Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone.

BACKGROUND: One emerging strategy to address the opioid crisis includes opioid-targeted immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT) conjugate vaccine to antagonize heroin, 6-acetylmorphine (6-AM), morphine, and fentanyl antinociception in rats. METHODS: Adult male and female Sprague Dawley rats received three doses of active or control vaccine at weeks 0, 2, and 4. Vaccine pharmacological selectivity was assessed by comparing opioid dose-effect curves in 50 °C warm-water tail-withdrawal procedure before and after active or control heroin-TT vaccine. Route of heroin administration [subcutaneous (SC) vs. intravenous [IV)] was also examined as a determinant of vaccine effectiveness. Continuous naltrexone treatment (0.0032-0.032 mg/kg/h) effects on heroin, 6-AM, and morphine antinociceptive potency were also determined as a benchmark for minimal vaccine effectiveness. RESULTS: The heroin-TT vaccine decreased potency of SC heroin (5-fold), IV heroin (3-fold), and IV 6-AM (3-fold) for several weeks without affecting IV morphine or SC and IV fentanyl potency. The control vaccine did not alter potency of any opioid. Naltrexone dose-dependently decreased antinociceptive potency of SC heroin, and treatment with 0.01 mg/kg/h naltrexone produced similar, approximate 8-fold decreases in potencies of SC and IV heroin, IV 6-AM, and IV morphine. The combination of naltrexone and active vaccine was more effective than naltrexone alone to antagonize SC heroin but not IV heroin. CONCLUSIONS: The heroin-TT vaccine formulation examined is less effective, but more selective, than chronic naltrexone to attenuate heroin antinociception in rats. Furthermore, these results provide an empirical framework for future preclinical opioid vaccine research to benchmark effectiveness against naltrexone.

Chronic High-Dose Buprenorphine Does Not Block Subjective High from Diacetylmorphine in a Patient in Heroin-Assisted Treatment.

We present the case of a 35-year-old woman in heroin-assisted treatment (HAT) expressing the wish for the transition to oral opioid agonist treatment. After failed attempts to change to oral diacetylmorphine and slow-release oral morphine, respectively, she was induced on overlapping buprenorphine (BUP) treatment with the Bernese method. Gradual dose increases to BUP 48 mg per day did not result in attenuation of subjective effects of IV diacetylmorphine (DAM) 190 mg. Instead, the patient showed increased sedation. BUP was then reduced to 32 mg per day. After the gradual reduction of IV DAM, she reinitiated illicit substance use. IV DAM was again raised to an effective dose leading to stabilization and reduction of illicit substance use. BUP was subsequently reduced to 8 mg per day. This combination was continued as the patient felt comfortable and reported less early morning withdrawal than with exclusive DAM treatment. We discuss possible underlying mechanisms and explanations as well as clinical implications.

Lorcaserin decreases the reinforcing effects of heroin, but not food, in rhesus monkeys.

Preclinical studies indicate that lorcaserin (Belviq®), an FDA-approved serotonin 2 C receptor agonist, may be a promising medication for the treatment of stimulant addiction. However, few studies have investigated its effects on self-administration of drugs of abuse from other pharmacological classes, including opioids. Here, adult male rhesus macaques (N = 3) responded under a fixed ratio 30 schedule of food (1-g banana-flavored pellets) and IV heroin delivery. Following stable self-administration of a range of heroin doses (0.32-32 µg/kg/inj, IV), the effects of acute pretreatment with lorcaserin (0.32-1.0 mg/kg, IM) on heroin- and food-maintained responding was determined. The ability of repeated treatment with lorcaserin (1.0 mg/kg) to produce sustained decreases in heroin and/or food intake and reinforcing strength were then analyzed using behavioral economic demand procedures. Results show that self-administration of intravenous heroin was dose-dependent, with peak responding maintained, on average, by the unit dose of 3.2 µg/kg/inj. Lorcaserin pretreatment produced a dose-dependent flattening of the dose-response function for heroin self-administration in each subject. On the other hand, lorcaserin did not decrease food-maintained responding. Repeated lorcaserin treatment reduced heroin intake by selectively decreasing its reinforcing strength, as evidenced by a leftward shift in the demand curves for heroin and the absence of comparable changes in the reinforcing strength of food. These results indicate that serotonin 2 C receptor agonists, such as lorcaserin, have behaviorally selective effects on IV self-administration behavior, and deserve further consideration as candidates for the management of opioid use disorder.

