Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

Interactions between lorcaserin and opioids: Ventilation and food-versus-drug choice.

Lorcaserin, a selective serotonin 2C (5-HT2C) receptor agonist, was approved for treating obesity and has been investigated for treating substance use disorders including those involving opioids. Although lorcaserin was withdrawn from the market, interest in the therapeutic potential of drugs acting at 5-HT2C receptors continues, supporting the need to further characterize potential adverse effects especially when combined with drugs of abuse. This study examined acute effects of lorcaserin on opioid-induced ventilatory depression, which is the primary cause of overdose, and opioid self-administration, which models factors contributing to opioid abuse, in male and female rhesus monkeys. In one group (n = 4), effects of morphine (0.178 to 5.6 mg/kg, s.c.), fentanyl (0.0032 to 0.1 mg/kg, s.c.), and lorcaserin (0.1 to 1.78 mg/kg, s.c.) alone as well as effects of lorcaserin with each opioid on ventilation were determined using head plethysmography. Another group (n = 5) responded under a food versus fentanyl (0.1 to 3.2 µg/kg/infusion, i.v.) choice procedure, and lorcaserin (0.32 to 1.78 mg/kg, i.v.) was given as a pretreatment. Lorcaserin dose-dependently decreased minute volume to below 70 % of baseline when administered alone and increased the potency of morphine and fentanyl. Consistent with previous studies, lorcaserin failed to alter choice of fentanyl over food. This study demonstrates the novel finding that lorcaserin alone decreases ventilation and enhances the ventilatory-depressant effects of opioids. Taken together with previous studies, these results suggest that combining a 5-HT2C receptor agonist such as lorcaserin with an opioid could increase the risk of ventilatory depression without the benefit of decreasing abuse.

Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder.

Opioid overdose and opioid use disorder continue to be significant public health challenges despite the availability of effective medications and significant efforts at all levels of society. The emergence of highly potent and efficacious opioids such as fentanyl and its derivatives over the last decade has only exacerbated what was already a substantial problem. Behavioral pharmacology research has proven invaluable for understanding the effects of drugs as well as developing and evaluating pharmacotherapies for disorders involving the central nervous system, including substance abuse disorders. This paper describes a program of research characterizing a potent, selective, and long-lasting mu opioid receptor antagonist, methocinnamox, and evaluating its potential for treating opioid overdose and opioid use disorder. Studies in rodents and nonhuman primates demonstrate that methocinnamox prevents and reverses opioid-induced ventilatory depression and selectively blocks opioid self-administration. This work, taken together with rigorous in vitro and ex vivo studies investigating methocinnamox neuropharmacology, lays a solid foundation for the therapeutic utility of this potentially life-saving medication. Moreover, these studies demonstrate how rigorous behavioral pharmacological studies can be integrated in a broader drug discovery and development research program.

Effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC/CBD mixtures on fentanyl versus food choice in rhesus monkeys.

INTRODUCTION: There is considerable interest in utilizing cannabis-based products as adjuvants to opioid agonist therapies as phytocannabinoids like Δ9-tetrahydrocannabinol (THC) or synthetic cannabinoid receptor agonists appear to enhance the pain-relieving effects of opioids without enhancing problematic effects of opioids. Cannabis is a pharmacologically complex plant with hundreds of compounds, some of which may have interactive effects. Therefore, studying compounds like THC in isolation does not accurately reflect the clinical use of cannabis. METHODS: This study examined the effects of THC and cannabidiol (CBD), the two most prominent compounds in cannabis, on the reinforcing effects of fentanyl in rhesus monkeys in a food versus drug choice procedure. Responding on one lever was reinforced by delivery of a sucrose pellet, and responding on another lever was reinforced by delivery of an i.v. infusion of fentanyl. In each monkey, the largest dose of fentanyl that produced less than 20 % drug choice and the smallest dose of fentanyl that produced more than 80% drug choice was determined. Effects of pretreatment with THC and CBD, alone and in mixtures, were then examined. RESULTS: THC, CBD, and THC:CBD mixtures did not reliably enhance or diminish choice for fentanyl up to doses that suppressed responding in most monkeys, though some individual differences were observed, with THC and THC:CBD mixtures decreasing choice for large doses of fentanyl in one monkey and increasing choice for small doses of fentanyl in another. CONCLUSIONS: Phytocannabinoids like THC and CBD, administered alone or in mixtures, do not appear to reliably alter the reinforcing effects of opioids.

