Μ-opioid Receptor Agonist Research Articles

Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans.

The synthesis of stereochemically pure oximes, amines, saturated and unsaturated cyanomethyl compounds, and methylaminomethyl compounds at the C9 position in 3-hydroxy-N-phenethyl-5-phenylmorphans provided μ-opioid receptor (MOR) agonists with varied efficacy and potency. One of the most interesting compounds, (2-((1S,5R,9R)-5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-yl)acetonitrile), was found to be a potent partial MOR agonist (EC50 = 2.5 nM, %Emax = 89.6%), as determined in the forskolin-induced cAMP accumulation assay. Others ranged in potency and efficacy at the MOR, from nanomolar potency with a C9 cyanomethyl compound (EC50 = 0.85 nM) to its totally inactive diastereomer, and three compounds exhibited weak MOR antagonist activity (the primary amine 3, the secondary amine 8, and the cyanomethyl compound 41). Many of the compounds were fully efficacious; their efficacy and potency were affected by both the stereochemistry of the molecule and the specific C9 substituent. Most of the MOR agonists were selective in their receptor interactions, and only a few had δ-opioid receptor (DOR) or κ-opioid receptor (KOR) agonist activity. Only one compound, a C9-methylaminomethyl-substituted phenylmorphan, was moderately potent and fully efficacious as a KOR agonist (KOR EC50 = 18 nM (% Emax = 103%)).

Human metabolism of four synthetic benzimidazole opioids: isotonitazene, metonitazene, etodesnitazene, and metodesnitazene

Following isotonitazene scheduling in 2019, the availability of alternative 2-benzylbenzimidazole opioids (nitazenes) on the global drug market increased, resulting in many fatalities worldwide. Nitazenes are potent µ-opioid receptor agonists with strong narcotic/analgesic effects, and their concentrations in biological matrices are low, making the detection of metabolite biomarkers of consumption crucial to document use in clinical and forensic settings. However, there is little to no data on the metabolism of the most recently available nitazenes, especially desnitro-analogues. The aim of the research was to assess isotonitazene, metonitazene, etodesnitazene, and metodesnitazene human metabolism and identify specific metabolite biomarkers of consumption. The four analogues were incubated with 10-donor-pooled human hepatocytes, and the incubates were analyzed by liquid chromatography-high-resolution tandem mass spectrometry and data mining with Compound Discoverer (Thermo Scientific); the analysis was supported by in silico metabolite predictions with GLORYx open-access software. Metabolites were identified in postmortem blood and/or urine samples from two metonitazene-positive and three etodesnitazene-positive cases following the same workflow, with and without glucuronide hydrolysis in urine, to confirm in vitro results. Twelve, nine, twenty-two, and ten metabolites were identified for isotonitazene, metonitazene, etodesnitazene, and metodesnitazene, respectively. The main transformations were N-deethylation at the N,N-diethylethanamine side chain, O-dealkylation, and further O-glucuronidation. In vitro and autopsy results were consistent, demonstrating the efficacy of the 10-donor-pooled human hepatocyte model to predict human metabolism. We suggest the parent and the corresponding O-dealkyl- and N-deethyl-O-dealkyl metabolites as biomarkers of exposure in urine after glucuronide hydrolysis, and the corresponding N-deethyl metabolite as additional biomarker in blood.

Effects of systemically administered tramadol hydrochloride on random pattern skin flap survival in rats

Aim: Tramadol is a weak centrally acting opioid analgesic with µ-opioid receptor agonist effects. It has been explored for its analgesic efficacy through various in-vitro and in-vivo studies. The skin, as the body’s largest organ and the protector barrier, is vulnerable to injuries and wounds that can cause significant challenges due to pain, economic burdens and psychological implications. Successful healing of wound involves complex processes and it is influenced by factors such as angiogenesis and nitric oxide levels. This study investigates the effects of tramadol on wound healing in experimental ischemic wound models in rats. Material and Methods: Two 6 mm ischemic wound models were created on the backs of 30 male Wistar Albino rats, with wound areas cut along the long edges and a sterile silicone material placed between the panniculus carnosus fascia and paraspinosus muscle. Rats were randomized into Tramadol, Control, and Sham groups. The wounds were imaged using a "SONY ILCE-7" camera on days 0, 3, 6, 10, and 14. Wound areas and healing percentages were calculated from the images and recorded for statistical purposes. After 14 days, the animals were sacrificed under general anesthesia for histopathological examination of tissue samples. CD31 and VEGF antibodies were used to evaluate the density and morphology of vascular structures. Results: Tramadol administration accelerated the healing of wound surface area. Significant differences were found between groups in terms of inflammation, and data recorded in CD34, CD31, and VEGF-stained preparations. Conclusion: The study found that tramadol positively contributes to wound healing in the acute phase of ischemic wounds by affecting various processes.

