Naltrexone-precipitated withdrawal in animals that receive morphine daily can include decreases in operant responding. However, naltrexone also can decrease operant responding in untreated animals, depending on prior naltrexone exposure and reinforcer contingencies. The present study was conducted to further evaluate changes in the behavioral effects of naltrexone consequent to morphine exposure and changes in behavioral context. Tolerance to the effects of both μ- (morphine, heroin, buprenorphine, methadone) and κ-opioid (U50,488) agonists during daily chronic morphine also was evaluated. Squirrel monkeys (n = 4) responded under a multiple schedule consisting of 4 18-minute cycles, each comprising a 10-minute timeout period followed by 3-minutes during which fixed-ratio responding was maintained by food presentation, a 2-minute timeout period, and 3-minutes during which fixed-ratio responding was maintained by stimulus-shock termination (SST). Control response rates were comparable under both schedule conditions. All drugs decreased food-maintained responding and, albeit requiring 0.5-1 log unit higher doses, morphine, heroin, methadone, and U50,488 also decreased SST-maintained responding. Daily morphine (3.2 mg/kg/day) produced tolerance to the rate-decreasing effects of μ-opioid agonists in the absence of sensitization to naltrexone's rate-decreasing effects. Doubling the daily dose of morphine and eliminating components of SST-maintained responding resulted in a 1.5-log unit leftward shift of the naltrexone dose-effect function. Full sensitization to naltrexone's ability to decrease food-maintained responding (3-log unit leftward shift) emerged after reintroducing SST-maintained performance into daily sessions. These results indicate that naltrexone's effects on operant responding during morphine maintenance can be influenced by behavioral context as well as the level of dependence. SIGNIFICANCE STATEMENT: Repeated administration of high naltrexone doses in nonopioid dependent individuals may result in behaviorally disruptive effects of low doses (naltrexone supersensitivity). Low doses of naltrexone also have disruptive effects during opioid dependence. These studies show that the expression of naltrexone effects during opioid dependence is a product of both pharmacological and behavioral factors.

The lack of an FDA-approved pharmacotherapy to combat cocaine use disorder (CUD) is an ongoing and urgent public health challenge. Emerging evidence suggests that the muscarinic acetylcholine system modulates mesolimbic dopamine release and thus may serve as a suitable target for novel CUD medications. The M1/M4-preferring muscarinic agonist xanomeline was recently approved by the Food and Drug Administration for schizophrenia management, and a previous study in male rats suggested that xanomeline treatment attenuated cocaine self-administration in a cocaine-vs-food choice procedure. The present study was conducted to further examine xanomeline treatment effectiveness on cocaine self-administration in male and female rats and nonhuman primates. Both male and female rats and monkeys were trained to self-administer cocaine during daily behavioral sessions. Repeated xanomeline treatment significantly decreased cocaine choice in rats similar to both pharmacological (amphetamine maintenance) and non-pharmacological (increasing alternative reinforcer value) positive controls. In separate groups of monkeys, acute xanomeline pretreatment decreased cocaine-vs-food choice in three out of four monkeys and selectively decreased cocaine-, but not food-maintained responding, under a multiple schedule of cocaine and food reinforcement in three out of four monkeys. Overall, the consistent effectiveness of xanomeline to reduce IV cocaine self-administration in both rodents and nonhuman primate supports its further evaluation as a CUD medication in humans.

Opioid addiction is a chronic relapsing disorder in which drug-seeking behavior during abstinence can be provoked by exposure to a µ-opioid receptor (MOR) agonist or opioid-associated cues. Opioid self-administration behavior in laboratory subjects can be reinstated by priming with MOR agonists or agonist-related stimuli, providing a procedure comparable to relapse. The opioid antagonist naltrexone has been forwarded as a pharmacologically effective approach to forestalling relapse and, in an extended-release formulation, has demonstrated some treatment success. However, chronic naltrexone treatment has not been extensively investigated in nonhuman subjects and aspects of its pharmacology remain uncertain. For example, the relative effectiveness of naltrexone in reducing the priming strength of opioid agonists differing in efficacy is not well understood. Here, using i.v self-administration and warm-water tail withdrawal procedures, we investigated changes in the direct reinforcing effects of oxycodone and in the priming strength and antinociceptive effects of opioid agonists in squirrel monkeys (n=4) during chronic treatment with naltrexone (0.2mg/kg/day). Results show that naltrexone produced: 1) a ten-fold rightward shift in the dose-response function for the reinforcing effects of oxycodone, and 2) in reinstatement and antinociception experiments, comparable rightward shifts in the dose-response functions for higher-efficacy MOR agonists (methadone, heroin, oxycodone) but rightward and downward shifts in the dose-response functions for lower-efficacy MOR agonists (buprenorphine, nalbuphine, butorphanol). These results suggest that, while chronic naltrexone should be effective in forestalling relapse following exposure to lower- and higher-efficacy agonists, the inability of lower-efficacy agonists to surmount naltrexone antagonism may complicate the prescription of opioids for pain. Significance Statement Though naltrexone is used in the treatment of OUD, its ability to reduce the priming strength of opioid agonists has not been extensively investigated. Here we show that chronic naltrexone treatment induces rightward shifts in the reinstatement and antinociceptive properties of higher efficacy opioid agonists, but rightward and downward shifts for lower efficacy opioid agonists, suggesting lower efficacy agonists may not surmount naltrexone-induced antagonism of these two effects and that perhaps naltrexone offers greater protection against lower efficacy agonists.

