Kappa-opioid Agonist Research Articles

Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models

Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids – termed oxa-iboga – defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential.

Pharmacological interventions for pruritus in adult palliative care patients.

Pharmacological interventions for pruritus in adult palliative care patients.

Synthesis and pharmacological activity of various organic and inorganic salts of phenyl derivatives of imidazobenzimidazole

Introduction: The creation of new opioid analgesics that are devoid of the main undesirable effects – euphoria, respiratory depression, tolerance – is an important task for the treatment of pain syndrome. Eighteen salts of 9-pyrrolidinoethyl-(1a), 9-piperidinoethyl-(1b), and 9-morpholinoethyl-2-(4-fluorophenyl)benzo[d]imidazo[1,2-a]imidazole (1c) were synthesized and tested for kappa agonist and analgesic activity. Materials and Methods: Specific analgesic activity studies were conducted using models of nociceptive pain in the “Hot/Cold-plate” and ”Plantar Test” tests, and in neuropathic pain against the background of sciatic nerve ligation. The relationship between the physicochemical and pharmacological properties of the compounds was studied in silico using quantum chemistry methods and artificial neural network technology. Results: The most active compound identified was 4-(2-(2-(4-fluorophenyl)-benzo[d]imidazo[1,2-a]imidazol-9-yl)ethyl)morpholine dihydrochloride (1c.2HCl). EC50, acute toxicity, and conditional therapeutic index values were calculated, which were 38.8 times superior to the kappa agonist U50488. It was established that compound 1c.2HCl exhibits a dose-dependent analgesic effect in the “Hot/Cold-plate” test, which is six times superior to that of butorphanol, maintaining a statistically significant effect for six hours in the “Plantar test” and without causing the formation of tolerance with a ten-day administration. In models of neuropathic pain syndrome, 1c.2HCl with a fourteen-day administration significantly reduced tactile and cold allodynia by three and 1.6 times, respectively, and was not inferior in activity to gabapentin. The kappa-opioidergic mechanism of the antinociceptive action of 1c.2HCl compound was confirmed. Quantum chemistry methods and artificial neural network technologies have shown that the high level of kappa-opioid agonist activity of hydrochlorides, in contrast to other salts, results in lower total energy production; therefore, there is a significant increase in energy during the formation of a salt supramolecular complex. Conclusion: The most active compound was identified – 1c.2HCl, for which kappa-opioid activity in vitro and analgesic properties were revealed in various in vivo models. It has been shown that the compound does not cause the formation of tolerance and is not toxic.

Central Inhibition of Antidiuretic Hormone by the Kappa Opioid Receptor Agonist Nalfurafine Prevents and Reverses Loop Diuretic Resistance

PURPOSE: Diuretic resistance is a failure to achieve a therapeutically desired increase in the renal excretion of sodium and water and reduction in edema despite a full dose of a loop diuretic. High levels of antidiuretic hormone (ADH) have been associated with reduced urine output in heart failure patients. However, ADH’s contribution to the development of diuretic resistance is not known. Assuming that ADH may be released in response to the diuresis produced by loop diuretics, we tested the premise that co-treatment of rats with nalfurafine, a centrally acting kappa opioid (KOR) agonist that inhibits the release of ADH would prevent and/or reverse diuretic resistance to the loop diuretic furosemide. METHODS: Changes in 5-hr urine output (metabolic cages; no water access during collection), urinary Na/K excretion, and osmolality were measured in male Sprague-Dawley rats administered twice-daily i.p. injections (9:00am, 2:00pm; n=6/group) for 11 days with 1) furosemide only (F, 10mg/kg, i.p.; days 1-11), 2) furosemide + nalfurafine (F+N, 10ug/kg, i.p.; days 1-11) or 3) F (days 1-5) followed by F+N (days 6-11). 5-hr urine collection was measured in between the morning and afternoon drug injections and rats were returned to home cages. Control 5-hr urine samples (saline, i.p.) were collected 2 days prior to beginning drug treatments. SUMMARY: Initial treatment (day 1) of rats with F alone and F+N markedly increased urine output. However, over days 6-10, urine output was significantly reduced (diuretic resistance) in rats that continued to receive F alone. Daily co-treatment of F+N beginning day 1 maintained a marked 5-hrdiuresis for all 11 days. Further, delaying addition of nalfurafine co-administration with F until day 6 reversed established diuretic resistance as noted by a marked increase in diuresis over days 6-10 with F+N cotreatment. Initial treatment (day 1) of rats with furosemide also produced a marked natriuresis and kaliuresis. However, on subsequent days (2-11) there was a significant decrease in the renal excretion of sodium and potassium that remained lower in all 3 treatment groups. In contrast, nalfurafine co-treatment beginning either day 1 (Group 2) or day 6 (Group 3) increased free-water clearance as compared to furosemide alone (Group 1). CONCLUSIONS: These results demonstrate that co-administration of the KOR agonist nalfurafine prevented and reversed diuretic resistance to furosemide without worsening electrolyte excretion. Further, these findings support the premise that in response to fluid loss caused by repeated loop diuretic administration, a compensatory release and renal action of ADH plays an important role in mediating loop diuretic resistance. NIH P30GM106392 (DK) LSUHSC REP243 (DK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electrophysiological effects of kappa-opioid analgesic, RU-1205, using machine learning methods

