Role of opioid antagonists in treating intravenous cocaine abuse

Intravenous cocaine abuse is a major probel in opioid abusers including those treated in methadone maintenance. Studying 138 opioid addicts, we found that speedballing by combining opioid agonists with cocaine may be blocked by opioid antagonists such as naltrexone and by partial antagonists such as buprenorphine. With both these treatments cocaine abuse was five to eight times less than with methadone treatment.     

Modification of the response to opioid and nonopioid drugs by chronic opioid antagonist treatment

Chronic exposure to opioid antagonists increases the analgesic actions of opioids such as morphine. In the present studies, morphine's analgesic potency was increased (supersensitivity) following an 8 day subcutaneous naltrexone implant in mice, but not following a 1 day implant. Supersensitivity was maximal 24hr following the 8 day implant and declined linearly and had returned to control levels by 120hr. Implantation of naltrexone pellets for 8 days was found to increase the relative analgesic potency of methadone by 120%, while the lethal potency of cocaine was slightly (19%), but significantly, decreased. In contrast, identical treatment did not alter the potency of the benzodiazepine alprazolam to induce ataxia.     

Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.     

Mechanisms of Metabonomic for a Gateway Drug: Nicotine Priming Enhances Behavioral Response to Cocaine with Modification in Energy Metabolism and Neurotransmitter Level

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. ¹H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.     

不同背景的同伴强化及催产素处理对雌性棕色田鼠可卡因条件位置偏爱的影响

同伴间的社会互作是一种天然奖赏,能够影响成瘾药物使用的敏感性。催产素（Oxytocin,OT)能够调节社会行为,并提高社会互作的奖赏价值。然而不同背景的同伴互作以及与OT合并使用是否对可卡因的奖赏效应有不同的影响尚不清楚。棕色田鼠(Microtus mandarinus)是一种单配制田鼠,个体间具有较复杂的社会行为。利用雌性棕色田鼠,我们首先检测了可卡因(20 mg/kg)单独强化以及与不同背景关系的同伴（熟性雌性、陌生雌性和陌生雄性）同时强化诱导的条件位置偏爱（conditioned place preference, CPP）及持续时间;其次检测了实验鼠外周注射OT (1 mg /kg)并给予不同背景同伴强化对可卡因CPP的影响。结果表明,可卡因单独强化时,实验鼠能够形成可卡因CPP并能持续至3周;用熟悉的雌性同伴强化时,实验鼠对可卡因CPP的维持时间缩短;用陌生的雌性或雄性同伴强化时可抑制可卡因CPP的形成。实验鼠注射OT后,用熟悉雌性或陌生雄性同伴分别强化时会抑制或反转可卡因CPP。这些结果表明不同背景关系的同伴强化对可卡因奖赏效应的影响不同。OT可促进同伴强化的奖赏价值,降低动物对可卡因的偏爱,且该效应因强化同伴的背景而不同。     

Naltrindole,an opioid delta receptor antagonist,blocks cocaine-induced facilitation of responding for rewarding brain stimulation

Recent experimental results have led to the suggestion that opioid antagonists can modulate the reinforcing properties of cocaine. In this experiment, rats were fixed with chronically indwelling bipolar electrodes for stimulation of the medial forebrain bundle (MFB) as it courses through the hypothalamus. Rats were taught to press a lever for brief trains of electrical stimulation of the MFB. Subsequently, they were allowed to press for varying intensities of stimulation daily until their response rates were stable. Cocaine (5 mg/kg, s.c.) enhanced the rate of pressing for lower intensities of brain stimulation. Naltrindole (3 mg/kg, i.p.) had no effect on response rate alone but blocked the cocaine-induced facilitation of pressing for rewarding brain stimulation. An implication that can be drawn from these data is that naltrindole, or other delta-selective opioid antagonists, might be effective as medicines for use in treating cocaine abuse.     