BACKGROUND:Opioid withdrawal symptoms (OWS) are highly aversive and prompt unprescribed opioid use, which increases morbidity, mortality, and, among individuals being treated for opioid use disorder (OUD), recurrence. OWS are driven by sympathetic nervous system (SNS) hyperactivity that occurs when blood opioid levels wane. We tested whether brief inhalation of xenon gas, which inhibits SNS activity and is used clinically for anesthesia and diagnostic imaging, attenuates naltrexone-precipitated withdrawal-like signs in morphine-dependent mice. METHODS:Adult CD-1 mice were implanted with morphine sulfate-loaded (60 mg/ml) minipumps and maintained for 6 days to establish morphine dependence. On day 7, mice were given subcutaneous naltrexone (0.3 mg/kg) and placed in a sealed exposure chamber containing either 21% oxygen/balance nitrogen (controls) or 21% oxygen/added xenon peaking at 30%/balance nitrogen. After 10 minutes, mice were transferred to observation chambers and videorecorded for 45 minutes. Videos were scored in a blind manner for morphine withdrawal behaviors. Data were analyzed using 2-way ANOVAs testing for treatment and sex effects. RESULTS AND CONCLUSIONS:Xenon-exposed mice exhibited fewer jumps (P = 0.010) and jumping suppression was detectible within the first 10-minute video segment, but no sex differences were detected. Brief inhalation of low concentration xenon rapidly and substantially attenuated naltrexone-precipitated jumping in morphine-dependent mice, suggesting that it can inhibit OWS. If xenon effects translate to humans with OUD, xenon inhalation may be effective for reducing OWS, unprescribed opioid use, and for easing OUD treatment initiation, which could help lower excess morbidity and mortality associated with OUD.

ID 21458 Poster Board 270 Aim: Biased signaling by mu-opioid agonists has been proposed to result in fewer opioid side effects and, consequently, an improved safety profile compared to conventional prescription opioids. We evaluated the acute effects of novel G-protein preferring opioid agonists in an assay of self-administration in nonhuman primates to determine whether G-protein preferring opioid agonists have reduced abuse liability. Methods: Squirrel monkeys (Saimiri sciureus, n=3) surgically implanted with IV catheters were trained to respond on one lever for a food reinforcer (20% sweetened condensed milk) and on another lever for an IV injection of 0.01 mg/kg heroin under concurrent fixed ratio schedules. Once trained, heroin dose-effect functions were established in each subject by varying the unit dose of heroin available for injection, from 0.001 to 0.032 mg/kg/inj, under a modified double alternation schedule. Next, under similar conditions, the reinforcing effects of the novel mu-opioid agonists EWB-3-1, EWB-2-189 and EG-1-203 were evaluated, as were the effects of the rapid acting opioid agonist, remifentanil. The reinforcing effects of heroin were periodically redetermined to ensure stability of performance. Results: Under the concurrent schedules of reinforcement, responding was primarily distributed to the food-associated lever when saline was available and was increasingly allocated to the injection-associated lever with increasing doses of heroin. Heroin maintained self-administration over the dose range of 0.0032 to 0.032 mg/kg/inj, with peak number of injections, 26±13, obtained at 0.0032 mg/kg/inj heroin. Higher doses maintained fewer injections, resulting in an inverted-U shaped dose response function. Remifentanil had qualitatively and quantitatively similar effects to heroin, although it was more potent with peak effects occurring at the unit dose of 0.00032 mg/kg/inj. The three novel opioids also maintained self-administration behavior: responding on the injection-associated lever increased with the unit dose of each novel compound, the peak number of injections was similar across drugs, ranging from 22±4 (EWB-1-203) to 29±3 (EWB-2-189), and inverted U-shaped functions were obtained with EWB-3-1 and EG-2-189. Solubility limits precluded testing doses of EWB-1-203 on the descending portion of the dose-effect curve. Conclusion: EWB-3-1, EG-1-203, and EWB-2-189 all had reinforcing effects in a self-administration procedure, indicative of potential abuse liability. These data demonstrate that the absence of β-arrestin recruitment by mu-opioid agonists does not necessarily predict lower abuse liability of opioid agonists. Funded by NIH/NIDA DA047574