Intravenous use of intranasal naloxone: A case of overdose reversal.

BACKGROUND: Opioid overdose is a growing concern in the United States and internationally. Prehospital or pre-medical personnel (layperson) administration of naloxone, an opioid antagonist, to reverse overdose, is an expanding mode of harm reduction. Recently, community clinics, methadone clinics, needle exchanges, some pharmacies, and other health care facilities have made naloxone available to the community. CASE: This case describes heroin overdose reversal of a 28-year-old male who had been using about a gram of heroin intravenously for 3 years but recently reduced frequency of use in an attempt to stop. He was seen initially 1 week prior to a buprenorphine induction in our clinic. After the initial intake, he used intravenous heroin, a larger amount than over the past several weeks in anticipation of abstinence, lost consciousness, and was difficult to arouse. A friend with him noted the patient's respirations to become shallow and administered naloxone nasal spray that the patient had obtained from a needle exchange, but did so intravenously by attaching an unused drug needle to the syringe barrel in place of the nasal atomizer. The patient's overdose was reversed and he recovered. DISCUSSION: This is the first known published case of a community-distributed naloxone nasal spray being used intravenously by a layperson (bystander). The case emphasizes the efficacy of naloxone in overdose reversal and also the need for education or instructions on naloxone use by others (not just the user). Finally, it highlights the risk of overdose in those entering treatment, seeking intoxication one last time.

Comparison of (+)- and (-)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice.

Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (-)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (-)-naloxone in the blood and brain. We found that (-)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (-)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers' ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling.

Stakeholder perceptions and operational barriers in the training and distribution of take-home naloxone within prisons in England.

BACKGROUND: The aim of the study was to assess potential barriers and challenges to the implementation of take-home naloxone (THN) across ten prisons in one region of England. METHODS: Qualitative interviews deploying a grounded theory approach were utilised over a 12- to 18-month period that included an on-going structured dialogue with strategic and operational prison staff from the ten prisons and other key stakeholders (n = 17). Prisoner perceptions were addressed through four purposive focus groups belonging to different establishments (n = 26). Document analysis also included report minutes and access to management information and local performance reports. The data were thematically interpreted using visual mapping techniques. RESULTS: The distribution and implementation of THN in a prison setting was characterised by significant barriers and challenges. As a result, four main themes were identified: a wide range of negative and confused perceptions of THN amongst prison staff and prisoners; inherent difficulties with the identification and engagement of eligible prisoners; the need to focus on individual prison processes to enhance the effective distribution of THN; and the need for senior prison staff engagement. CONCLUSIONS: The distribution of THN within a custodial setting requires consideration of a number of important factors which are discussed.

Two cases of intranasal naloxone self-administration in opioid overdose.

BACKGROUND: Overdose is a leading cause of death for former prisoners, exacting its greatest toll during the first 2 weeks post release. Protective effects have been observed with training individuals at high risk of overdose and prescribing them naloxone, an opioid antagonist that reverses the effects of the opioid-induced respiratory depression that causes death. CASES: The authors report 2 people with opiate use histories who self-administered intranasal naloxone to treat their own heroin overdoses following release from prison. Patient A is a 34-year-old male, who reported having experienced an overdose on heroin the day after he was released from incarceration. Patient B is a 29-year-old female, who reported an overdose on her first injection of heroin, 17 days post release from incarceration. Both patients self-administered the medication but were assisted at some point during the injury by a witness whom they had personally instructed in how to prepare and administer the medication. Neither patient experienced withdrawal symptoms following exposure to naloxone. DISCUSSION: Self-administration of naloxone should not be a goal of overdose death prevention training. A safer, more reliable approach is to prescribe naloxone to at-risk patients and train and also equip members of their household and social or drug-using networks in overdose prevention and response.

The NK1 receptor antagonist L822429 reduces heroin reinforcement.

Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin self-administration and heroin-induced reinstatement in rats.

Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5 mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5 mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5 mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement.

Is slow-onset long-acting monoamine transport blockade to cocaine as methadone is to heroin? Implication for anti-addiction medications.

The success of methadone in treating opiate addiction has suggested that long-acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadone's effects on heroin's actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48 h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroin's actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadone's actions, that is, functionally antagonizing cocaine's action while blocking monoamine transporters to augment synaptic DA.

Vaccines against morphine/heroin and its use as effective medication for preventing relapse to opiate addictive behaviors.

Current pharmacotherapies for treating morphine/heroin dependence are designed to substitute or block addiction by targeting the drug itself rather than the brain. The heroin addict is still being exposed to addictive opiates, and consequently may develop tolerance to and experience withdrawal and drug's toxic effects from the treatment with high incidence of relapse to addictive drug consumption. As for other drugs of abuse, an alternative approach for morphine/heroin addiction is an antibody-based antagonism of heroin's brain entry. This review summarizes the literature examining important aspects of neurobiological and pharmacological processes involved in opiate dependence. Thereafter, classical pharmacological interventions for opiate dependence treatment and its major clinical limitations are reviewed. Finally, relevant preclinical studies are examined for comparisons in the design, use, immunogenic profile and efficacy of several models of morphine/heroin vaccine as immunologic interventions on the pharmacokinetics and behavioral of morphine/heroin in the rat as animal model.

Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin.

RATIONALE: Naltrexone is an opioid antagonist that is currently approved as a treatment for opioid and alcohol dependence. Although it is highly effective in completely antagonizing the effects of opioids, medication noncompliance is a difficult obstacle to treatment. Therefore, a sustained-release form of naltrexone may improve treatment outcome. OBJECTIVE: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex). MATERIALS AND METHODS: Five heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, the effects of a range of heroin doses (0, 6.25, 12.5, and 25 mg, i.v.) were examined. Participants then received 384 mg naltrexone base. The effects of heroin were again evaluated for the next 6 weeks. One dose of heroin was tested per day and the entire dose range was tested each week. Doses were administered in non-systematic order. During a morning sample session, participants received a dose of heroin and $20 and subjective, performance, and physiological effects were measured both before and after drug administration. During an afternoon choice session, participants were given the opportunity to choose the sampled heroin dose and/or amount of money using a modified progressive ratio procedure. RESULTS: Depot naltrexone antagonized both the reinforcing and subjective effects of heroin for 4-5 weeks. Subjective ratings of withdrawal were reduced after week 2 and throughout the remainder of the study. The effects of heroin on mean trough pupil diameter began to emerge by week 5. There were no clinically significant effects on respiratory or cardiovascular function. CONCLUSIONS: The present results extend our previous findings by showing that the reinforcing effects of heroin were reduced for 4-5 weeks after administration of 384 mg depot naltrexone.

RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia.

Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes. However, pharmacological agents that would help define physiological roles for this peptide are still missing. Here we report the discovery of a potent and selective NPFF receptor antagonist, RF9, that can be administered systemically. This compound does not show any effects by itself but can block efficiently the increase in blood pressure and heart rate evoked by NPFF. When chronically coinjected with heroin, RF9 completely blocks the delayed and long-lasting paradoxical opioid-induced hyperalgesia and prevents the development of associated tolerance. Our data indicate that NPFF receptors are part of a bona fide antiopioid system and that selective antagonists of these receptors could represent useful therapeutic agents for improving the efficacy of opioids in chronic pain treatment.

Alterations of immune functions in heroin addicts.