Duration of opiate receptor blockade determines tumorigenic response in mice with neuroblastoma: a role for endogenous opioid systems in cancer

The relationship between the pharmacological properties of an opioid antagonist, naltrexone (NTX), and tumor response was studied in mice with transplanted neuroblastoma (NB). Animals receiving 0.1 mg/kg NTX every 6 hr, which blocked morphine-induced analgesia for 24 hr each day, had a 100% tumor incidence, no deviation in time before tumor appearance, and a 17% decrease from control values in total survival time. In contrast, once daily injections of either 0.1 mg/kg NTX or 0.4 mg/kg NTX (the equivalent of 0.1 mg/kg given 4 times daily), which blocked morphine-induced analgesia for less than 10 hr each day, resulted in a tumor incidence of 20% and 60%, respectively, delays in time prior to tumor appearance of 90% and 65%, respectively, and an increased total survival time of 10% and 24%, respectively, for tumor-bearing mice relative to control levels. Inoculation of NB in control animals resulted in 100% tumor appearance within 16 days and a mean survival time of 36 days. These results show that tumorigenic events are dictated by the duration of opiate receptor blockade rather than the dosage of opiate antagonist, and provide compelling evidence that endogenous opioid systems play a crucial role in neuro-oncogenic expression.     

Neuropeptide FF (NPFF) reduces the expression of cocaine-induced conditioned place preference and cocaine-induced sensitization in animals

The endogenous brain opioid system is believed to play an important role in mediating reward mechanisms. Opioid innervation is high in many limbic regions and reinforcing actions of many drugs of abuse, including cocaine, are thought to be mediated via endogenous opioid system. The aim of the present study was to indicate whether the anti-opioid peptide, neuropeptide FF (NPFF; FLFQPQRF-NH₂) was able to modify the rewarding effect of cocaine (5 mg/kg) measured in the expression of conditioned place preference (CPP) test in rats and the expression of sensitization to hyperlocomotor effect of cocaine (10 mg/kg) in mice. Our results indicate that NPFF (5, 10, and 20 nmol) given intracerebroventricularly (i.c.v.) inhibited the expression of cocaine-induced CPP at the dose of 10 nmol (P < 0.01) and 20 nmol (P < 0.001). Moreover, NPFF inhibited the expression of cocaine-induced sensitization to its hyperlocomotor effect at the dose of 20 nmol (P < 0.05) and acute hyperlocomotor effect of cocaine at doses of 5 nmol (P < 0.01), 10 nmol (P < 0.01), and 20 nmol (P < 0.05). Our study suggests that NPFF may participate in a rewarding effect of cocaine measured in the CPP paradigm. On the other hand, our experiments indicate that NPFF is involved in the mechanism of expression of sensitization to cocaine hyperlocomotion but this effect seems to be non-specific because NPFF also inhibited the acute hyperlocomotor effect of cocaine.     

Naltrexone modulates body and brain development in rats: a role for endogenous opioid systems in growth

Preweaning rats receiving daily injections of 20, 50, or 100 mg/kg naltrexone, a potent opiate antagonist, had body and brain weights that were increased 16-22% and 6-13%, respectively, from control levels on day 21 (weaning). All of these dosages of naltrexone blocked the opiate receptor for 24 hr/day as measured in opiate challenge experiments. Dosages of 0.1, 1, and 10 mg/kg naltrexone, which blocked the opiate receptor for less than 12 hr/day, inhibited growth. Repetitive administration of low dosages (3 mg/kg naltrexone, 3 times daily), which blocked the receptor 24 hr/day, increased body and brain development by 31% and 10%, respectively, whereas a cumulative dosage of 9 mg/kg naltrexone given once daily retarded growth. These results show that developmental events are dictated by the duration of opiate receptor blockade and provide compelling evidence that endogenous opioid systems play a crucial role in growth.     

