showed dose-dependency and was enhanced in MO-treated group (sensitisation). Only weak physical and no other behavioural (anxiety-like behaviour or hypolocomotion) withdrawal signs were precipitated by naloxone. The positive reinforcing effect of morphine and aversive effect of naloxone were markedly increased on conditioned place paradigm. Significant antinociceptive tolerance was not seen. CONCLUSION: Although human drug abuse can be hardly modelling under experimental circumstances, our constant, relatively moderate dose morphine treatment administered once daily during the whole pregnancy and lactation resulted in several subtle behavioural changes in dams. In perinatally opioid-exposed offspring short- and long-term behavioural disturbances can be detected which is well-known from literature. Besides direct pharmacological effects of morphine impaired maternal responsiveness and pup care could play a role in these disturbances.

Changes in adaptability following perinatal morphine exposure in juvenile and adult rats.

The problem of drug abuse among pregnant women causes a major concern. The aim of the present study was to examine the adaptive consequences of long term maternal morphine exposure in offspring at different postnatal ages, and to see the possibility of compensation, as well. Pregnant rats were treated daily with morphine from the day of mating (on the first two days 5mg/kgs.c. than 10mg/kg) until weaning. Male offspring of dams treated with physiological saline served as control. Behavior in the elevated plus maze (EPM; anxiety) and forced swimming test (FST; depression) as well as adrenocorticotropin and corticosterone hormone levels were measured at postpartum days 23-25 and at adult age. There was only a tendency of spending less time in the open arms of the EPM in morphine treated rats at both ages, thus, the supposed anxiogenic impact of perinatal exposure with morphine needs more focused examination. In response to 5min FST morphine exposed animals spent considerable longer time with floating and shorter time with climbing at both ages which is an expressing sign of depression-like behavior. Perinatal morphine exposure induced a hypoactivity of the stress axis (adrenocorticotropin and corticosterone elevations) to strong stimulus (FST). Our results show that perinatal morphine exposure induces long term depression-like changes. At the same time the reactivity to the stress is failed. These findings on rodents presume that the progenies of morphine users could have lifelong problems in adaptive capability and might be prone to develop psychiatric disorders.

Intermittent prenatal MDMA exposure alters physiological but not mood related parameters in adult rat offspring.

The recreational party drug "ecstasy" (3,4-methylenedioxymethamphetamine MDMA) is particularly popular among young adults who are in the childbearing age and thus there is a substantial risk of prenatal MDMA exposure. We applied an intermittent treatment protocol with an early first injection on pregnant Wistar rats (15 mg/kg MDMA s.c. on the E4, E11 and E18 days of gestation) to examine the potential physiological, endocrine and behavioral effects on adult male and female offspring. Prenatal MDMA-treatment provoked reduced body weight of offspring from the birth as far as the adulthood. Adult MDMA-offspring had a reduced blood-glucose concentration and hematocrit, altered relative spleen and thymus weight, had lower performance on wire suspension test and on the first trial of rotarod test. In contrast, no alteration in the locomotor activity was found. Anxiety and depression related behavioral parameters in elevated plus maze, sucrose preference or forced swimming tests were normal. MDMA-offspring had elevated concentration of the ACTH-precursor proopiomelanocortin and male MDMA-offspring exhibited elevated blood corticosterone concentration. No significant alteration was detected in the serotonergic marker tryptophan-hydroxylase and the catcholaminergic marker tyrosine-hydroxylase immunoreactive fiber densities in MDMA-offspring. The mothers exhibited reduced densities of serotonergic but not catecholaminergic fibers after the MDMA treatment. Our findings suggest that an intermittent prenatal MDMA exposure with an early first injection and a relatively low cumulative dose provokes mild but significant alterations in physical-physiological parameters and reduces motor skill learning in adulthood. In contrast, these adult offspring do not produce anxiety or depression like behavior.

Pain-inhibiting inhomogeneous static magnetic field fails to influence locomotor activity and anxiety behavior in mice: no interference between magnetic field- and morphine-treatment.

OBJECTIVES: We wanted to demonstrate (i) in the writhing test in mice, whether there was a prolonged analgesic effect induced by an inhomogeneous static magnetic field (SMF) exposure; (ii) whether SMF had an effect on the analgesic effect induced by 0.5mg/kgs.c. administered morphine, on the behavioral patterns, and on the hyperlocomotion-inducing effect of morphine. DESIGN: A magnetic exposure system developed by the present authors was used with peak-to-peak flux densities in the 2-754mT range. The writhing test was used for the assessment of pain. An elevated plus maze and a Conducta System was used for studying the anxiogenic or anxyolitic effect in mice, and the locomotor activity, respectively. OUTCOME MEASURES: We looked for the difference in the number of writhings and in the behavioral patterns between treated (s.c. morphine and/or SMF exposure) and control animals, respectively. RESULTS: (i) The antinociceptive effect could be identified 10-30min following SMF exposition in the writhing test in mice. (ii) SMF failed to affect the morphine-induced antinociception, the behavioral patterns in either type of tests, and the hyperlocomotion-inducing effect of morphine. CONCLUSIONS: (i) The long-lasting antinociceptive effect of SMF allows experiments under conditions, when in situ application of the SMF-producing device would be technically difficult or impossible; or where it would disturb the experiments. (ii) The results of behavioral tests with freely moving mice in or in the vicinity of inhomogeneous SMFs are not affected by the SMF in the applied flux density range. (iii) Morphine in treated subjects is not interacting with the inhomogeneous SMFs in the applied flux density range.