Effects of 2,5-Dimethoxy-4-Methylamphetamine (DOM) and 2-Piperazin-1-yl-Quinoline (Quipazine) on Fentanyl Versus Food Choice in Rhesus Monkeys.

There has been increasing interest in the potential therapeutic effects of drugs with agonist properties at serotonin 2A subtype (5-HT2A) receptors (e.g., psychedelics), including treatment of substance use disorders. Studying interactions between 5-HT2A receptor agonists and other drugs is important for understanding potential therapeutic effects as well as adverse interactions. Direct-acting 5-HT2A receptor agonists such as 2,5-dimethoxy-4-methylamphetamine (DOM) and 2-piperazin-1-yl-quinoline (quipazine) enhance some (e.g., antinociceptive) effects of opioids; however, it is unclear whether they alter the abuse-related effects of opioids. This study examined whether DOM and quipazine alter the reinforcing effects of fentanyl in rhesus monkeys (n = 6) responding under a food versus drug choice procedure. Responding on one lever delivered sucrose pellets and responding on the other lever delivered intravenous (i.v.) infusions. In one set of experiments, fentanyl (0.1-3.2 µg/kg/infusion) versus food choice sessions were preceded by noncontingent i.v. pretreatments with DOM (0032-0.32 mg/kg), quipazine (0.32-1.0 mg/kg), naltrexone (0.032 mg/kg), or heroin (0.1 mg/kg). In another set of experiments, fentanyl was available during choice sessions in combination with DOM (0.32-100 µg/kg/infusion) or quipazine (3.2-320 µg/kg/infusion) in varying dose ratios. Naltrexone decreased and heroin increased fentanyl choice, demonstrating sensitivity of responding to pharmacological manipulation. However, whether given as a pretreatment or made available in combination with fentanyl as a mixture, neither DOM nor quipazine significantly altered fentanyl choice. These results suggest that 5-HT2A receptor agonists do not enhance the reinforcing effects of opioids and, thus, will not likely enhance abuse potential. SIGNIFICANCE STATEMENT: Serotonin 2A subtype receptor agonists enhance some (e.g., antinociceptive) effects of opioids, suggesting they could be combined with opioids in some therapeutic contexts such as treating pain. However, it is unclear whether they also enhance adverse effects of opioids, including abuse. Results of this study indicate that serotonin 2A subtype receptor agonists do not reliably enhance opioid self-administration and, thus, are unlikely to enhance the abuse potential of opioids.

OREX-1038: a potential new treatment for pain with low abuse liability and limited adverse effects.

Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.

Effects of Daily Methocinnamox Treatment on Fentanyl Self-Administration in Rhesus Monkeys.

Methocinnamox (MCAM), a long-acting µ-opioid receptor antagonist, attenuates the positive reinforcing effects of opioids, such as heroin and fentanyl, suggesting it could be an effective treatment of opioid use disorder (OUD). Because treatment of OUD often involves repeated administration of a medication, this study evaluated effects of daily injections of a relatively small dose of MCAM on fentanyl self-administration and characterized the shift in the fentanyl dose-effect curve. Rhesus monkeys (3 males and 2 females) lever-pressed for intravenous infusions of fentanyl (0.032-10 µg/kg infusion) or cocaine (32-100 µg/kg infusion) under a fixed-ratio 30 schedule. MCAM (0.032 mg/kg) or naltrexone (0.0032-0.032 mg/kg) was administered subcutaneously 60 or 15 minutes, respectively, before sessions. When administered acutely, naltrexone and MCAM decreased fentanyl self-administration, with effects of naltrexone lasting less than 24 hours and effects of MCAM lasting for up to 3 days. Daily MCAM treatment attenuated responding for fentanyl, but not cocaine; effects were maintained for the duration of treatment with responding recovering quickly (within 2 days) following discontinuation of treatment. MCAM treatment shifted the fentanyl dose-effect curve in a parallel manner approximately 20-fold to the right. Naltrexone pretreatment decreased fentanyl intake with equal potency before and after MCAM treatment, confirming sensitivity of responding to antagonism by an opioid receptor antagonist. Although antagonist effects of treatment with a relatively small dose were surmountable, MCAM produced sustained and selective attenuation of opioid self-administration, supporting the view that it could be an effective treatment of OUD. SIGNIFICANCE STATEMENT: Opioid use disorder and opioid overdose continue to be significant public health challenges despite the availability of effective treatments. Methocinnamox (MCAM) is a long-acting µ-opioid receptor antagonist that blocks the reinforcing and ventilatory depressant effects of opioids in nonhuman subjects. This study demonstrates that daily treatment with MCAM reliably and selectively decreases fentanyl self-administration, further supporting the potential therapeutic utility of this novel antagonist.