All possible diastereomeric C9-hydroxymethyl-, hydroxyethyl-, and hydroxypropyl-substituted 5-phenylmorphans were synthesized to explore the three-dimensional space around the C9 substituent in our search for potent MOR partial agonists. These compounds were designed to lessen the lipophilicity observed with their C9-alkenyl substituted relatives. Many of the 12 diastereomers that were obtained were found to have nanomolar or subnanomolar potency in the forskolin-induced cAMP accumulation assay. Almost all these potent compounds were fully efficacious, and three of those chosen for in vivo evaluation, 15, 21, and 36, were all extremely G-protein biased; none of the three compounds recruited beta-arrestin2. Only one of the 12 diastereomers, 21 (3-((1S,5R,9R)-9-(2-hydroxyethyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), was a MOR partial agonist with good, but not full, efficacy (Emax = 85%) and subnanomolar potency (EC50 = 0.91 nM) in the cAMP assay. It did not have any KOR agonist activity. This compound was unlike morphine in that it had a limited ventilatory effect in vivo. The activity of 21 could be related to one or more of three well-known theories that attempt to predict a dissociation of the desired analgesia from the undesirable opioid-like side-effects associated with clinically used opioids. In accordance with the theories, 21 was a potent MOR partial agonist, it was highly G-protein biased and did not attract beta-arrestin2, and it was found to have both MOR and DOR agonist activity. All the other diastereomers that were synthesized were either much less potent than 21 or had either too little or too much efficacy for our purposes. It was also noted that a C9-methoxymethyl compound with 1R,5S,9R stereochemistry (41) was more potent than the comparable C9-hydroxymethyl compound 11 (EC50 = 0.65 nM for 41 vs. 2.05 nM for 11). Both 41 and 11 were fully efficacious.

ID 18116 Poster Board 4 Aim: Delta opioid receptor (DOR) signaling mechanisms have been proposed to decrease the side effect liability associated with morphine-like prescription opioids. We evaluated this proposition by determining the acute effects of six novel opioid agonists in assays of morphine discrimination in rats, and antinociception, operant performance and respiratory function in nonhuman primates. Methods: 6 novel 3-hydroxy-N-phenethyl-5-phenylmorphans (C9-alkyl substituted compounds with varying stereochemistry) were synthesized at the NIDA and NIAAA IRP. In vitro assays using commercially available kits (e.g. HitHunter for cAMP accumulation) indicated the compounds have no efficacy at kappa opioid receptors (KOR), no to low efficacy at DOR, and some inhibitory effects at DOR or KOR. The compounds had efficacy ranging from low (105) to moderate (76a, 111, 90b) to high (76b, 142) at mu opioid receptors (MOR). In behavioral studies, full dose-effect functions for all six compounds were first determined in rats (n=7-9) trained to discriminate 3 mg/kg morphine from saline. Next, effects in squirrel monkeys (n=3-5/group) were determined using cumulative dosing procedures in two assays. In one set of studies, tail-withdrawal latency from 52oC water (antinociception) and effects on food-maintained operant responding (behavioral disruption) were concurrently evaluated. In other studies, whole body plethysmography in the presence of normal air and air mixed with 5% CO2 was used to obtain respiratory parameters (breathing frequency, tidal volume, minute volume). Results: Four compounds (76b, 105, 142, and 111) fully substituted for morphine in discrimination studies; one compound (76a) partially substituted (>70% drug-lever responding), and one compound (90b) did not generalize from the morphine stimulus (∼25% drug -lever responding). All morphine-like discriminative stimulus effects were attenuated by pretreatment with 0.1 mg/kg naltrexone. In squirrel monkeys, compounds 76b and 142 had antinociceptive effects, behaviorally disruptive, and ventilatory effects similar to those of morphine. The remaining compounds had similarly disruptive effects on food-maintained operant responding but produced only limited effects on ventilation. Only three of the four (111, 90b, and 76a) had moderate to full antinociceptive effects. Conclusion: These data demonstrate that the presence of agonist or antagonist activity at DOR may have greater influence on the effects of partial MOR agonists (76a, 111, and 90b) than on either full agonists (76b, 142) or very low efficacy agonists (105). Supported by NIH Grant DA047574