The study is focused to the investigation of a new kappa-opioid agonist RU-1205, which exhibits an analgesic effect without causing dysphoric or aversive actions. It is assumed that this effects may be due to its functional selectivity, or the presence of an additional mechanism of action that involves blocking p38 mitogen-activated protein kinase (MAPK).The aim of the study was an experimental identification of RU-1205 mechanisms of action associated with the inhibition of MAPK p38 and functional selectivity for kappa opioid receptors.Materials and methods. The LFP activity was recorded in the male rats weighing 260–280 g (n=62) and implanted with chronic cortical and deep electrodes, after the intracerebroventricular administration of the well-studied reference substances: the selective kappa-opioid agonist U-50488 100 μg; the MAPK p38 blocker SB203580 1 μg; and the investigational compound RU-1205 at 350 μg. The weighted phase lag index (WPLI) was calculated. Subsequently, machine learning methods were employed to reduce the dimensionality and extract connectivity features using the principal component analysis method, then a signal classification was performed (models based on Gaussian processes). Using the local patch-clamp technique in the “whole-cell” configuration, the spike activity of pyramidal neurons in the basolateral amygdala was studied. Neurons were identified by their accommodation properties. After local perfusion of the test compounds, 3 dose-response curves were obtained for: (1) U-50488 at concentrations ranging from 0.001 to 10 μM; (2) combinations of U-50488 (0.001–10 μM) and RU-1205 (10 μM); and (3) the combinations of U-50488 (0.01–10 μM) and RU-1205 (100 μM).Results. The developed models made it possible to classify the compound RU-1205 as a “non-inhibitor” of MAPK p38 with a high probability. The results obtained were confirmed in patch-clamp experiments on acute brain slices where it was demonstrated that U-50488 statistically significantly increases the spike activity of pyramidal neurons of the basolateral amygdala (p <0.05), and RU-1205 interacts with U-50488, competitively suppressing its effect on the spike activity of neurons.Conclusion. The findings suggest that compound RU-1205 displays properties consistent with a functional kappa agonist activity and does not have a significant effect on MAPK p38. The study demonstrates the possibility of integrating electrophysiological measurements and advanced data analysis methods for a deep understanding of drug action and underscores the potential for further research in this area.

Effects of kappa-opioid agonist U-50488 and p38 MAPK inhibitor SB203580 on the spike activity of pyramidal neurons in the basolateral amygdala

Introduction: Kappa-opioid receptor (KOR) signaling in the basolateral amygdala (BLA) underlies KOR agonist-induced aversion. In this study, we aimed to understand the individual and combined effects of KOR agonist U-50488 and p38 MAPK inhibitor SB203580 on the spiking activity of pyramidal neurons in the BLA to shed light on the complex interplay between KORs, the p38 MAPK, and neuronal excitability. Materials and Methods: Electrophysiological experiments were performed using the patch-clamp technique in the whole-cell configuration. Rat brain slices containing the amygdala were prepared, and pyramidal neurons within the BLA were visually patched and recorded in the current clamp mode. The neurons were identified by their accommodation properties and neural activity signals were amplified and analyzed. Using local perfusion, we obtained three dose-response curves for: (a) U-50488 (0.001–10 μM); (b) U-50488 (0.001–10 μM) in the presence of SB203580 (1 μM); and (c) U-50488 (0.01–10 μM) in the presence of SB203580 (5 μM). Results: After the application of U-50488, pyramidal neurons had a higher action potential firing rate in response to a current injection than control neurons (p<0.001). The dose-dependent curves we obtained indicate that the combination of U-50488 and SB203580 results in non-competitive antagonism. This conclusion is supported by the observed change in the curve’s slope with reduction in the maximum effect of U-50488. Thus, it can be assumed that the increase in spike activity of pyramidal neurons of the amygdala is mediated through the beta-arrestin pathway. When this pathway is blocked, the spike activity reverts to its baseline level. Conclusion: Our study found that the KOR agonist-induced spiking activity of the BLA pyramidal neurons is mediated by the beta-arrestin pathway and can be suppressed by the application of the p38 MAPK inhibitor SB203580.