Food preference-based screening method for identification of effectors of substance use disorders using Caenorhabditis elegans

Substance use disorder (SUD) affects over 48 million Americans aged 12 and over. Thus, identifying novel chemicals contributing to SUD will be critical for developing efficient prevention and mitigation strategies. Considering the complexity of the actions and effects of these substances on human behavior, a high-throughput platform using a living organism is ideal. We developed a quick and easy screening assay using Caenorhabditis elegans. C. elegans prefers high-quality food (Escherichia coli HB101) over low-quality food (Bacillus megaterium), with a food preference index of approximately 0.2, defined as the difference in the number of worms at E. coli HB101 and B. megaterium over the total worm number. The food preference index was significantly increased by loperamide, a μ-opioid receptor (MOPR) agonist, and decreased by naloxone, a MOPR antagonist. These changes depended on npr-17, a C. elegans homolog of opioid receptors. In addition, the food preference index was significantly increased by arachidonyl-2′-chloroethylamide, a cannabinoid 1 receptor (CB1R) agonist, and decreased by rimonabant, a CB1R inverse agonist. These changes depended on npr-19, a homolog of CB1R. These results suggest that the conserved opioid and endocannabinoid systems modulate the food preference behaviors of C. elegans. Finally, the humanoid C. elegans strains where npr-17 was replaced with human MOPR and where npr-19 was replaced with human CB1R phenocopied the changes in food preference by the drug treatment. Together, the current results show that this method can be used to rapidly screen the potential effectors of MOPR and CB1R to yield results highly translatable to humans.

T-Type Ca2+ Channels Mediate a Critical Period of Plasticity in Adult-Born Granule Cells.

Adult-born granule cells (abGCs) exhibit a transient period of elevated synaptic plasticity that plays an important role in hippocampal function. Various mechanisms have been implicated in this critical period for enhanced plasticity, including minimal GABAergic inhibition and high intrinsic excitability conferred by T-type Ca2+ channels. Here we assess the contribution of synaptic inhibition and intrinsic excitability to long-term potentiation (LTP) in abGCs of adult male and female mice using perforated patch recordings. We show that the timing of critical period plasticity is unaffected by intact GABAergic inhibition such that 4-6-week-old abGCs exhibit LTP that is absent by 8 weeks. Blocking GABAA receptors, or partial blockade of GABA release from PV and nNos-expressing interneurons by a µ-opioid receptor agonist, strongly enhances LTP in 4-week-old GCs, suggesting that minimal inhibition does not underlie critical period plasticity. Instead, the closure of the critical period coincides with a reduction in the contribution of T-type Ca2+ channels to intrinsic excitability, and a selective T-type Ca2+ channel antagonist prevents LTP in 4-week-old but not mature GCs. Interestingly, whole-cell recordings that facilitate T-type Ca2+ channel activity in mature GCs unmasks LTP (with inhibition intact) that is also sensitive to a T-type Ca2+ channel antagonist, suggesting T-type channel activity in mature GCs is suppressed by native intracellular signaling. Together these results show that abGCs use T-type Ca2+ channels to overcome inhibition, providing new insight into how high intrinsic excitability provides young abGCs a competitive advantage for experience-dependent synaptic plasticity.

In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling.