Cessation of cannabinoid use in humans often leads to a withdrawal state that includes sleep disruption. Despite important health implications, little is known about how cannabinoid abstention affects sleep architecture, in part because spontaneous cannabinoid withdrawal is difficult to model in animals. In concurrent work we report that repeated administration of the high-efficacy cannabinoid 1 (CB1) receptor agonist AM2389 to mice for 5 days led to heightened locomotor activity and paw tremor following treatment discontinuation, potentially indicative of spontaneous cannabinoid withdrawal. Here, we performed parallel studies to examine effects on sleep. Using implantable electroencephalography (EEG) and electromyography (EMG) telemetry we examined sleep and neurophysiological measures before, during, and after 5 days of twice-daily AM2389 injections. We report that AM2389 produces decreases in locomotor activity that wane with repeated treatment, whereas discontinuation produces rebound increases in activity that persist for several days. Likewise, AM2389 initially produces profound increases in slow-wave sleep (SWS) and decreases in rapid eye movement (REM) sleep, as well as consolidation of sleep. By the third AM2389 treatment, this pattern transitions to decreases in SWS and total time sleeping. This pattern persists following AM2389 discontinuation and is accompanied by emergence of sleep fragmentation. Double-labeling immunohistochemistry for hypocretin/orexin (a sleep-regulating peptide) and c-Fos (a neuronal activity marker) in lateral hypothalamus revealed decreases in c-Fos/orexin+ cells following acute AM2389 and increases following discontinuation, aligning with the sleep changes. These findings indicate that AM2389 profoundly alters sleep in mice and suggest that sleep disruption following treatment cessation reflects spontaneous cannabinoid withdrawal.

NLX-112 (a.k.a. F13640 or befiradol) exhibits nanomolar affinity, exceptional selectivity and biased agonism at serotonin 5-HT1A receptors. NLX-112 displays robust analgesic activity in a number of rodent models of pain, and is currently developed as a treatment for L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD) patients. Noteworthy, PD patients can suffer from comorbid chronic pain, thus necessitating the use of analgesic drugs, such as opioids, which have potential for misuse. Additionally, dopamine agonists used to treat PD can produce cocaine-like effects in preclinical assays of misuse potential. The present study investigated whether NLX-112 possesses misuse potential of its own using two behavioural assays routinely used for this purpose: intracranial self-stimulation (ICSS) in rats, and cocaine discrimination in macaque monkeys. In rats, low doses of NLX112 (0.03 and 0.1 mg/kg p.o.) did not alter ICSS frequency-rate curves, while higher doses (0.3 and 1.0 mg/kg) shifted the curve to the right and flattened it, i.e., reduced ICSS. As expected, cocaine (10 mg/kg i.p.) shifted the curve to the left, i.e., facilitated ICSS, but NLX-112 (0.03 and 0.1 mg/kg p.o.) did not further enhance cocaine-induced facilitation of ICSS. In monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) from saline, NLX-112 (0.01-0.1 mg/kg p.o.) did not substitute for cocaine. Taken together, these results suggest that NLX-112, at doses displaying anti-dyskinetic activity in rat, marmoset and macaque models of LID, is free from misuse potential. From a translational perspective, this is a desirable property for a compound destined to be used in PD patients, who can suffer from comorbid chronic pain necessitating the use of potentially misused analgesic drugs.