Measuring naloxone antagonism of discriminative opioid stimulus

The numerous studies of opioids as discriminative stimuli, beginning in 1971, have shown specificity, similarity of several opioids, differences in potency (fentanyl greater than heroin greater methadone greater than morphine), and antagonism by naloxone and naltrexone. The discriminative opioid stimulus is differentiated from those of other classes of drugs, such as sedatives and anxiolytics. Greater potency of the opioid stimulus has been found in rats after subcutaneous (s.c.) than intraperitoneal administration. The discriminative opioid stimulus and its antagonism by naloxone or naltrexone have been demonstrated in rats, squirrel monkeys, gerbils, and pigeons. A few studies have quantified the competitive agonist-antagonist interaction at the receptor by calculating the pA2, which reflects the dose of the antagonist that requires doubling the agonist dose to obtain the original agonist response. The pA2 for naloxone is the same in groups of rats trained to discriminate different doses of morphine (1, 2, or 4 mg/kg s.c.) from saline. Higher pA2 values in tests after fentanyl and methadone than after heroin and morphine in rats trained to discriminate fentanyl (0.04 mg/kg s.c.) from saline reflect greater susceptibility of the synthetic than the natural exogenous opioids to antagonism by naloxone. Different pA2 values are usually interpreted as indicating differences among populations of receptors.     

Repeated administration of naltrexone and diprenorphine decreases food intake and body weight in squirrel monkeys

Although chronic administration of naloxone has been reported to reduce food intake and body weight in rats, there have been no comparable investigations using a nonhuman primate. We examined the effects of repeated injections of two long acting opiate antagonists - naltrexone and diprenorphine - on the ad libitum intake of a nutritional complete liquid diet and on body weight in squirrel monkeys. Naltrexone binds with highest affinity to the mu opioid receptor whereas diprenorphine binds with equally high affinity to several subtypes of opioid receptor. Diprenorphine (ED50 = 0.01 mg/kg) was 22 times more potent than naltrexone (ED50 = 0.22 mg/kg) in decreasing 2 h food intake, suggesting that more than one opioid receptor subtype may be involved in the anorectic effects of opiate antagonists. A 1.0 mg/kg dose of drug reduced 24 h food intake by 50% and was associated with a weekly reduction in body weight of 4 and 5% for naltrexone and diprenorphine, respectively. Thus, in contrast with shorter time intervals, 24 h food intakes were similar for the two drugs, and this was associated with comparable body weight profiles. The decreases in food intake and body weight remained constant over the period of drug administration. Some monkeys showed profuse salivation and "wet dog shakes" after 4 days of treatment with the 1.0 mg/kg dose but not after 1 day. Therefore, opiate antagonists given chronically to monkeys reduced food intake and body weight in a dose-dependent manner with no evidence of tolerance to these effects.     

Narcotic antagonists attenuate drinking induced by water deprivation in a primate

Pure narcotic antagonists such as naloxone and naltrexone have consistently been shown to attenuate drinking in the rat after periods of water deprivation. One objective of this study was to extend observations to a primate species, the squirrel monkey. Whereas naloxone and naltrexone have a greater relative affinity for opiate receptors preferentially binding morphine and other opiate alkaloids than for those with high affinity for the endogenous opioid peptides, diprenorphine, another pure opiate antagonist, binds with equally high affinity to both receptor subtypes. Therefore, a second objective was to determine the actions of diprenorphine on drinking in water-deprived rats and squirrel monkeys and to compare the effects of this drug to those of naloxone and naltrexone. All three narcotic antagonists suppressed water consumption of monkeys and rats deprived of water for 18 and 24 hr, respectively. Diprenorphine was the most potent compound tested in both species, producing significant reductions in water consumption of monkeys and rats at systemic doses as low as 0.01 and 0.1 mg/kg respectively. Moreover, diprenorphine was the longest acting of the three drugs in the monkey. These results demonstrate that the narcotic antagonists attenuate drinking in primates as well as in rodents and support the hypothesis that these drugs reduce water intake by interrupting the activity of endogenous opioid pathways mediating drinking behavior.     