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as μ-opioid receptor (MOR) agonists, are associated with serious intoxication and fatal overdose. Previous studies proposed that G-protein-biased MOR agonists are safer pain medications, while other evidence indicates that low intrinsic efficacy at MOR better explains the reduced opioid side effects. Here, we characterized the in vitro functional profiles of various NSOs at the MOR using adenylate cyclase inhibition and β-arrestin2 recruitment assays, in conjunction with the application of the receptor depletion approach. By fitting the concentration-response data to the operational model of agonism, we deduced the intrinsic efficacy and affinity for each opioid in the Gi protein signaling and β-arrestin2 recruitment pathways. Compared to the reference agonist [d-Ala2,N-MePhe4,Gly-ol5]enkephalin, we found that several fentanyl analogs were more efficacious at inhibiting cAMP production, whereas all fentanyl analogs were less efficacious at recruiting β-arrestin2. In contrast, the non-fentanyl 2-benzylbenzimidazole (i.e., nitazene) analogs were highly efficacious and potent in both the cAMP and β-arrestin2 assays. Our findings suggest that the high intrinsic efficacy of the NSOs in Gi protein signaling is a common property that may underlie their high risk of intoxication and overdose, highlighting the limitation of using in vitro functional bias to predict the adverse effects of opioids. In addition, the extremely high potency of many NSOs now infiltrating illicit drug markets further contributes to the danger posed to public health.

Risk Factors for Respiratory Depression Associated with Tramadol Based on the Global Pharmacovigilance Database (VigiBase).

Tramadol, a weak μ-opioid receptor agonist, has been used worldwide for pain management. It is considered to have a favorable safety profile without serious adverse events; however, safety issues of respiratory depression were proposed by regulatory governments. We aimed to examine the risk and contributing factors associated with tramadol-related respiratory depression using a real-world database, VigiBase. Disproportionality analysis of tramadol and tramadol/paracetamol was performed using proportional reporting ratios, reporting odds ratios, and information components for all drugs and opioids. Factors related to respiratory depression, including sex, age, presence of abuse, death, and various concomitant medications, were evaluated. Among 140,721 tramadol reports, respiratory depression was reported in 1126 cases, 81.3% of which were deemed serious. Five adverse events were detected as signals of tramadol-related acute central respiratory depression (ACRD) in 882 reports. A higher proportion of ACRD cases in children and adolescents was observed than all adverse events cases of tramadol. Concomitant users of CYP2D6 inhibitors, opioids, benzodiazepines, and anti-depressant drugs showed a higher proportion in ACRD cases than non-ACRD cases. ACRD was related to drug abuse and death. This pharmacovigilance study, using VigiBase, confirmed a high risk of respiratory depression (a serious, potentially fatal adverse event) secondary to the use of tramadol, especially in pediatric patients, drug abusers, or during concomitant use of opioids, benzodiazepines, or antidepressants.

Pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 tartrate, a novel G protein-biased μ-opioid receptor agonist, in healthy Chinese subjects.

Objective: YZJ-4729 is a novel G protein-biased μ-opioid receptor agonist for the treatment of acute pain in adult patients who require intravenous opioid analgesic therapy. The aim of this study was to assess the pharmacokinetics, metabolite profiling, safety and tolerability of YZJ-4729 in healthy Chinese subjects following the single intravenous doses ranged from 0.2mg to 6mg. Methods: This single-center, randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female Chinese subjects after single ascending doses of YZJ-4729 tartrate (0.2, 0.5, 1.5, 3, 4.5, and 6mg). Subjects in each cohort were assigned randomly to receive a single intravenous dose of YZJ-4729 tartrate injection or placebo at a ratio of 4:1. Pharmacokinetic characteristics, metabolite profiling, safety and tolerability profiles of the study drug were evaluated. Results: Overall, YZJ-4729 was safe and well tolerated in healthy Chinese subjects. The study drug reached peak plasma concentrations nearly at the end of the infusion. After administration, YZJ-4729 was eliminated rapidly with a terminal elimination half-life of 0.862-2.50h, and excreted little in human excreta. The maximum drug concentration and area under the plasma concentration-time curve increased with dose escalation across the entire dose range. YZJ-4729 experienced extensive metabolism in human body. A total of 19 metabolites were identified and the characteristic metabolic pathways involved hydroxylation, ketone formation, N-dealkylation and glucuronide conjugation. Metabolite M10 was the most abundant circulating metabolite, and represented over 10% of total drug-related systemic exposure. Further PK and safety evaluation of M10 was necessary. Conclusion: The clinical study results laid a foundation for the further clinical studies of YZJ-4729 in patients. Clinical Trial Registration: http://www.chinadrugtrials.org.cn, identifier CTR20222574.