[Central and peripheral mechanisms in antinociception: current and future perspectives]. / Centrális és perifériás mechanizmusok szerepe a fájdalomcsillapításban. Jelen és perspektívák.

As it is well known opioids are the most powerful drugs used for acute and chronic pain, although, their several serious side effects, such as respiratory depression, mental clouding, constipation, and tolerance dependence producing capacity, as well as large interpatient variability in responses limit their safe everyday use. Furthermore, the treatment of certain types of pain (e.g. neuropathic pain) is not very satisfactorily managed. Consequently, there is a continuous need to find analgesics efficient against chronic neuropathic pain and avoid these side actions and still retain opioid like potency. There are several possible way to find new targets for these purposes. Recently opioid receptors have been identified on peripheral processes of sensory neurons. These findings provide new insights into intrinsic mechanisms of pain control and suggest innovative strategies for developing drugs and alternative approaches to pain treatment. In the effort to discover better analgesic drugs for chronic pain, attention is being paid to specific ion channels at the periphery, include members of transient receptor potential family (TRPV1, capsaicin receptors), as well as P2x receptors, sensitive to purines released from tissue injury. A special tetradotoxin-resistant, voltage dependent type of sodium channel is associated with dorsal root ganglia neurons is blocked by mexiletine, used in chronic pain. A synthetic peptide analogue of marine snail toxin ziconitine blocks N-type calcium channels. GABA and NMDA receptors are also involved in the antinociceptive actions of gabapentin and ketamine, respectively. Furthermore nicotine and analogues (epibatidine) induce analgesia through nicotinic ACh receptors. We studied mostly the peripheral targets of hydrophilic heterocyclic opioids in antinociceptive processes.

Endomorphin-2 with a beta-turn backbone constraint retains the potent micro-opioid receptor agonist properties.

The constitutional similarity with different secondary structure preference between the Aba-Gly and the spiro-Aba-Gly scaffolds were exploited to design the novel endomorphin-2 analogs Tyr-spiro-( R/ S)-Aba-Gly-Phe-NH(2) ( 1 and 2) and Tyr-( R/ S)-Aba-Gly-Phe-NH(2) ( 3 and 4). The ( R)-spiro analog 1 was found to be a potent and selective micro-opioid agonist/partial agonist ( K (imicro) = 29.3 nM, IC(50) = 50 nM, K(e) = 0.57). NMR experiments and molecular modeling indicated that its backbone adopts mainly a beta-turn in aqueous solution.

3,4-Methylenedioxymethamphetamine (MDMA), but not morphine, alters APP processing in the rat brain.

The abuse of drugs such as opioids and 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') can have detrimental effects on the cognitive functions, but the exact molecular mechanism whereby these drugs promote neurodegeneration remains to be elucidated. The major purpose of the present pilot study was to determine whether the chronic in-vivo administration of morphine (10 mg/kg) or MDMA (1 mg/kg) to rats can alter the expression and processing of amyloid precursor protein (APP), the central molecule in the proposed pathomechanism of Alzheimer's disease. MDMA treatment significantly decreased the production of APP in the cytosolic fraction of the brain cortex. A concomitant 25% increase was found both in the beta-secretase (BACE) and APP mRNA levels (108%). In contrast, in the applied single dosage chronic morphine treatment did not influence either the APP and BACE protein levels or the APP mRNA production. These results indicate that the chronic use of 'ecstasy', but not morphine, may be harmful via a novel mode of action, i.e. by altering the APP expression and processing in the brain.

The development of tolerance to locomotor effects of morphine and the effect of various opioid receptor antagonists in rats chronically treated with morphine.

Behavioural measures are considered to be highly sensitive indices of opioid withdrawal. Opioids, depending on dose and time protocols may induce both reduction and enhancement of locomotor activity and chronic opioid treatment results in tolerance and sensitisation to these effects. In the present study the locomotor activity as experimental model was used to assess the development of tolerance to subcutaneous morphine challenge at different time points following morphine withdrawal in rats exposed to gradually increasing subcutaneous doses of morphine for 11 days. Tolerance developed to the inhibitory action of morphine (10 mg/kg) was observed even 8 weeks after morphine withdrawal, while tolerance to its locomotor activity enhancing effect (3 mg/kg) was detected 18 h after withdrawal, but not 3 weeks later. In the other series of experiments the locomotor activity of animals exposed to chronic morphine treatment was tested 18 h after spontaneous or subcutaneously administrated opioid antagonists precipitated withdrawal. Spontaneous withdrawal resulted in a moderate decrease of locomotion. Both the non-selective antagonist naloxone in low, mu opioid-receptor selective doses and the delta opioid-receptor selective naltrindole induced marked reduction of locomotor activity. The results provide further evidence that both mu and delta opioid-receptors might be affected during chronic morphine treatment.