Intravenous difelikefalin for the treatment of hemodialysis pruritus.

INTRODUCTION: Patients with chronic kidney disease (CKD) undergoing hemodialysis often experience significant itch secondary to their condition and a subsequent reduction in their overall quality of life. Current treatments are underwhelming, necessitating the search for new, effective therapeutic options to combat itch in this population. AREAS COVERED: The purpose of this review is to explore the available data for the use of intravenous difelikefalin in patients with CKD undergoing hemodialysis. The pathophysiology of CKD-associated itch is multifactorial, with one proposed mechanism involving an imbalance in the endogenous opioid system, favoring upregulation of itch-activating µ-opioid receptors (MORs) and downregulation of itch-inhibiting κ-opioid receptors (KORs). Dysregulation of the immune system is also involved. Difelikefalin is a recent FDA approved treatment that functions as peripherally acting KOR agonist, targeting this imbalance in the endogenous opioid system seen in CKD patients with itch and having an anti-inflammatory effect on immune cells. Clinical data on intravenous difelikefalin is promising regarding its ability to reduce itch in CKD patients on hemodialysis and improve patient quality of life, with few, mild adverse side effects. EXPERT OPINION: As intravenous difelikefalin becomes more widely used in the clinical setting, further studies assessing long-term efficacy and safety will be needed.

κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.

BACKGROUND: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo? METHODS: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used. RESULTS: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels. CONCLUSIONS: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion. TRIAL REGISTRATION: NCT00088699 ( ClinicalTrials.gov ).

Morphine-induced changes in the function of microglia and macrophages after acute spinal cord injury.

BACKGROUND: Opioids are among the most effective and commonly prescribed analgesics for the treatment of acute pain after spinal cord injury (SCI). However, morphine administration in the early phase of SCI undermines locomotor recovery, increases cell death, and decreases overall health in a rodent contusion model. Based on our previous studies we hypothesize that morphine acts on classic opioid receptors to alter the immune response. Indeed, we found that a single dose of intrathecal morphine increases the expression of activated microglia and macrophages at the injury site. Whether similar effects of morphine would be seen with repeated intravenous administration, more closely simulating clinical treatment, is not known. METHODS: To address this, we used flow cytometry to examine changes in the temporal expression of microglia and macrophages after SCI and intravenous morphine. Next, we explored whether morphine changed the function of these cells through the engagement of cell-signaling pathways linked to neurotoxicity using Western blot analysis. RESULTS: Our flow cytometry studies showed that 3 consecutive days of morphine administration after an SCI significantly increased the number of microglia and macrophages around the lesion. Using Western blot analysis, we also found that repeated administration of morphine increases ß-arrestin, ERK-1 and dynorphin (an endogenous kappa opioid receptor agonist) production by microglia and macrophages. CONCLUSIONS: These results suggest that morphine administered immediately after an SCI changes the innate immune response by increasing the number of immune cells and altering neuropeptide synthesis by these cells.

Role of kappa-opioid and mu-opioid receptors in pruritus: Peripheral and central itch circuits.

Modern genetic approaches in animal models have unveiled novel itch-specific neural pathways, emboldening a paradigm in which drugs can be developed to selectively and potently target itch in a variety of chronic pruritic conditions. In recent years, kappa-opioid receptors (KORs) and mu-opioid receptors (MORs) have been implicated in both the suppression and promotion of itch, respectively, by acting on both the peripheral and central nervous systems. The precise mechanisms by which agents that modulate these pathways alleviate itch remains an active area of investigation. Notwithstanding this, a number of agents have demonstrated efficacy in clinical trials that influence both KOR and MOR signalling. Herein, we summarize a number of opioid receptor modulators in development and their promising efficacy across a number of chronic pruritic conditions, such as atopic dermatitis, uremic pruritus and beyond.

Dynorphin/KOR inhibits neuronal autophagy by activating mTOR signaling pathway to prevent acute seizure epilepsy.