Interactions between impulsivity and MDPV self-administration in rats.

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are recreational drugs of abuse often identified in 'bath salts' preparations. Humans report compulsive patterns of bath salts use, and previous work suggests that a subset of rats develop unusually high levels of MDPV self-administration. This study aims to test the hypothesis that high levels of impulsivity (e.g., inability to withhold responding for a sucrose reward) will predispose rats to high levels of MDPV self-administration relative to rats with lower levels of impulsivity. The 1-choice serial reaction time task (1-CSRTT) was used to assess impulsivity (i.e., premature responding) in 10 female and 10 male Sprague Dawley rats. Rats were then allowed to self-administer 0.032 mg/kg/inf MDPV or 0.32 mg/kg/inf cocaine, after which full dose-response curves for MDPV (0.001-0.1 mg/kg/inf) or cocaine (0.01-1 mg/kg/inf) were generated under a FR5 schedule of reinforcement. After a history of self-administering MDPV or cocaine, impulsivity was reassessed under the 1-CSRTT, prior to evaluating the acute effects of MDPV (0.032-0.32 mg/kg) or cocaine (0.1-1 mg/kg) on impulsivity. Level of impulsivity was not correlated with subsequent levels of either MDPV or cocaine self-administration, and level of drug self-administration was also not correlated with subsequent levels of impulsivity, although acute administration of MDPV and cocaine did increase premature responding. In failing to find direct relationships between either impulsivity and subsequent drug-taking behaviour, or drug-taking behaviour and subsequent assessments of impulsivity, these findings highlight the complexity inherent in the associations between impulsive behaviour and drug-taking behaviour in both animal models and humans.

Interactions between opioids and stimulants: Behavioral pharmacology of abuse-related effects.

Opioid abuse continues to be a significant public health challenge, with rates of opioid-related overdose deaths increasing continuously over the last two decades. There also has been a sharp increase in overdose deaths involving stimulant drugs, primarily cocaine and methamphetamine. Recent estimates indicate a high prevalence of co-use of opioids and stimulants, which is a particularly complex problem. Behavioral pharmacology research over the last few decades has characterized interactions between opioids and stimulants as well as evaluated potential treatments. This chapter describes interactions between opioids and stimulants, with a focus on pre-clinical studies of abuse-related behavioral effects using self-administration, reinstatement, drug discrimination, place conditioning, and intracranial self-stimulation paradigms in laboratory animals. In general, the literature provides substantial evidence of mutual enhancement between opioids and stimulants for abuse-related effects, although such results are not ubiquitous. Enhanced abuse-related effects could manifest in many ways including engaging in drug seeking and taking behaviors with greater persistence, effort, and motivation and/or increased likelihood of relapse. Moreover, studies on opioid/stimulant combinations set the stage for evaluating potential treatments for polysubstance use. Behavioral pharmacology research has proven invaluable for elucidating these relationships using rigorous experimental designs and quantitative analyses of pharmacological and behavioral data.

Countermeasures for Preventing and Treating Opioid Overdose.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic "nanosponge" decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder.

Behavioral effects of benzylideneoxymorphone (BOM), a low efficacy µ opioid receptor agonist and a δ opioid receptor antagonist.

RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects often limit use. Drugs acting concomitantly as agonists at µ opioid receptors and antagonists at δ opioid receptors produce antinociceptive effects with a reduced profile of adverse effects; one such drug, benzylideneoxymorphone (BOM), might further limit adverse effects because it appears to have lower pharmacological efficacy than other µ opioid receptor agonists. OBJECTIVES: The current study compared the acute behavioral effects of BOM with the effects of other µ opioid receptor agonists. METHODS: Discriminative stimulus and rate-decreasing effects were studied in 1 group of 7 rats discriminating 3.2 mg/kg morphine while responding under a fixed-ratio 10 schedule of food presentation. Antinociceptive effects were determined in a second group of 8 rats using a warm water tail withdrawal procedure. Reinforcing effects were evaluated in a third group of 12 rats with a history of remifentanil self-administration. RESULTS: BOM produced morphine-lever responding and both discriminative stimulus and rate-decreasing effects were antagonized by naltrexone. BOM did not markedly increase tail-withdrawal latencies from water maintained at 50 °C and did not substantially attenuate the antinociceptive effects of morphine. BOM was not self-administered and did not change remifentanil self-administration. CONCLUSIONS: Some effects of BOM (e.g., discriminative stimulus effects) appear to be mediated by µ opioid receptors; however, BOM is not self-administered by rats, suggesting that it might have limited abuse liability and a reduced profile of adverse effects compared with currently prescribed opioids.