Although the behavioral effects of acute and chronic exposure to cannabinoids have been extensively studied in mice, spontaneous withdrawal following exposure to cannabinoids has not been well characterized in this species. To address this issue, different groups of mice were treated for 5 days with saline, 20–36 mg/kg/day of the CB partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), or 0.06–0.1 mg/kg/day of the CB high-efficacy agonist AM2389. Initial studies assessed changes in observable behavior (paw tremors) that were scored from the recordings taken at 4 or 24 h after the last injection. Subsequently, radiotelemetry was used to continuously measure body temperature and locomotor activity before (baseline), during, and after the 5-day dosing regimens. Results show that increases in paw tremors occurred following 5-day exposure to AM2389 or Δ9-THC. In telemetry studies, acute AM2389 or THC decreased both temperature and activity. Rapid tolerance occurred to the hypothermic effects of the cannabinoids, whereas locomotor activity continued to be suppressed following each drug injection. In contrast, increases in locomotor activity were evident 12–72 h after discontinuing daily injections of either 0.06 or 0.1 mg/kg/day AM2389. Increases in locomotor activity were also noted in mice treated daily with 30 or 36, but not 20 mg/kg/day Δ9-THC; these effects were smaller and appeared later than effects seen in AM2389-treated mice. These results indicate that the discontinuation of daily treatment with a CB high-efficacy agonist will yield evidence of spontaneous withdrawal that may reflect prior dependence, and that the degree of cannabinoid dependence may vary in relation to the dose or efficacy of the agonist injected daily.

In earlier work, we explored the SAR for the C3 side chain pharmacophore in the hexahydrocannabinol template represented by the drug nabilone, which resulted in the development of AM2389. In an effort for further optimization, we have merged features of nabilone and AM2389 and explored the C3 side chain with varying chain lengths and terminal substitutions. Of the compounds described here, a nabilone analog, AM8936, with the C6'-cyano-substituted side chain, was identified as the most successful analog capable of serving as a potential candidate for further development and a valuable tool for further in vivo studies. AM8936 behaved as a balanced and potent CB1 agonist in functional assays and was a potent and efficacious CB1 agonist in vivo. Our SAR studies are highlighted with the docking of AM8936 on the crystal structure of the hCB1 receptor. (C) 2021 Published by Elsevier Masson SAS.

Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the [35S]GTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.

Background: Synthetic cathinones display overlapping behavioral effects with psychostimulants (e.g., methamphetamine [MA]) and/or entactogens (e.g., 3,4-methylenedioxymethaphetamine [MDMA])-presumably reflecting their dopaminergic and/or serotonergic activity. The discriminative stimulus effects of MDMA thought to be mediated by such activity have been well characterized in rodents but have not been fully examined in nonhuman primates. Methods: The present studies were conducted to systematically evaluate the discriminative stimulus effects of 5 abused synthetic cathinones (methylenedioxypyrovalerone [MDPV], alpha-pyrrolidinovalerophenone [alpha-PVP], methcathinone [MCAT], mephedrone, and methylone) in adult male squirrel monkeys trained to distinguish intramuscular injections of MA (0.1 mg/ kg; n=4) or MDMA (0.6 mg/kg; n=4) from vehicle. Results: Each training drug produced dose-dependent effects and, at the highest dose, full substitution. MDMA produced predominantly vehicle-like responding in the MA-trained group, whereas the highest dose of MA (0.56 mg/kg) produced partial substitution (approximately 90% appropriate lever responding in one-half of the subjects) in the MDMA-trained group. MDPV, alpha-PVP, and MCAT produced full substitution in MA-trained subjects, but, at the same or higher doses, only substituted for MDMA in one-half of the subjects, consistent with primarily dopaminergically mediated interoceptive effects. In contrast, mephedrone and methylone fully substituted in MDMA-trained subjects but failed to fully substitute for the training drug in MA-trained subjects, suggesting a primary role for serotonergic actions in their interoceptive effects. Conclusions: These findings suggest that differences in the interoceptive effects of synthetic cathinones in nonhuman primates reflect differing compositions of monoaminergic actions that also may mediate their subjective effects in humans.

The abuse of synthetic cathinones ("bath salts") with psychomotor stimulant and/or entactogenic properties emerged as a public health concern when they were introduced as "legal" alternatives to drugs of abuse such as cocaine or MDMA. In this study, experiments were conducted in nonhuman primates to examine how differences in transporter selectivity might impact the reinforcing effects of synthetic cathinones. Rhesus monkeys (N = 5) were trained to respond for intravenous injections under a fixed-ratio (FR) 30, timeout 60-s schedule of reinforcement. The reinforcing effects of selected cathinones (e.g., MDPV, αPVP, MCAT, and methylone) with a range of pharmacological effects at dopamine and serotonin transporters were compared to cocaine and MDMA using dose-response analysis under a simple FR schedule and behavioral economic procedures that generated demand curves for two doses of each drug. Results show that one or more doses of all drugs were readily self-administered in each subject and, excepting MDMA (21 injections/session), peak levels of self-administration were similar across drugs (between 30 and 40 injections/session). Demand elasticity for the peak and the peak + 1/2-log dose of each drug did not significantly differ, and when data for the two doses were averaged for each drug, the following rank-order of reinforcing strength emerged: cocaine > MCAT = MDPV = methylone > αPVP = MDMA. These results indicate that the reinforcing strength of synthetic cathinones are not related to their selectivity in binding dopamine or serotonin transporter sites.