A morphine/heroin vaccine with new hapten design attenuates behavioral effects in rats

Heroin use has seriously threatened public heath in many countries, but the existing therapies continue to have many limitations. Recently, immunotherapy has shown efficacy in some clinical studies, including vaccines against nicotine and cocaine, but no opioid vaccines have been introduced in clinical studies. The development of a novel opioid antigen designed specifically for the prevention of heroin addiction is necessary. A morphine-keyhole limpet hemocyanin conjugate was prepared and administered subcutaneously in rats. Antibody titers in plasma were measured using an enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess the selectivity of the antibodies. Dopamine concentrations in the nucleus accumbens in rats after vaccine administration were determined by high-performance liquid chromatography with electrochemical detection. The effects of the vaccine on the heroin-primed restatement of self-administration and locomotor sensitization were evaluated. A novel hapten, 6-glutarylmorphine, was produced, and the vaccine generated a high antibody titer response. This vaccine displayed specificity for both morphine and heroin, but the anti-morphine antibodies could not recognize dissimilar therapeutic opioid compounds, such as buprenorphine, methadone, naloxone, naltrexone, codeine, and nalorphine. The morphine antibody significantly decreased morphine-induced locomotor activity in rats after immunization. Importantly, rats immunized with this vaccine did not exhibit heroin-primed reinstatement of heroin seeking when antibody levels were sufficiently high. The vaccine reduced dopamine levels in the nucleus accumbens after morphine administration, which is consistent with its behavioral effects. These results suggest that immunization with a novel vaccine is an effective means of inducing a morphine-specific antibody response that is able to attenuate the behavioral and psychoactive effects of heroin.     

Modulators of N-methyl-D-aspartate protect against diazepam- or phenobarbital-resistant cocaine convulsions.

The anticonvulsants diazepam (1-10 mg/kg) and phenobarbital (30-100 mg/kg) protected against lethality without altering clonic convulsions induced by 75 mg/kg cocaine (CD100) in male Swiss Webster mice. In contrast, the non-competitive N-methyl-D-aspartate (NMDA) antagonists, MK-801 (dizocilpine) and phencyclidine, produced dose-dependent protection against cocaine convulsions. The competitive NMDA antagonists, CPP and NPC 12626, were also anti-convulsant, without producing the behavioral disturbances associated with non-competitive antagonists. Diazepam and phenobarbital protected against convulsions induced by 60 mg/kg cocaine (90% convulsions alone). Compounds that act at the strychnine-insensitive glycine receptor of the NMDA receptor complex, ACPC and 7-chlorokynurinic acid, also protected against convulsions induced by 60 mg/kg cocaine. In contrast, the non-opioid antitussive anticonvulsants (dextromethorphan, caramiphen, and carbetapentane) were not active against either dose of cocaine. The efficacy of compounds as antagonists of the convulsant effects of cocaine and NMDA appear related. These results suggest a potential role for the NMDA receptor complex in the convulsant actions of cocaine and new molecular targets for drug discovery in treating cocaine toxicity.     

The analgesia produced by food deprivation in 4-month old, 14-month old, and 24-month old rats

The analgesia produced by 24 hr of food deprivation was examined in 4-mo, 14-mo, and 24-mo old rats. To assess opioid and hormonal involvement in food deprivation induced analgesia, different groups of rats from each age group were injected with naltrexone (7 mg/kg), dexamethasone (0.4 mg/kg), or equivolume saline. Results revealed that food deprivation produced an equivalent analgesic response in each saline-treated age group. Also, naltrexone and dexamethasone were equally potent in blocking food deprivation induced analgesia in each age group. These results demonstrated that food deprivation activates an endogenous opioid-mediated analgesic system that involves hormonal factors and that this system does not change in function with increasing age.     

Pimozide blocks establishment but not expression of cocaine-produced environment-specific conditioning

Two experiments were conducted to examine the effects of pimozide on cocaine-produced conditioning to a specific environmental context. On 8 treatment days, 12 rats were injected with cocaine (10 mg/kg i.p.) and 12 with saline prior to placement for 60 min into a test chamber outfitted with infrared emitters and detectors. Following each treatment session the saline group received cocaine in their home-cages and the cocaine group received saline. Cocaine produced a significant increase in vertical activity on treatment days. On test days all rats received saline. Significantly greater vertical activity was observed in the group previously receiving cocaine in the test environment. All rats then received 8 more treatment sessions. On saline test days, pimozide (0.4 mg/kg i.p.) pretreatment failed to antagonize expression of the conditioned effect. In experiment 2, pimozide was given prior to treatment and no evidence of conditioning was seen on saline test days. Thus, pimozide blocked the establishment but not the expression of cocaine-produced environment-specific conditioning. These results suggest that during conditioning, the effects of cocaine on dopaminergic neurons may have produced a change that subsequently influenced behaviour even when dopaminergic systems were blocked.     