Influence of kappa-agonist of opioid receptors compound RU-1205 on the generative function of male rats

The effect of a new kappa-opioid agonist benzimidazole derivative (compound RU-1205) on the generative function of outbred male rats was studied after oral administration for 2 months at doses of 5 mg/kg – experimentally proven therapeutic dose (TD) and 500 mg/kg (the highest dose is 100 TD). The absence of a damaging effect of the compound RU-1205 on the motivational sexual behavior of males and the processes of spermatogenesis was established.

Aversion-related effects of kappa-opioid agonist U-50488 on neural activity and functional connectivity between amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens

Introduction: Among the various receptor systems in the brain, the opioid receptors have been the subject of extensive research due to their integral role in pain modulation, reward processing, and emotional regulation. The kappa-opioid receptor (KOR) system, in particular, stands apart due to its unique contribution to stress response, aversive behaviors, and dysphoric states. This paper aims to provide an understanding of the neural activity underlying the aversion-associated effects of the KOR agonist U-50488.
 Materials and Methods: Rats underwent stereotaxic surgery to implant electrodes into the amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens. The rats were subjected to conditioned place preference test to measure aversion to U-50488. After that, local field potential (LFP) recordings were made. LFP data were processed and analyzed using spectral and coherence analysis methods. A stepwise multiple linear regression was employed to identify the LFP features most significantly correlated with aversion to U-50488.Results: The administration of U-50488 resulted in significant changes in LFP signals across multiple brain regions. These changes were particularly notable in the theta, gamma, and delta bands of brain waves (p<0.05). Theta and gamma activities were especially sensitive to the effects of U-50488. Connectivity calculations revealed shifts in coherence between brain regions, particularly highlighting the amygdala's involvement. While changes were also observed in the ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens (p<0.05), they contributed less to aversion. Using the stepwise multiple linear regression method, we established a final model with the 3 most significant variables: (1) coherence between the amygdala and medial prefrontal cortex, (2) coherence between the amygdala and hippocampus, and (3) theta power in the amygdala.
 Conclusion: Overall, the data provided insights into how electrical neural activity mediates aversion in response to KOR activation. The results showed that the severity of aversion can be reasonably predicted (r = 0.72±0.02, p = 0.0099) using LFP band power and functional connectivity data. We concluded that the amygdala is a brain region that contributes the most to the KOR agonist-induced aversion.

Treatment of Diuretic Resistance with a Kappa Opioid Agonist, an Inhibitor of Central Vasopressin Secretion

Treatment of Diuretic Resistance with a Kappa Opioid Agonist, an Inhibitor of Central Vasopressin Secretion

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

Combinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects. The present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A. Adult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018mg/kg/injection). Once trained, cocaine (0.018mg/kg/injection) or oxycodone (0.0056mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1-3.2µg/kg/injection), nalfurafine (0.0032-0.1µg/kg/injection), triazole 1.1 (3.2-100.0µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components. Cocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed. These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

Kappa opioid agonists in the treatment of itch: just scratching the surface?

Chronic pruritus is a debilitating condition affecting 23–44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.

What are the effects of gamma-aminobutyric acid (GABA) analogs or kappa-opioid agonists for adults with uremic pruritus?

What are the effects of gamma-aminobutyric acid (GABA) analogs or kappa-opioid agonists for adults with uremic pruritus?

Models of neuroinflammation for the assessment of kappa-opioid receptor ligands

The development of new drugs to combat neuroinflammation is highly relevant as it opens up possibilities for the treatment of a wide range of diseases, including Alzheimer’s disease, Parkinson’s disease, epilepsy, schizophrenia, depression, and others. Kappa-opioid agonists represent a promising class of compounds with а high potential to be used in the treatment of neurological conditions accompanied by neuroinflammation.The aim of the study was to provide a summary of the current strategies employed to evaluate the neurotropic anti-inflammatory effects of kappa-opioid ligands in laboratory animals with induced neuroinflammation.Materials and methods. The databases, such as Google Scholar, PubMed, ScienceDirect, Scopus, e-Library were used as search tools. The search comprised the following keywords and phrases in Russian and English: kappa opioids + neuroinflammation; kappa opioid receptors + neuroinflammation; neuroinflammation models; neuroinflammation models in rats, neuroinflammation models in mice. 148 relevant articles were found, 122 were included in this review.Results. Various experimental models of neuroinflammation, including chemically-induced and bacterial endotoxin-induced neuroinflammation, as well as traumatic and genetic models in mice and rats were evaluated. In addition, the strengths and limitations of each model were critically assessed to identify the most appropriate and reliable approach for investigating the relationship between neuroinflammation and signaling pathways associated with kappa-opioid receptors.Conclusion. The neurotropic anti-inflammatory activity of kappa-opioid ligands have been comprehensively described. The review discusses both experimental models where the effects of kappa-opioid agonists have been investigated, as well as the models where the anti-inflammatory properties of kappa-opioid agonists have not been studied yet.