Remifentanil: a review of its analgesic and sedative use in the perioperative period

Adequate perioperative pain relief is an integral part of anesthesia. Opioid analgesics occupy one of the key places in the purchase of acute and chronic pain in the world. The article presents current data on the clinical effectiveness of remifentanil, a derivative of fentanyl, which is a selective ultra-short-acting μ-opioid receptor agonist when used in the perioperative period for the treatment of acute and chronic pain. Comparisons of the therapeutic activity and physicochemical properties, pharmacokinetic and pharmacodynamic characteristics of remifentanil with other opioids (fentanyl, sufentanil, alfentanil) are provided. Its unique properties (eg, organ function-independent metabolism, non-accumulation, rapid onset of action, and short duration of action) distinguish it from other opioid agents. Remifentanil is at least as effective as comparator opioids such as fentanyl, sufentanil in relieving pain and sedating patients during the perioperative period. In addition, it provides rapid and predictable extubation and is associated with shorter duration of mechanical ventilation and shorter length of hospitalization than comparators in some studies. In addition, remifentanil is well tolerated in both adults and children. Thus, remifentanil is a desirable addition to currently available pharmacologic agents used to treat period pain in patients

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor(Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use.One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.

Cold nociception as a measure of hyperalgesia during spontaneous heroin withdrawal in mice

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests—thermal gradient ring (5–30 °C, 5–50 °C, 15–40 °C, and 25–50 °C), dynamic cold plate (4 °C to −1 °C at −1 °C/min, −1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)—to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to −1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used μ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full μ-opioid receptor agonist methadone and μ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential μ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a β2-adrenergic receptor antagonist (butoxamine), an α2-adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists.

Identification and quantification of kukoamine A and kukoamine B as novel μ-opioid receptor agonists in potato and other solanaceous plants.

Activation of the µ-opioid receptor (µOR) by food components could lead to reward effects or to the modulation of motor functions in the gastrointestinal tract. In an unbiased search for novel µOR agonists in food, a three-step virtual-screening process selected 22 promising candidates with potential to interact with the µOR. Radioligand binding studies showed that ten of these substances indeed bind to the receptor. Functional assays identified kukoamine A as a full agonist (EC50=5.6µM) and kukoamine B as a partial agonist (EC50=8.7µM) to µOR. After extraction, both kukoamines were analyzed by LC-MS/MS in potato, tomato, pepper, and eggplant. Depending on the potato variety, up to 16µg of kukoamine A and 157µg of kukoamine B per gram dry weight could be determined in the whole tuber, mainly concentrated in the potato peel. Cooking did not influence the kukoamine contents.

Restless legs syndrome, neuroleptic-induced akathisia, and opioid-withdrawal restlessness: shared neuronal mechanisms?

Restlessness is a core symptom underlying restless legs syndrome (RLS), neuroleptic-induced akathisia, and opioid withdrawal. These three conditions also share other clinical components suggesting some overlap in their pathophysiology. Recent prospective studies demonstrate the frequent incidence of RLS-like symptoms during opioid withdrawal and supervised prescription opioid tapering. Based on the therapeutic role of µ-opioid receptor (MOR) agonists in the three clinical conditions and recent preclinical experimental data in rodents, we provide a coherent and unifying neurobiological basis for the restlessness observed in these three clinical syndromes and propose a heuristic hypothesis of a key role of the specific striatal neurons that express MORs in akathisia/restlessness.

