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Species and age-dependent differences of functional coupling between opioid delta-receptor and G-proteins and possible involvement of protein kinase C in striatal membranes.

[D-Ser2,Leu5]-enkephalin-Thr6 (DSLET) and [D-Pen2,5]-enkephalin (DPDPE), both delta-agonists, stimulated the high affinity GTPase in the rat striatal membranes in a naltrindole-reversible manner. Similar stimulation was also observed in the striatal membrane preparations of 16-week-old guinea pigs, while not in those preparations of 4-week-old ones. When calphostin C, a protein kinase C inhibitor, was added to the reaction mixture, DSLET showed a marked stimulation in this activity in 4-week guinea pig striatal membranes. There was no effect of KT5720, a cyclic AMP-dependent protein kinase inh

κ-opioid receptor activation protects against myocardial ischemia-reperfusion injury via AMPK/Akt/eNOS signaling activation.

This study aims to investigate the effect of κ-opioid receptor activation on myocardial ischemia and reperfusion(I/R) injury and elucidate the underlying mechanisms. Myocardial I/R rat model and simulated I/R cardiomyocytes model were established. In vivo study showed that U50,488 H improved cardiac function, reduced myocardial infarct size and serum cTnT significantly. The effect of U50,488 H was abolished by nor-BNI(a κ-opioid receptor antagonist), Compound C(an AMPK inhibitor), Akt inhibitor and L-NAME(an eNOS inhibitor). AICAR, an AMPK activator, mimicked the effect of U50,488 H. U50,488 H

Sex- and Gender-Related Differences in Obesity: From Pathophysiological Mechanisms to Clinical Implications.

Obesity, primarily characterized by excessive fat accumulation, is a multifactorial chronic disease with an increasing global prevalence. Despite the well-documented epidemiology and significant advances in understanding its pathophysiology and clinical implications, the impact of sex is typically overlooked in obesity research. Worldwide, women have a higher likelihood to become obese compared to men. Although women are offered weight loss interventions more often and at earlier stages than men, they are more vulnerable to psychopathology. Men, on the other hand, are less likely to pursue wei

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… Specifically, 85.5% of naltrexone/bupropion, 82.2% of phentermine/topiramate, and 72.4% of liraglutide prescriptions were given to females [ 133 ]. … Preregistration clinical trials of the combination naltrexone/bupropion and phentermine/topiramate also showed a tendency of higher weight loss in females than males [ 142 ]. …

Prurigo Nodularis: Pathogenesis and the Horizon of Potential Therapeutics.

Chronic pruritus that lasts for over 6 weeks can present in various forms, like papules, nodules, and plaque types, with prurigo nodularis (PN) being the most prevalent. The pathogenesis of PN involves the dysregulation of immune cell-neural circuits and is associated with peripheral neuropathies, possibly due to chronic scratching. PN is a persistent and challenging condition, involving complex interactions among the skin, immune system, and nervous system. Lesional skin in PN exhibits the infiltration of diverse immune cells like T cells, eosinophils, macrophages, and mast cells, leading to

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… Targeting opioid receptor (Nalbuphine, Butorphanol, Naltrexone) At the spinal cord level, an imbalance in the activity of the itch-promoting MOR and the itch-inhibiting KOR is implicated in non-histaminergic itching [ 210 ]. … Additionally, the MOR antagonist naltrexone ( Figure 2 C) (50 mg) has exhibited anti-pruritic effects in certain subsets of PN patients [ 212 ]. …

Activation of κ-opioid receptor exerts the glucose-homeostatic effect in streptozotocin-induced diabetic mice.

Opioid and its receptors play important roles in glucose homeostasis. However, few reports were available for the study of κ-opioid receptor in glucose regulation. In our study, we found that the blood glucose of diabetic mice dropped significantly following the treatment with U50,488H (a selective κ-opioid receptor agonist). This phenomenon was time-dependent and associated with the coincident alteration of Glut4 translocation in the skeleton muscles. U50,488H increased the serum adiponectin, but not serum insulin in diabetic mice. U50,488H increased the AdipoR1 expression at both mRNA and pr

[κ-opioid receptor agonist U50, 488H attenuates myocardial ischemia-reperfusionvia modulating Toll-like receptor 4/nuclear factor-κB signaling in rat].