In previous studies, we found that dynorphin exerts antiepileptic effect by activating the kappa opioid receptor (KOR). However, the role of neuronal autophagy in dynorphin/KOR-mediated antiepileptic is still unclear. This study aimed to investigate the molecular mechanism of dynorphin's antiepileptic effect by inhibiting autophagy and reducing neuronal apoptosis. Here, a pilocarpine-induced rat model of epilepsy was established and hippocampal neurons were treated with Mg2+ -free exposed for epileptiform activity induction. The real-time polymerase chain reaction and Western blot analysis were used to evaluate messenger RNA and protein expression. The TdT-mediated dUTP-biotin nick end labeling staining and flow cytometry were used to analyze cell apoptosis in vivo and in vitro. Neuron cells viability was detected by Cell Counting Kit-8 assay. Immunofluorescent staining and green fluorescent protein-light chain 3 immunofluorescence were used to measure autophagy in vivo and in vitro. Results showed that overexpression of prodynorphin alleviated neuronal apoptosis, activated the mammalian target of rapamycin (mTOR) signaling pathway, and inhibited neuronal autophagy in epileptic rats. Dynorphin inhibited Mg2+ -free-induced seizure-like neuron apoptosis, partially reversing the effect of Mg2+ -free on the mTOR signaling pathway and seizure-like neuron autophagy. Further, using rapamycin, we found that dynorphin inhibited Mg2+ -free-induced seizure-like neuron autophagy and apoptosis by activating the mTOR signaling pathway. In conclusion, dynorphin inhibits autophagy by activating the mTOR signaling pathway and has a protective effect on epilepsy acute seizure and epilepsy-induced brain injury.

Topical κ-opioid receptor agonist asimadoline improves dermatitis in a canine model of atopic dermatitis.

This prospective, 4-week, placebo-controlled, cross-over study aimed to investigate the efficacy of 1% topical κ-opioid agonist, asimadoline, in a model of canine atopic dermatitis (AD). Fourteen beagles were challenged with house dust mites every 3-4 days for a total of 9 challenges. Severity of dermatitis was assessed, and pruritus was monitored using GoPro HERO cameras. Pruritus scoring was evaluated at 10 time periods; baseline, 4 h post allergen challenge and the last day of the study on Day 28. Scoring was done blindly by personnel using BORIS software. A global subjective score was also given using a visual analogue scale (VAS). A 4-week washout period occurred and dogs were crossed-over, the study was repeated, and the results were analysed using combined data. Gel was applied once daily on inguinal area (0.6 ml/dog). ANOVA showed significant effect of time (p < 0.0001) and group (p = 0.0001) on dermatitis scores. Overall, no statistically significant effect on pruritus was found due to a crossing of scores on Day 17. Overtime the placebo scores increased while the active ingredient showed decrease after first 3 weeks. It is concluded that this approach is promising in dogs with AD and longer studies with more frequent application may be beneficial.

Occupancy of the kappa opioid receptor by naltrexone predicts reduction in drinking and craving.

The efficacy of naltrexone to treat alcohol use disorder (AUD) is modest. A better understanding of the neurobiology underlying naltrexone effects could optimize treatments. We evaluated the occupancy of the kappa opioid receptor (KOR) by naltrexone measured with [11C]-LY2795050 positron emission tomography (PET) as a predictor of response to naltrexone. Response to naltrexone was defined as the difference in craving and the difference between the number of drinks consumed during an alcohol drinking paradigm (ADP) before and after 1 week of supervised 100 mg daily oral naltrexone. Forty-four (14 F) nontreatment seeking heavy drinkers meeting criteria for AUD were enrolled. Participants drank 47 ± 16 drinks per week and were balanced in family history of alcoholism (FH, 26 positive). High KOR occupancy (92 ± 1%) was achieved. Occupancy was negatively associated with number of years drinking (YOD) in FH positive, but not FH negative, participants (t3,42 = 4.00, p = 0.0003). Higher KOR occupancy by naltrexone was associated with higher alcohol craving during the ADP (F1,81 = 4.88, p = 0.030). The reduction in drinking after naltrexone was negatively associated with KOR occupancy, with significant effects of FH status (t1,43 = -2.08, p = 0.044). A logistic regression model including KOR occupancy, YOD, and FH variables achieved an 84% prediction accuracy for ≥50% reduction in drinking. These results confirm that naltrexone binds at the KOR site and suggest that KOR occupancy by naltrexone may be related to clinical response. Based on our results, we propose that differential affinities for the mu and KOR could explain why lower doses of naltrexone can have greater clinical efficacy.