Loperamide Misuse Mimicking Symptoms of Severe Malnutrition

Loperamide, an oral over-the-counter μ-opioid receptor agonist used to treat diarrhea, acts primarily in the gut and, when used as recommended, has little to no systemic effect. At high doses, it may cause a “high” like other opioids. Recent literature describes an increasing incidence of loperamide misuse and overdose in the setting of the US opioid epidemic. In this case, we describe a 16-year-old with anorexia nervosa who developed dizziness, syncope, and constipation at the time of weight loss. These symptoms were originally attributed to malnutrition; however, after weight restoration, her symptoms worsened. She did not respond to initial management of suspected postural orthostatic tachycardia syndrome (POTS). She then developed acute urinary retention requiring hospitalization. Her symptoms were ultimately found to be caused by chronic surreptitious high-dose loperamide use. Her symptoms rapidly improved after cessation. This case illustrates the non-specific symptoms associated with loperamide misuse and the potential overlap with other common adolescent conditions. Adolescent medicine clinicians must be aware of the signs and symptoms of loperamide misuse as well as familiar with recommendations for both the management of acute complications and the treatment of the substance misuse.

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges.

Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with the emergence of extremely potent fentanyl derivatives, sold as standalone products or adulterants in counterfeit prescription opioids or heroin. The incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (OUD). Prescription and illicit opioids reduce pain perception by activating µ-opioid receptors (MOR) localized to the central nervous system (CNS). Dysregulation of meso-corticolimbic circuitry that subserves reward and adaptive behaviors is fundamentally involved in the progressive behavioral changes that promote and are consequent to OUD. Although opioid-induced analgesia and the rewarding effects of abused opioids are primarily mediated through MOR activation, serotonin (5-HT) is an important contributor to the pharmacology of opioid abused drugs (including heroin and prescription opioids) and OUD. There is a recent resurgence of interest into psychedelic compounds that act primarily through the 5-HT2A receptor (5-HT 2A R) as a new frontier in combatting such diseases (e.g., depression, anxiety, and substance use disorders). Emerging data suggest that the MOR and 5-HT2AR crosstalk at the cellular level and within key nodes of OUD circuitry, highlighting a major opportunity for novel pharmacological intervention for OUD. There is an important gap in the preclinical profiling of psychedelic 5-HT2AR agonists in OUD models. Further, as these molecules carry risks, additional analyses of the profiles of non-hallucinogenic 5-HT2AR agonists and/or 5-HT2AR positive allosteric modulators may provide a new pathway for 5-HT2AR therapeutics. In this review, we discuss the opportunities and challenges associated with utilizing 5-HT2AR agonists as therapeutics for OUD.

Analysis of Tianeptine in Dietary Supplements

In the United States (US), tianeptine is sold as a dietary supplement under the trade name Tianaa™. Tianeptine is a synthetic drug prescribed by physicians as an antidepressant in parts of Europe, Asia and South America. The drug is not permitted for use by physicians in the US, because it is a μ-opioid receptor agonist with a propensity for severe addiction. As the incidence of Tianaa™-related opioid addiction across the southern US escalates, the current study aimed to quantify tianeptine in over-the-counter Tianaa™ White, Red, and Green products. The results of this investigation measured tianeptine levels between 3.1 and 10.9 mg per 531 mg capsules. Tianaa™ White capsules consistently contained the least tianeptine, while Green had the most. The close inspection of Tianaa™ products showed that capsule mass varied by as much as 16% from label claim, and the amount of tianeptine per capsule varied by as much as 35% from the average measured amount for each product. Tianaa™ Red contains kava leaf extract, which led to the identification of four kavapyrone components by mass spectrometry. The data presented provide insight into tianeptine quantity and capsule mass variation for Tianaa™ supplements sold to customers naive to the risk of addiction.

Novel multi-objective affinity approach allows to identify pH-specific μ-opioid receptor agonists

Opioids are essential pharmaceuticals due to their analgesic properties, however, lethal side effects, addiction, and opioid tolerance are extremely challenging. The development of novel molecules targeting the mu-opioid receptor (MOR) in inflamed, but not in healthy tissue, could significantly reduce these unwanted effects. Finding such novel molecules can be achieved by maximizing the binding affinity to the MOR at acidic pH while minimizing it at neutral pH, thus combining two conflicting objectives. Here, this multi-objective optimal affinity approach is presented, together with a virtual drug discovery pipeline for its practical implementation. When applied to finding pH-specific drug candidates, it combines protonation state-dependent structure and ligand preparation with high-throughput virtual screening. We employ this pipeline to characterize a set of MOR agonists identifying a morphine-like opioid derivative with higher predicted binding affinities to the MOR at low pH compared to neutral pH. Our results also confirm existing experimental evidence that NFEPP, a previously described fentanyl derivative with reduced side effects, and recently reported beta-fluorofentanyls and -morphines show an increased specificity for the MOR at acidic pH when compared to fentanyl and morphine. We further applied our approach to screen a >50K ligand library identifying novel molecules with pH-specific predicted binding affinities to the MOR. The presented differential docking pipeline can be applied to perform multi-objective affinity optimization to identify safer and more specific drug candidates at large scale.

