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Chronic Pruritus: A Review.

IMPORTANCE: Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Appr … ntin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. CONCLUSIONS AND RELEVANCE: Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such …

Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig.

We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cat … (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated by a central and/or a peripheral site of action, we hypothesize that selective oral NOP agonists that do not penetrate the blood-brain barrier may provide a novel approa …

Evaluation of medications used for opioid use disorder in emergency departments: A cross-sectional analysis of the 2020 National Hospital Ambulatory Medical Care Survey.

INTRODUCTION: Opioid use disorder (OUD) is a significant health issue impacting millions in the United States (US). Medications used for OUD (MOUD) (e.g., buprenorphine, methadone, naltrexone) and medications for overdose and symptom management (e.g., naloxone, clonidine) have been shown to be safe and effective tools in clinical management. MOUD therapy in Emergency Departments (EDs) improves patient outcomes and enhances engagement with formal addiction treatment; however, provider factors and institutional barriers have created hurdles to ED-based MOUD treatment and heterogeneity in ED base…

Kappa-opioid receptors, dynorphin, and cocaine addiction: a positron emission tomography study.

Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stress-induced relapse. Our goal was to investigate changes in kappa-opioid receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist [11C]GR103545. Subjects with cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administratio

Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model.

Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious comorbidities, such as dependence, tolerance, immunosuppression and gastrointestinal disorders limit their long-term use. In the current study, a morphine-murine model was used to investigate the role of the gut microbiome and metabolome as a potential mechanism contributing to the negative consequences associated with opioid use. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-indu

Cannabis use during treatment for alcohol use disorders predicts alcohol treatment outcomes.

AIMS: To compare post-treatment alcohol use between those who use cannabis and those who abstain during treatment for alcohol use disorders (AUD); and to examine potential cannabis use thresholds by comparing post-treatment alcohol use between four frequency groups of cannabis users relative to abstainers. DESIGN: Secondary analyses of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, a randomized control trial of AUD treatments. The current study compares longitudinal drinking data between those who used cannabis versus those who abstained during COMBINE treatment.

Coactivation of μ- and κ-Opioid Receptors May Mediate the Protective Effect of Testosterone on the Development of Temporomandibular Joint Nociception in Male Rats.

AIMS: To investigate whether the protective effect of testosterone on the development of temporomandibular joint (TMJ) nociception in male rats is mediated by the activation of central opioid mechanisms. METHODS: Experiments were performed on 156 male Wistar rats. A pharmacologic approach was used to assess the ability of opioid receptor antagonists infused into the dorsal portion of the brainstem and adjacent to the caudal component (subnucleus caudalis) of the spinal trigeminal nucleus to block the protective effect of testosterone in male rats. The TMJ injection of 0.5% formalin was used a

In with the old and out with the new? A comparison of the old and new binge drinking standards.

BACKGROUND: There is consistent evidence that the binge drinking standard of 5+ drinks per drinking occasion for men (4+ for women) is associated with risk for negative consequences. Yet, many have questioned the adequacy of this measure as an index of intoxication (e.g., a blood alcohol concentration [BAC] of 0.08 g%). In response to these concerns, a National Institute on Alcohol Abuse and Alcoholism task force recommended adding a time qualifier of 2 hours to this criterion. Although conceptually appealing, there has been little effort to determine whether this new measure better captures d

Constitutive μ-opioid receptor activity leads to long-term endogenous analgesia and dependence.

Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced μ-opioid receptor (MOR) constitutive activity (MOR(CA)) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including a

Physical presence of nor-binaltorphimine in mouse brain over 21 days after a single administration corresponds to its long-lasting antagonistic effect on κ-opioid receptors.

In the mouse 55°C warm-water tail-withdrawal assay, a single administration of nor-binaltorphimine (nor-BNI; 10 mg/kg i.p.) antagonized κ-opioid receptor (KOR) agonist-induced antinociception up to 14 days, whereas naloxone (10 mg/kg i.p.)-mediated antagonism lasted less than 1 day. In saturation binding experiments, mouse brain membranes isolated and washed 1 or 7 (but not 14) days after nor-BNI administration demonstrated a significant time-dependent decrease in maximal KOR agonist [(3)H]U69,593 binding. To determine whether brain concentrations of nor-BNI were sufficient to explain the anta

Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion.

BACKGROUND: Methadone is an opioid agonist often given to manage acute and chronic pain. We sought to determine whether methadone compared with morphine dose dependently reduces myocardial infarct size (IS) and whether the mechanism is delta-opioid receptor mediated. Furthermore, we examined whether myocardial IS reduction varies with the timing of methadone administration or duration of induced ischemia. METHODS: After surgical instrumentation, we divided male Sprague-Dawley rats into 3 sets. The first set was divided into groups, which received methadone (0.03-3 mg/kg), morphine (0.03-3 mg/

Beta-endorphin differentially affects inflammation in two inbred rat strains.