Increased abuse of synthetic cannabinoids (SCBs) continues to be a public health concern. Preclinical studies have identified SCBs as being THC‐like; however, occurrences of emesis, hallucinations, and seizures have been reported with their usage. These studies examined the premise that the hallucinogenic effects of AM8936, a highly potent synthetic CB1 agonist, resemble the discriminative stimulus effects of another hallucinogen, the 5HT2A agonist (R)(−)2,5‐dimethoxy‐4‐iodoamphetamine (DOI). Male and female Sprague‐Dawley rats (n=6/group) were trained to discriminate either 0.18 mg/kg AM8936 or 0.56 mg/kg DOI from saline under a shock avoidance schedule of reinforcement. In both DOI and AM8936 trained subjects, their respective training dose produced full (>80%) substitution. In the DOI trained subjects, AM8936 (0.032 – 0.18 mg/kg), delta‐9‐tetrahydrocannabinol (Δ9‐THC) (1 – 10 mg/kg), and JWH‐018 (0.1 – 3.2 mg/kg) produced dose‐dependent increases in DOI‐lever responding, but only JWH‐018 and AM8936 produced full substitution. In the AM8936 trained subjects, DOI (0.56 – 3.2 m/k), Δ9‐THC (1 – 10 mg/kg), and JWH‐018 (0.1 – 10 mg/kg) produced dose‐dependent increases in AM8936‐lever responding, but only JWH‐018 produced full (>80%) substitution. Doses of DOI that produced AM8936‐appropriate responding (0.56 – 3.2 mg/kg) were higher than those that resulted in DOI‐appropriate responding (0.1 – 0.8 mg/kg). In addition, the mu‐opioid receptor agonist morphine (1 – 10 mg/kg) (negative control) engendered less than 20% DOI‐lever responding or AM8936‐lever responding up to doses that produced behavioral disruption. These studies indicate that there is bi‐directional overlap in the discriminative stimulus effects of SCBs and a 5‐HT2A agonist, suggesting similarities in their subjective effects.Support or Funding InformationAcknowledgementsFunded by NIH/NIDA: DA043700

(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Buprenorphine, a partial agonist at the μ-opioid receptor, is commonly prescribed for the management of opioid addiction. Notwithstanding buprenorphine’s clinical popularity, the relationship between its effectiveness in attenuating relapse-related behavior and its opioid efficacy is poorly understood. Furthermore, changes in the antinociceptive potency or effectiveness of opioid drugs that might occur during buprenorphine treatment have not been characterized. Here, we address these questions by assessing the ability of daily buprenorphine treatment to protect against the reinstatement of drug-seeking behavior by six opioids differing in efficacy (methadone, heroin, oxycodone, buprenorphine, butorphanol, nalbuphine) and, in separate experiments, by determining how such treatment may modify their antinociceptive effects. In one set of experiments, squirrel monkeys were trained to respond under concurrent schedules (choice) of food or intravenous oxycodone presentations. The priming strength of different opioids during sessions in which saline, rather than oxycodone, was available for intravenous self-administration was determined before and during chronic buprenorphine treatment (0.1 or 0.32 mg/kg per day). In other subjects, antinociceptive effects of the different opioids were assessed using cumulative dosing procedures in a modified warm-water tail withdrawal procedure before and during buprenorphine treatment. Results show that, notwithstanding some tolerance, full agonists retain high efficacy in producing priming and antinociceptive effects. In contrast, both the priming strength and antinociceptive effectiveness of partial agonists were decreased. These results suggest that the utility of buprenorphine in the management of opioid addiction, and how it alters the analgesic effects of opioids, can vary depending on the efficacy of the abused or prescribed opioid. SIGNIFICANCE STATEMENT Our findings indicate that the pharmacological efficacy of abused opioids may predict the ability of buprenorphine to attenuate their relapse-related priming and analgesia-related antinociceptive effects. This information can help inform physicians as to the effectiveness and limitations of buprenorphine as a pharmacotherapy for opioid addiction.