Los Antagonistas de los Receptores Opioides en el Tratamiento del Alcoholismo / Opioid Receptor Antagonists in the Treatment of Alcoholism

Objetivos: A partir de los recientes progresos en la farmacoterapia del alcoholismo, hemos efectuado una revisión sobre los fármacos antagonistas de los receptores opioides, que tienen aprobada la indicación para el tratamiento del alcoholismo, como son naltrexona y nalmefeno. Metodología: Hemos revisado más de 100 publicaciones sobre péptidos y receptores opioides, el efecto de los fármacos antagonistas de los receptores opioides sobre el consumo de alcohol, tanto en animales como en humanos, tanto en el laboratorio como para el tratamiento del alcoholismo. También se describen las características farmacológicas de naltrexona y de nalmefeno y su utilidad en la práctica clínica. Resultados: Múltiples evidencias han demostrado la eficacia de naltrexona y nalmefeno para reducir el consumo de alcohol, tanto en animales de laboratorio como también en personas estudiadas en situación de bar experimental, aunque debido al diferente perfil receptorial, nalmefeno ha sido relacionado con una mayor eficacia para la reducción del consumo de alcohol, en ratas que presentan dependencia del alcohol. Además, un gran número de ensayos clínicos controlados han demostrado la eficacia de naltrexona para la prevención de recaídas, en personas que presentan un trastorno por dependencia del alcohol. Ensayos clínicos controlados recientes han demostrado la eficacia de nalmefeno "a demanda" para reducir el consumo de alcohol, en personas que presentan un trastorno por dependencia del alcohol de baja gravedad. Conclusiones: Tanto naltrexona como nalmefeno han demostrado ser fármacos seguros, bien tolerados, de manejo sencillo, y eficaces para el tratamiento del trastorno por dependencia del alcohol, (actualmente llamado trastorno por consumo de alcohol). A partir de recientes ensayos clínicos controlados se ha comprobado que nalmefeno produce una reducción significativa del consumo de alcohol, lo cual supone un nuevo objetivo que amplía las posibilidades de tratamiento para los pacientes que no desean la abstención continuada, sino una reducción de su consumo de alcohol

Objectives: On the basis of the recent advances in drug therapy of alcoholism, we conducted a review on opioid receptor antagonist drugs with approved indication for the treatment of alcoholism, such as naltrexone and nalmefene. Methods: We reviewed over 100 publications on peptides and opioid receptors, as well as studies conducted in experimental animals and in humans on the effect of opioid receptor antagonists on alcohol consumption in the treatment of alcoholism. We also reviewed the pharmacological characteristics of naltrexone and nalmefene, and the usefulness of these drugs in clinical practice. Results: Much evidence has demonstrated the efficacy of naltrexone and nalmefene for the reduction of alcohol consumption, in experimental animals as well as in humans examined under experimental bar conditions; however, due to its different receptor profile, nalmefene has been associated with higher efficacy levels in reducing alcohol consumption in alcohol-dependent rats. In addition, a great number of controlled clinical trials have demonstrated the efficacy of naltrexone for relapse prevention in patients with an alcohol dependence disorder. Recent controlled clinical trials have demonstrated the efficacy of nalmefene "as-needed" in the reduction of alcohol consumption in subjects with mild alcohol dependence. Conclusions: Both naltrexone and nalmefene have proved to be safe, well tolerated, easy to manage, and efficient drugs for the treatment of alcohol dependence disorder (currently known as alcohol use disorder). On the basis of recent controlled clinical trials, nalmefene has been shown to result in a significant reduction of alcohol consumption, thereby representing a new objective that extends the therapeutic possibilities for those patients who do not wish for a continuous abstinence, but rather a reduction of alcohol consumption

Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome.