Interactions between opioids and cannabinoids: Economic demand for opioid/cannabinoid mixtures.

BACKGROUND: Opioid abuse remains a significant public health challenge. With continuing emergence of novel psychoactive substances (e.g., synthetic cannabinoids found in "K2" or "spice" preparations), the co-administration of opioids and other novel drugs is likely to become more prevalent, which might increase the risk for abuse and other adverse effects. This study examined whether the synthetic cannabinoid receptor agonist JWH-018 alters the reinforcing effectiveness of the mu opioid receptor agonist remifentanil in rhesus monkeys (n = 4) using economic demand analyses. METHODS: Lever presses delivered intravenous infusions of a drug or drug mixture according to a fixed-ratio schedule. For each condition, the ratio progressively increased in quarter-log unit steps across sessions yielding a demand curve: consumption (infusions obtained) was plotted as a function of price (fixed-ratio value). RESULTS: When available alone, remifentanil (0.00032 mg/kg/infusion) occasioned the highest consumption at the lowest cost and highest essential value, while JWH-018 (0.0032 mg/kg/infusion) alone occasioned lower unconstrained demand and essential value. Unconstrained demand for a mixture of remifentanil and JWH-018 was lower than for remifentanil alone, but essential value of the mixture was not significantly different from that of remifentanil alone. CONCLUSION: These data indicate that synthetic cannabinoids such as JWH-018 might alter some aspects of opioid self-administration (i.e., decreased consumption at the lowest price) but do not enhance reinforcing effectiveness as measured by sensitivity of consumption to increasing costs. Opioid/cannabinoid mixtures do not appear to have greater or lesser abuse potential compared with opioids alone.

Developing Improved Translational Models of Pain: A Role for the Behavioral Scientist.

The effective management of pain is a longstanding public health concern. Although opioids have been frontline analgesics for decades, they also have well-known undesirable effects that limit their clinical utility, such as abuse liability and respiratory depression. The failure to develop better analgesics has, in some ways, contributed to the escalating opioid epidemic that has claimed tens of thousands of lives and has cost hundreds of billions of dollars in health-care expenses. A paradigm shift is needed in the pharmacotherapy of pain management that will require extensive efforts throughout biomedical science. The purpose of the present review is to highlight the critical role of the behavioral scientist to devise improved translational models of pain for drug development. Despite high heterogeneity of painful conditions that involve cortical-dependent pain processing, current models often feature an overreliance on simple reflex-based measures and an emphasis on the absence, rather than presence, of behavior as evidence of analgesic efficacy. Novel approaches should focus on the restoration of operant and other CNS-mediated behavior under painful conditions.

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys.

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.

Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors.

Despite the therapeutic utility of opioids for relieving pain, other behavioral effects, including their potential for abuse and overdose, can be quite detrimental to individuals as well as society and have contributed to the ongoing opioid crisis. The dramatic escalation in overdose deaths over the last 15 years was initially driven by abuse of prescription opioids, although abuse of heroin, fentanyl, and fentanyl analogs has been increasing, largely due to increased availability and lower cost compared with prescription opioids. All of these opioids share pharmacological properties, acting as agonists at mu opioid receptors, and produce similar behavioral effects, including abuse-related, pain-relieving, dependence-producing, and respiratory-depressant effects. Despite their similarities, opioids are not pharmacologically identical. In fact, drugs that act at mu opioid receptors, including abused opioids, can vary on a number of dimensions, including pharmacological efficacy, drug-receptor interactions, receptor selectivity, and pharmacokinetics. Overall, these differences impact behavioral effects of drugs acting at mu opioid receptors, and this chapter describes variations in those behavioral effects and how these differences continue to provide new strategies that can be developed to address the ongoing opioid epidemic.

Impact of order of fixed-ratio presentation on demand for self-administered remifentanil in male rats.