The alteration of peripheral blood T-and B-lymphocyte proliferative responses were determined during different periods of withdrawal in heroin (Hw) and heroin / bhang (HBw) addicts. The results clearly demonstrated a significant decrease in the response of T- lymphocytes to PHA-stimulation and secretion of IL-2 in both Hw and HBw addicts. The in vitro presence of naloxone induced further inhibition of the PHA proliferative response and IL-2 production. Our data also indicated a significant suppression of IFN-gamma levels by human blood lymphocytes from Hw and HBw addicts. Additionally, a significant suppression of IFN-gamma production was demonstrated in the presence of naloxone. Moreover, IL-4 production was suppressed in Hw, but not in HBw groups and the in vitro presence of naloxone did not affect the level of IL-4 in both groups. However, IL-10 production was significantly increased in both groups accompanied by a significant suppression of IL-10 secretion in the presence of naloxone. In contrast, IL-5 levels stimulated by PHA showed a significant increase in both groups, while no significant effect of naloxone could be observed. Our results suggested that heroin administration can cause measurable suppression of some components of the human cellular immune system. The results further demonstrated that the immunsuppressive effect observed after heroin use are naloxone-mediated and suggested that activation of the adrenal gland is one potential mechanism for this effect.

Cannabinoid receptor antagonist reduces heroin self-administration only in dependent rats.

Functionality of the endogenous cannabinoid system undergoes relevant changes in reward-related brain areas in animal models of opiate addiction. By using a limited access heroin self-administration paradigm we show that cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 0.03-3.0 mg/kg) suppresses heroin self-administration only in opiate-dependent rats but not in non-dependent animals. These results further support the study of cannabinoid CB(1) receptor antagonists for the treatment of opiate addiction.

[Preparation and characterization of anti-morphine antiserum].

OBJECTIVE: To prepare the holoantigens of morphine and morphine-6-succinyl, and to evaluate the efficacy of both of the haptens in eliciting immune responses and their effects on morphine withdrawal symptoms in male mice. METHODS: Morphine-6-succinyl was prepared using acid anhydride mixture, and conjugated, along with morphine, with Blue carrier in the presence of carbodi imide. Immunization of mice with both the holoantigens and Freund adjuvant was performed, followed by determination of the antibody titer in the mouse serum with competitive ELISA and morphine dependence evaluation. RESULTS: The titers of the antibodies exceeded 1:8 000 in the serum of mice immunized with both holoantigens, and morphine- 6-succinyl induced a higher titer that was maintained for a longer period. The inhibition rates of the antisera to morphine and morphine-6-auccinyl had both reached 50%, and increased in a dose-dependent manner. CONCLUSION: Both morphine carrier conjugates can elicit high-titer antibody response in mice and relieve morphine addiction.

Effects of heroin and its metabolites on schedule-controlled responding and thermal nociception in rhesus monkeys: sensitivity to antagonism by quadazocine, naltrindole and beta-funaltrexamine.

Recent studies have reported differences in the receptor mechanisms and intrinsic efficacies of heroin and its metabolites 6-acetylmorphine and morphine in rodents. The present study examined the generality of these findings to rhesus monkeys using two behavioral procedures. In an assay of schedule-controlled behavior, response rates were recorded under a fixed-ratio 30 schedule of food presentation. In an assay of thermal nociception, tail-withdrawal latencies were measured from warm water (42-58 degrees C). Heroin, 6-acetylmorphine and morphine produced dose-dependent rate-decreasing and antinociceptive effects. Antagonism studies were conducted with the competitive mu-selective antagonist quadazocine, the competitive delta-selective antagonist naltrindole, and the irreversible mu-selective antagonist beta-funaltrexamine (beta-FNA). Quadazocine dose-dependently antagonized the effects of all three opioids. Quadazocine pA2 values were similar across drugs and assays (7.4-7.8) and similar to quadazocine pA2 values for antagonism of other mu agonists. In contrast, naltrindole did not alter the effects of any of the opioids. beta-FNA antagonized the rate-decreasing and antinociceptive effects of heroin and morphine. Dose-effect data for heroin- and morphine-induced antinociception alone and after beta-FNA treatment were used to estimate in vivo apparent efficacy values (tau). Tau values (95% confidence limits) were 8.1 (6.9-9.6) for heroin and 2.6 (2.5-2.9) for morphine, but this difference is relatively small. These results suggest that the rate-decreasing and antinociceptive effects of heroin, 6-acetylmorphine and morphine are mediated by pharmacologically similar populations of mu opioid receptors in rhesus monkeys. The in vivo apparent efficacy of heroin at mu receptors was similar to or only slightly greater than that of morphine.