BACKGROUND: In models of irritable bowel syndrome (IBS), asimadoline, a kappa-opioid agonist, improves pain and abnormal bowel function. AIM: To evaluate the effects of three doses of asimadoline and placebo in subjects with IBS through a double-blind, randomized, placebo-controlled trial. METHODS: Patients were randomly assigned to receive asimadoline 0.15, 0.5, 1.0 mg or placebo BID for 12 weeks. The primary efficacy measure was number of months of adequate relief of IBS pain or discomfort, with a prospective plan to evaluate adequate relief data by entry baseline pain and subtype. Several other endpoints were also evaluated. RESULTS: Five hundred and ninety-six patients were randomized. In the ITT population, statistically significant improvement on the primary endpoint was not seen. However, in diarrhoea-predominant IBS patients with at least baseline moderate pain, asimadoline (0.5 mg) produced significant improvement on total number of months with adequate relief of IBS pain or discomfort (46.7% vs. 20.0%), adequate relief of IBS symptoms (46.7% vs. 23.0%), pain scores (week 12: -1.6 vs. -0.7), pain free days (42.9% vs. 18.0%), urgency and stool frequency (-2.3 vs. -0.3). In patients with alternating IBS, significant improvement was seen on adequate relief endpoints. Asimadoline was well tolerated. CONCLUSION: Asimadoline warrants further evaluation as a treatment for IBS.

U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.

RATIONALE: Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. OBJECTIVES: This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. METHODS: During daily test sessions, the dose-effect curve (0.015-1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. RESULTS: U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. CONCLUSIONS: These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine.

Arginine vasopressin release inhibitor RU51599 attenuates brain oedema following transient forebrain ischaemia in rats.

RU51599 is an arginine vasopressin (AVP) release inhibitor and a selective kappa opioid agonist which has a pure water diuresis effect without associated electrolyte excretion. The effect of RU51599 on brain oedema following transient forebrain ischaemia in rats was examined. Under microscopy, the visible vertebral arteries at the second vertebra could be easily electrocauterized and completely cut by microscissors to yield complete cessation of circulation of both vertebral arteries. Transient forebrain ischaemia was induced by this improved highly reproducible technique of four-vessel occlusion model. Forty-three male Wistar rats were separated into six groups; saline-treated (1 ml/kg) normal rats (n = 10), RU51599-treated (1 mg/kg) normal rats (n = 4), saline-treated (1 ml/kg) rats with complete occlusion of both vertebral arteries (n = 5), RU51599-treated (1 mg/kg) rats with complete occlusion of both vertebral arteries (n = 5), saline-treated (1 ml/kg) rats with both complete occlusion of both vertebral arteries and carotid occlusion bilaterally during 45 minutes followed by 60 minutes of reperfusion (n = 11), RU51599-treated (1 mg/kg) rats with both complete occlusion of both vertebral arteries and carotid occlusion bilaterally during 45 minutes followed by 60 minutes of reperfusion (n = 8). The brain water content was determined by the dry-wet weight method. Cerebral blood flow was monitored during ischaemia and reperfusion was performed by laser Doppler flowmetry to make sure to obtain reversible forebrain ischaemia. Effects of RU51599 on concentration of glutamate released from the hippocampal CA1 of rats subjected to 5 minutes four-vessel occlusion and 60 minutes of reperfusion were also investigated by the microdialysis method. This modified four-vessel occlusion method produced reversible forebrain ischaemia with a high level of success. Bilateral carotid occlusion followed by 60 minutes reperfusion caused a significant increase in brain water content (P < 0.01), which was significantly attenuated by RU51599 (P < 0.01). These findings indicate that the AVP-release inhibitor RU51599 reduced brain oedema following transient forebrain ischaemia in rats.

Attenuation of cryogenic induced brain oedema by arginine vasopressin release inhibitor RU51599.