The behavioral economics framework has been used extensively to study factors that control operant behavior, including quantification of reinforcing effectiveness of drugs of abuse. Generally, consumption of a commodity decreases with increasing price, and the rate of decrease reflects demand elasticity, which is inversely related to reinforcing effectiveness. Drugs with low elasticity have greater effectiveness than those with greater elasticity. Price is often manipulated by varying the number of responses required to obtain an infusion (e.g. fixed ratio schedule); however, many studies present the fixed ratio in only one order (usually ascending), which could introduce sequence effects that influence estimates of demand. This study examined the impact of the order of fixed ratio presentation on demand for the mu opioid receptor agonist remifentanil (0.0032 mg/kg/infusion) using an ascending and a mixed order of fixed ratio presentation. Seven male rats lever pressed for intravenous infusions. The fixed ratio varied across 3-session blocks, yielding a demand curve. During the first and third phases, the fixed ratio increased, and, during the second phase, fixed ratio values were presented in a mixed order. On average, rats obtained more than 60 infusions per session under baseline (fixed ratio 1) during the each of the three phases, with the number of infusions received decreasing progressively with increasing fixed ratio values. Estimates of elasticity across the three phases were not statistically different indicating that the order of fixed ratio presentation did not markedly alter estimates of demand and further demonstrating the robustness of price as a source of control over operant behavior, including behavior maintained by drug reinforcers.

OREX-1019: A Novel Treatment of Opioid Use Disorder and Relapse Prevention.

There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the µ opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at µ opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-a-go-go-related gene) K+ channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.

Effects of the synthetic cannabinoid receptor agonist JWH-018 on abuse-related effects of opioids in rhesus monkeys.

Opioid abuse remains a public health crisis despite a tremendous outpouring of resources to address the problem. One factor that might complicate this issue is polydrug abuse. While cannabis is increasingly available due to legalization by states, phytocannabinoids do not appear to alter the abuse-related effects of opioids. Synthetic cannabinoids, which are not pharmacologically identical to phytocannabinoids, are also increasingly available, and differences among cannabinoids might affect their interactions with opioids. This study assessed the impact of one synthetic cannabinoid, JWH-018, on the effects of two µ opioid receptor agonists using two procedures that address different aspects of abuse. First, four monkeys could choose to self-administer the opioid remifentanil alone (0.32 µg/kg/infusion) or a mixture containing 0.32 µg/kg/infusion remifentanil and JWH-018 (1-10 µg/kg/infusion). On separate occasions, monkeys could choose between remifentanil available alone or combined with 100 µg/kg/infusion cocaine. While monkeys chose the remifentanil/cocaine mixture over remifentanil alone, they responded equally for remifentanil alone and the remifentanil/JWH-018 mixture. The ability of JWH-018 to reinstate extinguished responding previously maintained by heroin was examined in four other monkeys. When presented with drug-associated stimuli, heroin, but not JWH-018, reinstated responding, and when combined, JWH-018 did not increase the potency of heroin. While opioids and synthetic cannabinoids, including JWH-018, are abused, these results indicate that JWH-018 does not modify the behavioral effects of opioids in monkeys in a manner that would predict greater abuse liability of cannabinoid/opioid mixtures, a result that is consistent with a growing literature on mixtures of opioids and phytocannabinoids.

Effects of amphetamine, methylphenidate, atomoxetine, and morphine in rats responding under an adjusting stop signal reaction time task.

RATIONALE: Stop signal reaction time procedures are used to investigate behavioral and neurobiological processes that contribute to behavioral inhibition and to evaluate potential therapeutics for disorders characterized by disinhibition and impulsivity. The current study examined effects of amphetamine, methylphenidate, atomoxetine, and morphine in rats responding under an adjusting stop signal reaction time task that measures behavioral inhibition, as well as motor impulsivity. METHODS: Rats (n = 8) completed a two-response sequence to earn food. During most trials, responses following presentation of a visual stimulus (go signal) delivered food. Occasionally, a tone (stop signal) was presented signifying that food would be presented only if the second response was withheld. Responding after the stop signal measured inhibition and responding prior to the start of the trial (premature) measured motor impulsivity. Delay to presentation of the stop signal was adjusted for individual subjects based on performance. RESULTS: Amphetamine and methylphenidate increased responding after presentation of the stop signal and markedly increased premature responding. Atomoxetine modestly improved accuracy on stop trials and decreased premature responding. Morphine did not alter stop trial accuracy or premature responding up to doses that decreased the number of trials initiated. CONCLUSIONS: These data demonstrate the sensitivity of an adjusting stop signal reaction time task to a range of drug effects and shows that some drugs that enhance dopaminergic transmission, such as amphetamine, can differentially alter various types of impulsive behavior.

Long-Lasting Effects of Methocinnamox on Opioid Self-Administration in Rhesus Monkeys.

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n = 5) or cocaine (n = 4) under a fixed-ratio schedule. Another group (n = 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n = 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.