Serum naltrexone and 6-beta-naltrexol levels from naltrexone implants can block very large amounts of heroin: a report of two cases.

The maximum dose of heroin that is blocked by customary doses of oral naltrexone (NTX) and its active metabolite 6-beta-naltrexol (6BNT) is unknown, particularly at trough serum levels which show much interindividual variation and can be low. NTX has only once been tested formally against opiate equivalents of more than 25 mg of diamorphine. Increasing interest in long-acting implantable NTX preparations makes it important to have objective information about blocking activity at various blood levels of NTX and 6BNT. Two cases are described in which NTX and 6BNT levels as low as 2.8 and 9.0 ng/ml, respectively, were sufficient to block doses of pure diamorphine as high as 500 mg.

Antagonism of the antinociceptive and discriminative stimulus effects of heroin and morphine by 3-methoxynaltrexone and naltrexone in rhesus monkeys.

It has been suggested that heroin and morphine may act on different opioid receptor populations in rodents. In support of this hypothesis, the opioid antagonist 3-methoxynaltrexone was reported to be more potent as an antagonist of the antinociceptive effects of heroin than of morphine in mice and rats. To assess the generality of this finding across species and experimental endpoints, the present study compared the potencies of naltrexone and 3-methoxynaltrexone as antagonists of heroin and morphine in two behavioral assays in rhesus monkeys. In the thermal nociception study, tail-withdrawal latencies were measured from water heated to 50 degrees C. In the heroin discrimination study, monkeys were trained to discriminate 0.1 mg/kg heroin from saline in a two-key, food-reinforced drug discrimination procedure, and percentage of heroin-appropriate responding and response rates were measured. Both heroin and morphine produced dose-dependent antinociception, increases in percentage of heroin-appropriate responding, and decreases in response rates. Heroin was approximately 20-fold more potent than morphine. Naltrexone (0.032-0.1 mg/kg) was equipotent in antagonizing all effects of heroin and morphine (pA(2) values = 7.90-8.22). 3-Methoxynaltrexone (0.1-3.2 mg/kg) was also equipotent in antagonizing the antinociceptive, discriminative stimulus, and rate-suppressant effects of heroin and morphine; however, 3-methoxynaltrexone was approximately 100-fold less potent than naltrexone (pA(2)/pK(B) values = 5.96-6.36). These results suggest that heroin and morphine act on pharmacologically similar populations of opioid receptors in rhesus monkeys, and also indicate that 3-methoxynaltrexone does not differentially antagonize the effects of heroin and morphine in rhesus monkeys.

Characterization of the discriminative stimulus effects of buprenorphine in pigeons.

RATIONALE: Buprenorphine is a low-efficacy mu opioid agonist that can reduce drug taking in opioid abusers; however, the mechanism by which buprenorphine modifies the actions of other drug taking and the consequences of repeated treatment with buprenorphine are not fully understood. OBJECTIVE: The purposes of this study were to evaluate the time- and dose-dependence of discriminative stimulus effects in pigeons receiving buprenorphine repeatedly and to examine possible interactions between buprenorphine and heroin. METHODS: Six pigeons discriminated between vehicle and 0.178 mg/kg buprenorphine while responding under an FR schedule for food. Substitution and drug combination studies characterized the potency and time course for buprenorphine, as well as interactions between buprenorphine and heroin. RESULTS: Stimulus control by buprenorphine was maintained throughout the study and was not changed by repeated daily dosing or by an acute injection of large doses of buprenorphine. Mu opioid agonists substituted for buprenorphine with the following order of potency: heroin > or = butorphanol > nalbuphine > or = morphine. Ketamine, enadoline, spiradoline, amphetamine and cocaine failed to substitute completely for buprenorphine. The discriminative stimulus effects of buprenorphine lasted 2-72 h, depending on dose, and naltrexone prevented but did not reverse the effects of buprenorphine. CONCLUSION: Despite a very long duration of action and apparent irreversibility, under these conditions in pigeons, buprenorphine does not modulate the discriminative stimulus effects of itself or heroin. Thus, simple agonism might account for the therapeutic effectiveness of buprenorphine in opioid abusers.