The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01–0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.32–1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01–0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0–56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.

Sex- and β-arrestin-dependent effects of kappa opioid receptor-mediated ethanol consumption

The kappa opioid receptor is a known regulator of ethanol consumption, but the molecular mechanisms behind its actions have been underexplored. The scaffolding protein β-arrestin 2 has previously been implicated in driving ethanol consumption at the related delta opioid receptor and has also been suggested to be a driver behind other negative kappa opioid receptor mediated effects. Here, we used kappa opioid agonists with different efficacies for recruiting β-arrestin 2 and knockout animals to determine whether there is a role for β-arrestin 2 in the modulation of voluntary ethanol consumption by the kappa opioid receptor. We find that an agonist with low β-arrestin 2 efficacy more consistently lowers ethanol consumption than agonists with high efficacy for β-arrestin 2. However, knockdown of β-arrestin 2 amplifies the ethanol consumption-promoting effects of the arrestin-recruiting kappa agonists U50,488 and nalfurafine. We control for potentially confounding sedative effects at the kappa opioid receptor and find that β-arrestin 2 is not necessary for kappa opioid receptor-mediated sedation, and that sedation does not correlate with effects on ethanol consumption. Overall, the results suggest a complex relationship between agonist profile, sex, and kappa opioid receptor modulation of ethanol consumption, with little role for kappa opioid receptor-mediated sedation.

NEUROPROTECTIVE ACTION OF BUTORPHANOL AND RU-1205 WITH EVALUATION OF THEIR EFFECT O N THE BIOELECTRICAL ACTIVITY OF THE BRAIN IN THE GLOBAL ISCHEMIA MODEL

Since ischemic stroke is an extremely common and dangerous pathology, it is important to use drugs with neuroprotective activity. The depth and degree of brain damage due to ischemia are reflected in its bioelectrical activity. This makes it possible to use the electrocorticography or intracranial electroencephalography (EEG) as a tool for evaluating the effectiveness of neuroprotective therapy. In the present study the neuroprotective properties of the experimental compound RU-1205 and the kappa-opioid agonist butorphanol were analyzed. The neuroprotective effect of the substances was assessed by measuring the extent of the neurological deficit and the changes in bioelectrical activity of the ischemic brain of rats. Compound RU-1205 (10 mg/kg, i.v.) as well as the reference drug butorphanol (2,5 mg/kg, i.v.) restored to normal neurological status and power of the EEG signal in delta and theta frequency bands.

Effect of adjuvant drugs on the analgesic activity of opioid morphine analgesics and compound RU-1205

Introduction: Adjuvant medications can be used to increase the analgesic effect of opioid analgesics, reduce the manifestation of side effects, and also for premedication. This paper provides information on the effect of clonidine, haloperidol, metocloparmide, diazepam, midazolam on opioid analgesics: - morphine and the selective kappa-opioid agonist compound RU-1205.
 Materials and methods: A probable interaction between RU-1205, morphine and adjuvant drugs in pain behaviors was carried out on the model of somatogenic pain. 95 male mice received either RU-1205 (5 mg/kg, i.p.) and morphine (1 mg/kg, i.p.) separately or in combination with haloperidol (0.45 mg/kg, i.p.); midazolam (0.3 mg/kg, i.p.); diazepam (1 mg/kg, i.p.); metoclopramide (5 mg/kg, i.p.), and clonidine (1 mg/kg, i.p.). The analgesic effect was assessed by tail flick test. Registration of the latent period of the reaction was carried out 30, 60 and 90 minutes after the adjuvant drug administration.
 Results: When studying the interaction with morphine, it was found that clonidine, haloperidol and metoclopramide enhanced the effects; diazepam offset them, and midazolam had no affect on the analgesic properties. In the course of the studies, RU-1205 showed an increase in analgesic activity when combined with clonidine, a slight increase with midazolam, and a decrease when co-administered with diazepam. Haloperidol had no influence on the effect of RU-1205, while metoclopramide both potentiated and reduced the analgesic effect.
 Discussion: Pharmacodynamic and pharmacokinetic interactions of RU-1205 with an α2AR agonist, benzodiazepine receptor agonists, D2P antagonist, and σ-receptor blocker were established.
 Conclusion: The presented data make it possible to more accurately formulate ideas about the localization and action mechanism of the kappa-agonist of opioid receptors, the compound RU-1205.