OBJECTIVE: To observe the effects of κ-opioid receptor agonist U50, 488H on myocardial ischemia and reperfusion injury and related mechanism. METHODS: Rats were randomly divided into sham operation, myocardial ischemia and reperfusion(I/R, 30 min ischemia followed by 120 min reperfusion), and MI/R+U50, 488H (1.5 mg/kg) and I/R+U50, 488H+ selective κ-opioid receptor antagonist Nor-BNI (2 mg/kg, n = 8 each). The infarction size and the incidence of ventricular arrhythmias were observed.Real-time PCR and DAB staining were used to define the myocardium Toll-like receptor 4(TLR4) expression. Myelo

Working memory fMRI activation in cocaine-dependent subjects: association with treatment response.

Functional magnetic resonance imaging (fMRI) studies of early abstinence cocaine users offer information about the state of the brain when most cocaine users seek treatment. This study examined the relationship between pretreatment brain function and subsequent treatment response in 19 treatment-seeking early abstinence cocaine-dependent (CD) subjects. These subjects and 14 non-drug-using control subjects underwent fMRI while performing a working memory task with three levels of difficulty. CD subjects were then randomized to treatment studies. Results showed CD subjects had significantly lowe

The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone.

This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human de…

Analgesia-producing mechanism of processed Aconiti tuber: role of dynorphin, an endogenous kappa-opioid ligand, in the rodent spinal cord.

The analgesia-producing mechanism of processed Aconiti tuber was examined using rodents whose nociceptive threshold was decreased by loading repeated cold stress (RCS). The antinociceptive effect of processed Aconiti tuber (0.3 g/kg, p.o.) in RCS-loaded mice was antagonized by pretreatment with a kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg, s.c.), and was abolished by an intrathecal injection of anti-dynorphin antiserum (5 microg). The Aconiti tuber-induced antinociception was inhibited by both dexamethasone (0.4 mg/kg, i.p.) and a dopamine D2 antagonist, sulpiride (10 mg/kg, i.p.),

Opioid receptor-mediated control of acetylcholine release in human neocortex tissue.

The effects of various opioid receptor agonists and antagonists on evoked acetylcholine release were studied in slices of human neocortex prelabelled with [3H]-choline, superfused and depolarized electrically (2 min, 3 Hz, 2 ms, 24 mA) or by K+ (20 mM). The delta-opioid receptor agonist DPDPE and the kappa-opioid receptor agonist U50488 reduced the evoked [3H]-overflow (acetylcholine release) in a concentration-dependent fashion; the delta-opioid receptor antagonist naltrindole and the kappa-opioid receptor antagonist norbinaltorphimine, respectively, antagonized these effects. Application of

The use of specific opioid agonists and antagonists to delineate the vagally mediated antinociceptive and cardiovascular effects of intravenous morphine.

Intravenous (i.v.) administration of morphine produces a dose-dependent inhibition of the tail-flick (TF) reflex, depressor response, and bradycardia in the rat. Some of these effects depend on interactions of i.v. morphine with peripheral opioid receptors and the integrity of cervical vagal afferents. The present studies used the relatively specific mu, delta, and kappa opioid receptor agonists (DAGO, DPDPE or U-50,488H) and the relatively specific mu, delta, and kappa opioid receptor antagonists (beta-FNA, naloxonazine, naltrindole or nor-BNI) in either intact rats or rats with bilateral cer

Obesity Pillars roundtable: Excessive weight reduction with highly effective anti-obesity medications (heAOMs).

BackgroundHistorically, many anti-obesity medications (AOMs) were withdrawn from development and/or the market due to safety concerns. Another challenge was that, with some exceptions, most of these AOMs had limited weight reducing efficacy. Approved AOMs often did not meet the weight reduction expectations of either clinicians, or their patients. Currently, newer approved and investigational AOMs achieve greater weight reduction than older AOMs. This has prompted an emerging new challenge of "too much weight loss" with some of these highly effective anti-obesity medications (heAOM) - somethin

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… and 2% achieving ≥5%, ≥10%, ≥15% and ≥20% categorical weight reduction respectively | [ 3 , 6 ] Overall mean = 9% ≥5% = 66% top dose ≥10% = 41% top dose ≥15% = NA SEQUEL 56-week extension study: [ 6 ] Overall mean = 10% ≥5% = 79% top dose ≥10% = 54% top dose ≥15% = 32% top dose ≥20% = 15% top dose Naltrexone … A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II) Obesity. 2013;21:935–943. doi: 10.1002/oby.20309. 8. Davidson M.H., Hauptman J., DiGirolamo M., Foreyt J.P., Halsted C.H., Heber D., et al. …

Effects of Methylnaltrexone on Ticagrelor-Induced Antiplatelet Effects in Coronary Artery Disease Patients Treated With Morphine.