It has been shown that inflammation of rat paws elicits accumulation of opioid peptide beta-endorphin-containing immune cells in the inflamed subcutaneous tissue, contributing to immunocyte-produced pain suppression. However, the possible mechanisms involved in the pharmacological application of beta-endorphin in rat paw inflammation have not been investigated. The present study was set up to explore the effects of intraplantar injection of beta-endorphin on Concanavalin A-induced paw edema in two inbred rat strains, Albino Oxford (AO) and Dark Agouti (DA). Both high dose-induced suppression a

The selective kappa-opioid receptor agonist U50,488H attenuates voluntary ethanol intake in the rat.

Non-selective opioid receptor antagonists are increasingly used in the treatment of alcohol dependence. The clinical effects are significant but the effect size is rather small and unpleasant side effects may limit the benefits of the compounds. Ligands acting at mu- and/or delta- receptors can alter the voluntary intake of ethanol in various animal models. Therefore, the attenuating effects of selective opioid receptor ligands on ethanol intake may be of clinical interest in the treatment of alcoholism. The objective of this study was to examine the effects of a selective kappa-receptor agoni

Effects of opioid receptor antagonists on the effects of i.v. morphine on carrageenin evoked c-Fos expression in the superficial dorsal horn of the rat spinal cord.

This study performed in freely moving rats evaluated the ability of specific opioid receptor antagonists to reverse the inhibitory effects of morphine on carrageenin-induced c-Fos expression in the spinal cord. Our study focused on the superficial dorsal horn (laminae I-II), which is the main termination site of nociceptive primary afferent fibers and is rich in opioid receptors. In order to replicate clinical routes of administration, all agents were administered intravenously (i.v.). As previously demonstrated, pre-administered i.v. morphine (3 mg/kg) produced a marked decrease (58+/-5%) in

7-Arylidenenaltrexones as selective delta1 opioid receptor antagonists.

A series of 7-arylidinenaltrexones (2a-m) related to the prototypical delta1-selective antagonist, 7-benzylidenenaltrexone 1 (BNTX), have been synthesized in an effort to develop more selective ligands. Testing in smooth muscle preparations revealed that members of the series exhibited varying degrees of selectively for delta receptors, with the o-methoxy (2e) and o-chloro (2j) congeners being most potent and most selective (Ke approximately 0.8 nm). Evaluation of 1, 2e, and 2f sc in mice using the tail-flick procedure indicated that they are selective delta1 opioid receptor antagonists in the…

[A molecular mechanism for supersensitization of adenylyl cyclase system in cloned opioid receptor-transfected cells following sustained opioid treatment].

Chronic opioid treatment has been shown to develop supersensitization of adenylyl cyclase (AC) system or cAMP overshoot. In this study, we investigated the molecular mechanism of supersensitization of AC system using CHO cells expressing one of the cloned mu-, delta- and kappa-opioid receptors. In naive cells, acute treatment with an opioid agonist, but not antagonist, suppressed forskolin-stimulated cAMP accumulation. In the cells sustainedly (4 hr) treated with the agonist, the challenge by antagonist induced the cAMP overshoot over the naive level (supersensitization of AC system), but had

Involvement of the Opioid Peptide Family in Cancer Progression.

Peptides mediate cancer progression favoring the mitogenesis, migration, and invasion of tumor cells, promoting metastasis and anti-apoptotic mechanisms, and facilitating angiogenesis/lymphangiogenesis. Tumor cells overexpress peptide receptors, crucial targets for developing specific treatments against cancer cells using peptide receptor antagonists and promoting apoptosis in tumor cells. Opioids exert an antitumoral effect, whereas others promote tumor growth and metastasis. This review updates the findings regarding the involvement of opioid peptides (enkephalins, endorphins, and dynorphins

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… Naltrexone also inhibited ovarian tumor progression and, with cisplatin, exerted an enhanced inhibitory effect [ 246 ]. A low dose of naltrexone blocked colorectal cancer progression in vivo and in vitro by inducing the apoptosis of tumor cells [ 161 ]. … MET declined the tumor mitotic index, which was counteracted with naltrexone: a complete blockade with naltrexone increased neuroblastoma cell proliferation, whereas an intermittent blockade inhibited cancer cell proliferation [ 239 ]. …

Alcohol-Related Liver Disease: A Review.

IMPORTANCE: Alcohol-related liver disease (ALD) is the leading cause of liver-related morbidity and mortality, and the most common indicatio … ational enhancement therapy, cognitive behavioral therapy, and pharmacologic therapy (eg, baclofen, naltrexone) are recommended to prevent disease progression. Because alcohol consumption is often underreported, screening tools, such as the Alcohol Use Disorders Identification Test, and sensitive biomarkers of recent alcohol intake (eg, blood phosphatidyleth …

Activation of μ receptors by SR-17018 through a distinctive mechanism.

Agonists at μ opioid receptors relieve acute pain, however, their long-term use is limited by side effects, which may involve β-arrestin2. Agonists biased against β-arrestin2 recruitment may be advantageous. However, the classification of bias may be compromised by assays utilising overexpressed μ receptors which overestimate efficacy for G-protein activation. There is a need for re-evaluation with restricted receptor availability to determine accurate agonist efficacies. We depleted μ receptor availability in PathHunter CHO cells using the irreversible antagonist, β-funaltrexamine (β-FNA), an

Endogenous opioid and cannabinoid systems modulate the muscle pain: A pharmacological study into the peripheral site.

The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the express