Opioid regulation of food intake and body weight in humans

Relatively few studies of humans have evaluated the effects of opioids on food intake and body weight. Most have focused on the potential role of opioids in the etiology of obesity. Measurements of endogenous opioids in plasma or spinal fluid of humans reveal higher levels, particularly of beta-endorphin, in obese subjects. Opioid agonists such as methadone and butorphanol tartrate stimulate food intake, and all studies with naloxone, an opioid antagonist, demonstrate a reduction of short-term food intake in obese or lean humans. Long-term studies with naltrexone, an antagonist similar to naloxone, show no effect on food intake or body weight. Opioid agonists or antagonists have little effect on nutrient selection in humans. The effects on feeding-related hormones is equivocal. Further studies with more specific opioid receptor activities are needed.     

Interindividual variability of methadone response: impact of genetic polymorphism

Methadone, an opioid analgesic, is used clinically in pain therapy as well as for substitution therapy in opioid addiction. It has a large interindividual variability in response and a narrow therapeutic index. Genetic polymorphisms in genes coding for methadone-metabolizing enzymes, transporter proteins (p-glycoprotein; P-gp), and mu-opioid receptors may explain part of the observed interindividual variation in the pharmacokinetics and pharmacodynamics of methadone. Cytochrome P450 (CYP) 3A4 and 2B6 have been identified as the main CYP isoforms involved in methadone metabolism. Methadone is a P-gp substrate, and, although there are inconsistent reports, ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics and influence dose requirements. Genetic polymorphism is the cause of high interindividual variability of methadone blood concentrations for a given dose; for example, in order to obtain methadone plasma concentrations of 250 ng/mL, doses of racemic methadone as low as 55 mg/day or as high as 921 mg/day can be required in a 70-kg patient without any co-medication. The clinician must be aware of the pharmacokinetic properties and pharmacological interactions of methadone in order to personalize methadone administration. In the future, pharmacogenetics, at a limited level, can also be expected to facilitate individualized methadone therapy.     

Adrenoceptor mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys.

The purpose of the current experiment was to study the role of various adrenoceptor subtypes in the cardiovascular response to cocaine in conscious squirrel monkeys. A variety of adrenoceptor antagonists were administered i.v. prior to the administration of 0.3 mg/kg cocaine (i.v.). Cocaine alone produced an increase in both blood pressure and heart rate. The non-selective alpha adrenoceptor antagonist phentolamine produced a dose-dependent antagonism of the pressor effect of cocaine, as did the alpha-1 selective antagonist prazosin. The alpha-2 selective antagonist yohimbine had no effect on the pressor effect of cocaine. The non-selective beta antagonist propranolol enhanced the pressor effect of cocaine as did the beta-1 selective antagonist atenolol. However, the effect of atenolol was not dose-dependent. The beta-2 selective antagonist ICI 118,551 and labetalol, which blocks both alpha and beta adrenoceptors, did not alter the pressor effect of cocaine. Propranolol, atenolol, and labetalol all antagonized the tachycardiac effect of cocaine in a dose-dependent manner, while the beta-2 antagonist ICI 118,551 did not. Phentolamine, prazosin and yohimbine also reduced the tachycardiac effect of cocaine, although these effects were dose-dependent only for yohimbine, which also significantly elevated baseline heart rate. These results indicate that alpha-1 adrenoceptor mechanisms mediate the pressor effect of cocaine, while beta-1 adrenoceptor mechanisms are involved in the tachycardiac effect of cocaine in squirrel monkeys. Propranolol potentiated cocaine's pressor effect through beta-2 independent mechanisms. Thus, neither alpha-2 nor beta-2 adrenoceptor mechanisms appear to be involved in cocaine's cardiovascular effects.