OBJECTIVES: The aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor. BACKGROUND: Morphine delays the onset of action of oral P2Y12 receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia. METHODS: In this …

Hypoxic preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest through regulation of delta opioid receptor system.

This study was designed to investigate whether delta opioid receptor (DOR) is involved in the neuroprotective effect induced by hypoxic preconditioning (HPC) in the asphyxial cardiac arrest (CA) rat model. Twenty-four hours after the end of 7-day HPC, the rats were subjected to 8-min asphyxiation and resuscitated with a standardized method. In the asphyxial CA rat model, HPC improved the neurological deficit score (NDS), inhibited neuronal apoptosis, and increased the number of viable hippocampal CA1 neurons at 24 h, 72 h, or 7 days after restoration of spontaneous circulation (ROSC); however,

Effects of differential modulation of mu-, delta- and kappa-opioid systems on bicuculline-induced convulsions in the mouse.

The present study investigated the effects of micro-, delta- and kappa-opioid receptor agonists on seizures produced by blockade of gamma-aminobutyric acid (GABA)-mediated synaptic transmission in the mouse. The selective GABA(A) receptor antagonist bicuculline (1.25-3 mg/kg) given subcutaneously caused dose-dependent clonic-tonic convulsions. These convulsions were potentiated by the prototypic mu-opioid receptor agonist morphine given subcutaneously 20 min prior to a subconvulsive dose of bicuculline. The potentiation by morphine was completely reversed by pretreatment intraventricularly wit

Agonists and antagonists bind to different domains of the cloned kappa opioid receptor.

Opium and its derivatives are potent analgesics that can also induce severe side effects, including respiratory depression and addiction. Opioids exert their diverse physiological effects through specific membrane-bound receptors. Three major types of opioid receptors have been described, termed delta, kappa, and mu. The recent molecular cloning of these receptor types opens up the possibility to identify the ligand-binding domains of these receptors. To identify the ligand-binding domains of the kappa and delta receptors, we have expressed in COS-7 cells the cloned mouse delta and kappa recep

Activation of kappa-opioid receptors depresses electrically evoked excitatory postsynaptic potentials on 5-HT-sensitive neurones in the rat dorsal raphé nucleus in vitro.

Intracellular recordings from dorsal raphé neurones in slices from rat brains were used to study the actions of kappa-opioid receptor agonists on an excitatory postsynaptic potential (epsp) evoked by local electrical stimulation of afferent terminals. The epsp was observed on all 5-HT-sensitive neurones and was blocked by 1 microM TTX. The epsp was reduced in a dose-dependent manner by the specific kappa-opioid receptor agonist [5R-(5 alpha,7 alpha,8 beta)]-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4.5]dec-8-yl]-4-benzofuranacetamide monohydrochloride (CI-977) (1-100 nM). The effects of CI-97

Cancer Metabolism as a Therapeutic Target and Review of Interventions.

Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and

Drug therapy for obstructive sleep apnoea in adults.

BACKGROUND: The treatment of choice for moderate to severe obstructive sleep apnoea (OSA) is continuous positive airways pressure (CPAP) via … Odds Ratio 29.2 (95% CI 2.8 to 301.1) but there was no change in the apnoea frequency. In one trial naltrexone did reduce AHI, but total sleep time favoured placebo. No significant beneficial effects were found for medroxy progesterone, clonidine, mibefradil, cilazapril, buspirone, aminophylline, theophylline doxapram, ondansetron or sabeluzole. AUTHORS' CO …

Chordoma combined with Trousseau syndrome: a case report and literature review.

BackgroundTrousseau syndrome (TS) refers to spontaneous, recurrent, and wandering arterial and venous thromboembolic events in patients with tumors. It results from abnormalities in coagulation and fibrinolytic mechanisms of varying degrees throughout the course of the disease. It has a high fatality rate, and it is commonly seen in patients with highly invasive tumors, such as lung, pancreatic, gastrointestinal, and breast cancers; however, to date, there has been no report of TS combined with chordoma.Case descriptionA 56-year-old male with a diagnosis of chordoma underwent surgery, immunoth

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… According to the National Comprehensive Cancer Network (NCCN) guidelines ( 7 ) and the American Society of Clinical Oncology (ASCO) study ( 8 ), the treatment regimen was changed to naltrexone heparin (0.6 mL, 1/day) via subcutaneous injection in the morning. … The patient continued to receive anticoagulant therapy with naltrexone heparin. …