Automatic Pulp and Teeth Three-Dimensional Modeling of Single and Multi-Rooted Teeth Based on Cone-Beam Computed Tomography Imaging: A Promising Approach With Clinical and Therapeutic Outcomes.

Background Cone-beam computed tomography (CBCT) imaging offers high-quality three-dimensional (3D) acquisition with great spatial resolution, given by the use of isometric voxels, when compared with conventional computed tomography (CT). The current literature supports a median reduction of 76% (up to 85% reduction) of patients' radiation exposure when imaged by CBCT versus CT. Clinical applications of CBCT imaging can benefit both medical and dental professions. Because these images are digital, the use of algorithms can facilitate the diagnosis of pathologies and the management of patients. There is pertinence to developing rapid and efficient segmentation of teeth from facial volumes acquired with CBCT. Methodology In this paper, a segmentation algorithm using heuristics based on pulp and teeth anatomy as a pre-personalized model is proposed for both single and multi-rooted teeth. Results A quantitative analysis was performed by comparing the results of the algorithm to a gold standard obtained from manual segmentation using the Dice index, average surface distance (ASD), and Mahalanobis distance (MHD) metrics. Qualitative analysis was also performed between the algorithm and the gold standard of 78 teeth. The Dice index average for all pulp segmentation (n = 78) was 83.82% (SD = 6.54%). ASD for all pulp segmentation (n = 78) was 0.21 mm (SD = 0.34 mm). Pulp segmentation compared with MHD averages was 0.19 mm (SD = 0.21 mm). The results of teeth segmentation metrics were similar to pulp segmentation metrics. For the total teeth (n = 78) included in this study, the Dice index average was 92% (SD = 13.10%), ASD was low at 0.19 mm (SD = 0.15 mm), and MHD was 0.11 mm (SD = 0.09 mm). Despite good quantitative results, the qualitative analysis yielded fair results due to large categories. When compared with existing automatic segmentation methods, our approach enables an effective segmentation for both pulp and teeth. Conclusions Our proposed algorithm for pulp and teeth segmentation yields results that are comparable to those obtained by the state-of-the-art methods in both quantitative and qualitative analysis, thus offering interesting perspectives in many clinical fields of dentistry.

The effects of wireless devices on male reproductive health: A literature overview.

PURPOSE: The aim of this study was to summarize the evidence of radiofrequency electromagnetic radiation (RF-EMR) exposure from wireless devices on total motile sperm count (TMSC) and identify gaps in the literature that could help clarify this link. MATERIALS AND METHODS: A literature search was conducted using PubMed/MEDLINE to find relevant studies examining the effects of EMR on male fertility, with a specific focus on TMSC, published from 2000 to 2019. R was used for data analyses. RESULTS: Motility was identified as the parameter linked to TMSC that was most negatively impacted by EMR exposure. Many gaps were found including geographic and lack of standardization with EMR factors such as exposure time and operating frequency. CONCLUSION: The EMR emitted by wireless devices may negatively affect TMSC, which is one of the better predictors of achieving pregnancies and impairs male fertility. Our findings highlight the need for clinicians to explore wireless device usage to help guide treatment decisions in men or couples with subfertility concerns.

Precuneal epilepsy: Clinical features and surgical outcome.

OBJECTIVE: The precuneus is a complex and highly connected structure located in the medial portion of the superior parietal lobule. The clinical presentation of precuneal epilepsy is poorly characterized, mostly because these patients have seldom been distinguished from those with other types of parietal lobe epilepsy. The present study aims to improve the understanding of precuneal epilepsy by detailing its clinical features and surgical outcomes. METHODS: Six previously unreported cases of drug-resistant precuneal epilepsy investigated between 2002 and 2014 were retrospectively studied. Seizure focus was confirmed by presence of a lesion, intracranial monitoring, or post-operative seizure control when applicable. RESULTS: Seizures arising from the precuneus have heterogeneous presentations, including body movement sensation, visual auras, eye movements, vestibular manifestations, and complex motor behaviors. Two patients with an anterior precuneus lesion described body movement sensations whereas two others with a posterior precuneus lesion experienced visual symptoms. Two of the five patients who underwent epilepsy surgery achieved good seizure control (Engel IA). One patient underwent gamma knife surgery with an Engel IV outcome. Surgical complications included contralateral visual field impairment, limb hypoesthesia and hemispatial neglect. One patient developed late-onset epilepsia partialis continua from a Rolandic subdural grid-related contusion. SIGNIFICANCE: In absence of a clear precuneal epileptogenic lesion, recognition of a precuneal focus is challenging. Magnetoencephalography may sometimes localize the generator but invasive EEG remains in well-selected cases necessary to identify the seizure focus. Surgical failures may be explained by the widespread connectivity of the precuneus with distant and adjacent structures. Different ictal manifestations of precuneal epilepsy in this series provide a clinical correlate to the described functional subdivisions of the precuneus.