How do kappa-opioid agonists compare with placebo for adults on hemodialysis who have uremic itch associated with chronic kidney disease?

How do kappa-opioid agonists compare with placebo for adults on hemodialysis who have uremic itch associated with chronic kidney disease?

Interactive effects of (±)-trans-U50488 and its stereoisomers with cannabinoids

The adverse effects of mu opioid agonists have spurred a renewed interest in using kappa opioid receptor (KOR) agonists as analgesics. KOR agonists also have potential for development as diuretics for the treatment of edema and hypertension. Here, we evaluated the discriminative stimulus, antinociceptive, and diuretic effects of the kappa agonist (±)-trans-U-50488 and its stereoisomers (−)-(1S,2S)-U-50488 or (+)-(1R,2R)-U-50488) alone and in combination with the cannabinoid agonist (−)-CP 55,940. To establish (±)-U-50488 as a discriminative stimulus, rats (n = 12) were trained to discriminate intraperitoneal (i.p.) administration of 5.6 mg/kg of (±)-trans-U-50488 from saline under a fixed-ratio 20 (FR-20) schedule of food reinforcement. Then, antinociception was assessed using two procedures: warm water tail withdrawal and von Frey paw withdrawal. Diuretic effects were assessed in separate rats (n = 6/group). Doses of (±)-U-50488 and (−)-U-50488 that served as discriminative stimuli produced significant increases in urine output, but at lower doses than those that produced antinociception. In contrast, (+)-U-50488 alone had no discriminative stimulus or diuretic effects at the doses tested, but did produce antinociception in the von Frey assay. When three cannabinoids and morphine were tested in the (±)-U-50488 discrimination procedure to determine the similarity of these drugs' discriminative stimulus effects to those for (±)-U-50488, the rank order similarity was (−)-CP 55,940 > (−)-trans-THC > (+)-WIN 55,212–2 ≥ morphine. (−)-CP 55,940 alone (0.056 mg/kg) partially substituted for the discriminative stimulus effects of (±)-U-50488 and produced significant diuretic and antinociceptive effects. (−)-CP 55,940 in combination with (±)-U-50488 also produced a two-fold leftward shift in the discriminative stimulus curve for (±)-U-50488, and near-additive antinociception with (±)-U-50488 and (+)-U-50488. Further, the diuretic effect of (−)-CP 55,940 was enhanced by a dose of (+)-U50488, which itself did not alter urine output. These data together indicate that a combination of cannabinoid and kappa opioid agonists can enhance diuresis, but may have limited potential for serving as opioid-sparing pharmacotherapeutics for treatment of pain.

Evaluation of Antinociceptive Effects of Chitosan-Coated Liposomes Entrapping the Selective Kappa Opioid Receptor Agonist U50,488 in Mice.

Background and Objectives: The selective kappa opioid receptor agonist U50,488 was reported to have analgesic, cough suppressant, diuretic and other beneficial properties. The aim of our study was to analyze the effects of some original chitosan-coated liposomes entrapping U50,488 in somatic and visceral nociceptive sensitivity in mice. Materials and Methods: The influence on the somatic pain was assessed using a tail flick test by counting the tail reactivity to thermal noxious stimulation. The nociceptive visceral estimation was performed using the writhing test in order to evaluate the behavioral manifestations occurring as a reaction to the chemical noxious peritoneal irritation with 0.6% acetic acid (10 mL/kbw). The animals were treated orally, at the same time, with a single dose of: distilled water 0.1 mL/10 gbw; 50 mg/kbw U50,488; 50 mg/kbw U50,488 entrapped in chitosan-coated liposomes, according to the group they were randomly assigned. Results: The use of chitosan-coated liposomesas carriers for U50,488 induced antinociceptive effects that began to manifest after 2 h, andwere prolonged but with a lower intensity than those caused by the free selective kappa opioid in both tests. Conclusion: In this experimental model, the oral administration of nanovesicles containing the selective kappa opioid agonist U50,488 determined a prolonged analgesic outcome in the tail flick test, as well as in the writhing test.