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.

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.

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.

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.

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.

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.

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.

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.

Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-phenylpropoxymetopon: an extremely powerful analgesic.

The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxymetopon (PPOM; 7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (1) and even etorphine. 14-Phenylpropoxymetopon (PPOM; 7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds 6 and 8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-methoxymetopon (1).

Synthesis and biological evaluation of 14-alkoxymorphinans. 18. N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: extending the scope of common structure-activity relationships.

The synthesis, biological, and pharmacological evaluations of 14beta-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14beta-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (mu, kappa, delta), with the N-propyl derivative 19 displaying the highest affinity for the mu-receptor (K(i) = 0.09 nM).

Synthesis and biological evaluation of 14-alkoxymorphinans. 21. Novel 4-alkoxy and 14-phenylpropoxy derivatives of the mu opioid receptor antagonist cyprodime.

The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at mu, delta, and kappa opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the mu opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase mu affinity in the case of benzyloxy, while a phenylpropoxy group reduces mu affinity. The delta and kappa affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the mu opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at delta and kappa receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [(35)S]GTPgammaS binding assay, all tested compounds were partial agonists at mu and delta receptors. Compounds 8 and 17 showed antagonism at kappa receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.

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.

Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys.

Despite oxycodone's (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) history of clinical use and the attention it has received as a drug of abuse, few reports have documented its pharmacology's relevance to its abuse or its mechanism of action. The purposes of the present study were to further characterize the analgesic effects of oxycodone, its mechanism of action, and its effects in terms of its relevance to its abuse liability. The results indicate that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays, in which it appeared to be acting as a mu-opioid receptor agonist. It generalized to the heroin discriminative stimulus and served as a positive reinforcer in rats and completely suppressed withdrawal signs in morphine-dependent rhesus monkeys. These results suggest that the analgesic and abuse liability effects of oxycodone are likely mediated through mu-opioid receptors and provide the first laboratory report of its discriminative stimulus, reinforcing, and morphine cross-dependency effects.

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.