Exploring pharmacological activities and signaling of morphinans substituted in position 6 as potent agonists interacting with the µ opioid receptor.

BACKGROUND: Opioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The µ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures. RESULTS: This study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone. CONCLUSION: Development of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.

Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible µ opioid receptor antagonist effects.

We have previously shown that cinnamoyl derivatives of 14ß-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7α-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible µ opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid ß-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of ß-FNA is clearly κ opioid receptor (KOR) mediated.

l-theanine attenuates abstinence signs in morphine-dependent rhesus monkeys and elicits anxiolytic-like activity in mice.

l-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid found in green tea (Camellia sinensis), is sold in the United States as a dietary supplement to reduce stress and improve cognition and mood. The observations that l-theanine has been shown to inhibit caffeine's stimulatory effects and that caffeine produces precipitated withdrawal signs in opioid-addicted monkeys and some opioid withdrawal signs in some normal monkeys, suggest that l-theanine may suppress opioid withdrawal signs. Additionally, l-theanine produces anxiolytic effects in humans indicating that it has anti-anxiety properties. Thus, in these studies we determined whether l-theanine attenuates opioid-withdrawal signs in morphine-dependent rhesus monkeys, a model for spontaneous opioid withdrawal in human opioid addicts. We also evaluated whether l-theanine decreases anxiety-like behavior in mice, using the elevated plus maze and marble burying assays. l-theanine significantly attenuated designated opioid withdrawal signs, including fighting, rigid abdominal muscles, vocalizing on palpation of abdomen, pacing, retching, wet-dog shakes, and masturbation. It had a relatively quick onset of action that persisted for at least 2.5h. l-theanine also produced anxiolytic-like effects in the elevated plus maze and the marble burying assay in naïve mice at doses that did not significantly affect motor behavior. The results of these studies suggest that l-theanine may be useful in the pharmacotherapy of treating opioid withdrawal as well as anxiety-associated behaviors.

MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys.

MDAN-21, 7'-{2-[(7-{2-[({(5α, 6α)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006-0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032-0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain.

Determining the basis for a taxonomy of mechanical ventilation.

BACKGROUND: Mechanical ventilation technology has evolved rapidly over the last 30 years. One consequence is the creation of an unmanageable number of names to describe modes of ventilation. The proliferation of names makes education of end users difficult, potentially compromising the quality of patient care. OBJECTIVE: To determine if stakeholders are familiar enough with published constructs related to modes of mechanical ventilation to form a basis for a consensus, by surveying the medical, education, and business communities. The hypotheses tested were: there is concordance (> 50%) on 10 basic constructs related to modes; concordance with the basic constructs varies among stakeholders according to professional training and professional activity; and concordance varies among the set of constructs. METHODS: The survey was distributed through an Internet-based tool to 2,994 physicians, respiratory therapists, nurses, engineers, and others involved with mechanical ventilation. Hypotheses were tested with chi-square, with P < .05 considered significant. RESULTS: The response rate was 15%. Respondents were 55% respiratory therapists, 35% physicians, 3% nurses, 1% engineers, and 5% other professionals. There was an 82% concordance with the 10 constructs (P < .001). Respiratory therapists showed the highest degree of concordance (84%) and "other profession" showed the lowest (79%) (P = .006). No significant difference (P = .07) in concordance was observed when data were grouped by professional activity. Concordance differed significantly among the survey questions (P < .001). CONCLUSIONS: Survey results indicate that respondents were either familiar with or amenable to the previously published literature that the survey constructs represented. The degree of familiarity and concordance with these constructs represents a sufficient basis for attempting to formalize a taxonomy. Further analysis of the pattern of concordance among the constructs will inform future educational and consensus building efforts.

Removal of continuous nicotine infusion produces somatic but not behavioral signs of withdrawal in mice.

The introduction of transgenic and knockout mice has shaped new interest in developing novel and modified behavioral methods for mice that evaluate the various manifestations of nicotine withdrawal syndromes. This study assessed the disruption of operant baselines during drug withdrawal, an established rat model of nicotine dependence, in mice. Subjects were trained to lever press for food reinforcement during daily operant sessions. After stable operant baselines were established, mice were implanted with osmotic minipumps containing 0 (saline), 6, 12, 24, or 48 mg/kg/day nicotine base. Operant responding was assessed for disruptions in daily sessions throughout the experiment. Somatic signs of withdrawal were assessed after the operant session on day 7, following administration of mecamylamine (1 mg/kg), and on days 12, 13, and 14, following spontaneous removal of nicotine. Spontaneous removal of nicotine increased somatic signs of withdrawal but did not disrupt operant responding. Mecamylamine failed to produce signs of precipitated withdrawal in either procedure. This study demonstrated nicotine dependence in mice during spontaneous removal of nicotine. Moreover, since signs of behavioral withdrawal (i.e. disruptions in operant response rates) were not observed, these findings suggest the importance of considering differences in the apparent manifestations of withdrawal syndromes while evaluating nicotine dependence.