The Effects of Chronic Naltrexone on Reinstatement of Opioid-Induced Drug-Seeking Behavior and Antinociception.

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 suitable for relapse-related studies. The opioid antagonist naltrexone has been forwarded as a medication that can forestall 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 intravenous 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 (0.2 mg/kg/d). Results show that naltrexone produced: 1) a 10-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, and oxycodone) but rightward and downward shifts in the dose-response functions for lower-efficacy MOR agonists (buprenorphine, nalbuphine, and butorphanol). These results suggest that, although 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: Although naltrexone is commonly used in the treatment of opioid use disorder, its ability to reduce the priming strength of opioid agonists has not been extensively investigated. This study shows 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 be able to surmount naltrexone-induced antagonism of these two effects, and perhaps naltrexone offers greater protection against lower efficacy agonists.

Neurocognitive effect of biased µ-opioid receptor agonist oliceridine, a utility function analysis and comparison with morphine.

Oliceridine (Olinvyk®) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. We determined the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. The study had a randomized, double-blind, placebo-controlled, partial block 3-way crossover design. Experiments were performed in 20 male and female volunteers. Subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose) or placebo on three separate occasions. Prior to and following dosing, neurocognitive tests, cold pressor test and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as measure of benefit, slowing of saccadic peak velocity and increased body sway as measures of neurocognitive harm. The oliceridine and morphine C50's, i.e. the effect-site concentrations causing 50% effect, were: antinociception 13±2 and 23±7 ng/mL, saccadic peak velocity 90±14 and 54±15 ng/mL, and body sway 10±2 and 5.6±0.8 ng/mL, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI 0.17-0.7; p<0.01) for saccadic peak velocity and 0.33 (0.16-0.50; p<0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5-77 ng/mL, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from zero from 0-100 ng/mL. Over the concentration range 15-50 ng/mL the oliceridine utility was superior to that of morphine (p < 0.01). Similar observations were made for body sway. These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

PEG-4000 Ameliorates morphine-induced constipation in mice through inhibition of AQP-3 mRNA Expression

Morphine is μ-opioid receptor (MOR) agonist that is used clinically for patients suffering from moderate to severe pain. Morphine can cause constipation due to activation of μ-opioid receptors in the central nervous system and the nervous system in the gastrointestinal tract. It is caused by increasing the expression of AQP-3 in the instestine through increased of serotonin by enterochromaffin cells. PEG 4000 is one of the osmotic laxatives used to treat Opioid Induced Constipation (OIC). PEG 4000 affects the upregulation of serotonin re-uptake which can lead to expression enhancement of AQP-3. The purpose of this study was to analyze the effect of PEG 4000 on expression changes of aquaporin-3 in mice colon induced acute constipation with morphine.Constipation conditions and the effectiveness of laxative therapy are indicated by constipation parameters in the form of fecal water content and stool weight. This study used 36 male mice of the Balb/c line genus which were divided into 3 groups, normal saline, morphine, and morphine + PEG 4000. Each group was further divided into 2 subgroups based on the time of observation, namely the first hour and fifth hour after morphine induced. The expression of AQP-3 was observed using Polymerase Chain Reaction (PCR) method. The result of this study showed that the administration of PEG 4000 to mice induced constipation with morfine could decrease the expression of AQP-3 from (146,413±1,736) to (118,411±3,476) with p value &lt;0,05, increase the percentage of fecal water content from (0,000±0,000%) to (28,903±12,930%) with p value &lt;0,05 and increase the stool weight from (0,000±0,000g) to (0,928±0,178g) with p value &lt;0,01 From these results, it can be concluded that the administration of PEG 4000 in morphine induced constipation to mice was effective in reducing AQP-3 expression as well as increasing the percentage of fecal water content and stool weight.