Centrally released arginine vasopressin (AVP) has been implicated in the regulation of the brain water content and is elevated in the cerebrospinal fluid of patients with ischaemic and traumatic brain injuries. The protective effect of RU51599, which is a selective kappa opioid agonist as an AVP release inhibitor, on brain oedema was examined. Male Wistar rats, weighing 300 to 400 g each, were used. The cortical cryogenic injury was produced by application of a previously prepared metal probe cooled with dry ice to the dura of the right patietal region. Animals were separated into three groups. Group 1: sham operated rats without lesion production. Group 2: saline-treated rats with lesion production. Group 3: RU51599-treated rats with lesion production. In Group 3, rats were treated with RU51599 (0.1-3 mg/kg) at 30 minutes before lesion production, 1 hour, 2 hours, and 4 hours after lesion production. After 6 hours, animals were decapitated and brain water contents were measured using the dry-wet weight method. The extent of blood brain barrier (BBB) disruption was determined by assessment of Evans blue uptake based on extraction from tissue using dimethylformamide. The primary injured infarcted area was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Sodium and potassium contents in serum and brain tissue were measured using atomic absorption spectrophotometry. The antagonism of naloxone against protective effects of RU51599 on cryogenic induced brain oedema and on antinociceptive effects in acetic-acid treated animals was examined. Statistical analysis was performed using Dunnett-test and U-test following Kruskal-Wallis test. RU51599 significantly reduced the brain water contents on the injured side and the contralateral non-injured side (p < 0.01) after 4 administration of 1 and 3 mg/kg. RU51599 neither significantly inhibited BBB disruption nor reduced the primary injured infarcted area. RU51559 significantly increased brain sodium and potassium contents in the injured brain and also increased serum sodium levels (p < 0.01). Naloxone antagonized the anti-oedema effects and anti-nociceptive effects of RU51599. These findings indicate that the AVP release inhibitor, RU51599 possibly mediated by opioid receptors, has a potential protective effect on cryogenic-induced brain oedema and that centrally released AVP plays an important role in the progression of vasogenic brain oedema.

Treatment of acute intracranial hypertension with RU 51599, a selective kappa opioid agonist.

RU 51599, a selective kappa opioid agonist which is a potent aquaretic, was studied for its effect on acute intracranial hypertension. In ketamine anesthetized cats acute intracranial hypertension was induced by progressive inflation of an epidural balloon with physiological saline at a constant rate of 0.5 ml/hr for three hours. In the control group (n = 8), the balloon was maintained inflated for another an hour after which it was deflated. In the post deflation period monitoring was continued for one hour. In the treatment group (n = 8), cats were treated by an intravenous (i.v.) injection of RU 51599, at a dose of 1 mg/kg every hour at the beginning of balloon inflation, during balloon inflation, at the completion of inflation, and after deflation. Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), blood gases, serum electrolytes and osmolality, and brain water content water content were studied in both groups. In the control group, epidural brain compression resulted in significant increases in the mean ICP up to 80.7 +/- 9.8 mmHg at 3 hrs (during balloon inflation), 68.6 +/- 8.3 after complete inflation, and 62.1 +/- 11.4 mmHg after deflation (P < 0.01), and significant decreases in CPP to 55.5 +/- 14.0 mmHg at 3 hrs (during balloon inflation), 43.0 +/- 11.2 mmHg after inflation, and 36.3 +/- 9.9 mmHg after deflation (P < 0.01). In the treatment group there were significant decreases in the mean ICP to 35.2 +/- 6.8 mmHg at 3 hrs (during balloon inflation), 32.3 +/- 7.9 after inflation, and 16.1 +/- 3.6 mmHg after deflation (P < 0.01), and significant increases in CPP to 103.2 +/- 6.1 mmHg at 3 hrs (during balloon inflation), 109.0 +/- 8.8 mmHg after inflation, and 102.7 +/- 8.2 mmHg after deflation (P < 0.01). Brain water content was also significantly reduced (P < 0.05). There were no significant changes in the serum electrolytes and osmolality throughout the experiments. Our results suggest that, the mechanism by which RU 51599 reduces ICP is related to reduction in the brain water content.