Mixed kappa/mu opioid receptor agonists: the 6 beta-naltrexamines.

Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6 beta-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, nonselective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist and therefore somewhat similar to the previously evaluated analogues 3-6, while 12b displayed predominant MOR agonist activity.

The influence of esters and carboxylic acids as the N-substituent of opioids. Part 1: Benzomorphans.

To investigate the effects of carboxylic ester and acid moieties as the N-substituent of opioids, a short series of racemic N-substituted normetazocines was prepared. The introduction of both groups as the normetazocine N-substituent produced compounds which displayed low potency in vitro and in vivo, with the esters displaying the greater activity. The pharmacology of the compounds is discussed with implications resulting from potential in vivo metabolic hydrolysis.

Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series.

Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9alpha-methyl, C9-methylene, C9-keto, and C9alpha- and C9beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S)-(+)-14), and (1R,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (Ki = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (1R,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9beta-OH substituent in (1R,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the mu-opioid receptor.

Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a micro-agonist delta-antagonist and delta-inverse agonists.

Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl moiety on the nitrogen atom, were synthesized and their binding affinity to the mu-, delta-, and kappa-opioid receptors was examined. The higher affinity ligands were further examined in the [(35)S]GTPgammaS assay to study their function and efficacy. 3-((1R,5S)-(-)-2-(4-Nitrophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) was found to be a mu-agonist and delta-antagonist in that functional assay and was about 50 fold more potent than morphine in vivo. 3-((1R,5S)-(-)-2-(4-Chlorophenethyl)-2-aza-bicyclo[3.3.1]nonan-5-yl)phenol ((-)-) and several other ligands displayed inverse agonist activity at the delta-opioid receptor. The absolute configuration of all of the reported compounds was established by chemical conversion of (-)- to 1R,5S-(-)-.HBr.

NIH 11082 produces anti-depressant-like activity in the mouse tail-suspension test through a delta-opioid receptor mechanism of action.

The present study examined the effects of NIH 11082 ((-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride), a benzomorphan analogue, in the mouse tail-suspension, an assay used to detect anti-depressant agents. NIH 11082 significantly decreased immobility time during tail-suspension, with a comparable magnitude as the tricyclic anti-depressant desipramine. Importantly, NIH 11082 failed to elicit convulsions or other overt behavioral signs of toxicity. The delta-opioid receptor antagonist naltrindole (AD50=2.0 mg/kg), but not the non-selective mu-opioid receptor antagonist naltrexone or the kappa-opioid receptor antagonist nor-BNI, blocked the effects of NIH 11082 in the tail-suspension test. These results reinforce the notion that delta-opioid receptor agonists can produce significant effects in a behavioral model used to screen anti-depressant drugs.

Pharmacological studies with a nonpeptidic, delta-opioid (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082).

In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50=1.9 (0.7-5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50=0.75 (0.26-2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

Exempt preparations: Historical perspectives.

This article is part of a supplemental issue of the journal devoted entirely to papers on how abuse liability of medications is affected by their formulation for medical use. This article reviews the history of the development of the concept of "exempt preparations" from its first use internationally to its current use, both nationally and internationally. The role of the WHO Expert Committee on Drug Dependence (ECDD) and the College on Problems of Drug Dependence (CDPP) is presented. Examples of exempt preparations are given and the use of the concept to permit useful therapeutic agents to be marketed with reduced regulatory control is discussed.

Effects of JDTic, a selective kappa-opioid receptor antagonist, on the development and expression of physical dependence on morphine using a rat continuous-infusion model.

JDTic, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide, is a potent and selective kappa-opioid antagonist with a very long duration of action [Carroll, F.I., Thomas, J.B., Dykstra, L.A., Granger, A.L., Allen, R.M., Howard, J.L., Pollard, G.T., Aceto, M.D., Harris, L.S., 2004. Pharmacological properties of JDTic: A novel k-opioid receptor antagonist. Eur. J. Pharmacol. 501, 111-119.]. When given 24 h prior to a continuous 4-day infusion of morphine sulfate in rats, JDTic did not prevent the stereotypy that developed during the infusion of morphine. It had no effect on the dramatic loss of body weight associated with the abrupt withdrawal of morphine. However, it decreased the number of important withdrawal signs designated wet-dog shakes and facial rubs. These data suggest that JDTic may find some application in the treatment of opiate abuse.

Effect of a 6-cyano substituent in 14-oxygenated N-methylmorphinans on opioid receptor binding and antinociceptive potency.

In a continued effort to find new substitution patterns in morphinans that would produce strong antinociception while inducing lesser side effects, 4,5-oxygen bridge-opened 6-cyano-substituted N-methylmorphinans (1-3) were synthesized. All compounds showed high affinities in the low nanomolar range to the mu opioid receptor and decreased interaction with delta and kappa receptors, thus being mu selective. When tested in vivo, the 6-cyanomorphinanas acted as potent antinociceptive agents which were either more active or equipotent to their 6-keto analogues 4-6.

Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist.

Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.