Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain ...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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Conditions:   Opioid-induced Constipation;   Cancer;   Cancer Pain Intervention:   Other: Treatment algorithm for OIC Sponsors:   Royal Surrey County Hospital NHS Foundation Trust;   Kyowa Hakko Kirin UK, Ltd. Completed
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Celiac disease (CD), triggered by the ingestion of gluten, occurs in people genetically predisposed to develop the chronic autoimmune condition. During the past few decades, doctors have learned much about how the disease develops, including genetic and other risk factors. However, results from studies on whether people with CD have an increased risk of premature death linked to the condition have been mixed. A recent study shows a small but statistically significant increased mortality rate. Celiac disease can affect the entire body Until recently, CD was considered a mainly pediatric gastrointestinal disorder, associated...
Source: Harvard Health Blog - Category: Consumer Health News Authors: Tags: Allergies Autoimmune diseases Source Type: blogs
Conclusions: The commonness of undesirable experiences attributed to daily ingestion of 60 mg iron and 0.4 mg folic acid and their deterrence to longer supplementation durations suggest the need for considering a weekly intermittent regimen for some antenatal women in such set-ups. Our study demonstrated that potentially, more counselling on nausea as a side effect might be critical in advancing iron-folate supplementation compliance. PMID: 32455019 [PubMed - as supplied by publisher]
Source: Journal of Pregnancy - Category: OBGYN Tags: J Pregnancy Source Type: research
AbstractChronic constipation is one of the five most common symptoms seen by gastroenterologist. In the absence of alarm symptoms, a confident symptom-based diagnosis can often be made using the Rome criteria. Three different subtypes have been identified to date: normal transit constipation, defaecatory disorders and slow transit constipation. Differentiation between these subtypes can be made through functional testing using tests such as anorectal manometry with balloon expulsion and a radio-opaque marker test. In general, patients are initially advised to increase their fluid and fibre intake. When these general lifest...
Source: Drugs - Category: Drugs & Pharmacology Source Type: research
CONCLUSION: Pharmacist-led inpatient opioid de-escalation is effective, does not increase pain intensity, and reduces constipation. Hospitals should explore the viability of extending pharmacist-led opioid de-escalation to other surgical patients and following hospital discharge, aiming for opioid cessation. PMID: 32421837 [PubMed - in process]
Source: Journal of Opioid Management - Category: Addiction Tags: J Opioid Manag Source Type: research
Tuft cells are rare chemosensory sentinels found in the gut epithelium. When triggered by helminth infection, tuft cells secrete interleukin-25 (IL-25) basolaterally and subsequently evoke an immune response. Irritable bowel syndrome (IBS) is a common and heterogeneous disorder characterized by bowel dysfunction and visceral pain sensitivity. Dysfunctional gut-brain communication and immune activation contribute to the pathophysiology of this disorder. The study aims were to investigate changes in tuft cell density in non-post-infectious IBS patients. Immunofluorescent labeling of DCLK1-positive tuft cells was carried out ...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
(Natural News) Patients with depression often experience gastrointestinal distress, a group of digestive disorders marked by lingering symptoms, such as constipation, bloating, diarrhea, abdominal pain and cramping. According to a study published in the journal Gastroenterology, the two disorders are connected by a common cause: low levels of serotonin, also known the “happy chemical.” Depression and gastrointestinal distress go hand...
Source: NaturalNews.com - Category: Consumer Health News Source Type: news
The diagnosis of Parkinson's disease (PD) relies on the clinical effects of dopamine deficiency, including bradykinesia, rigidity and tremor, usually manifesting asymmetrically. Misdiagnosis is common, due to overlap of symptoms with other neurodegenerative disorders such as multiple system atrophy and progressive supranuclear palsy, and only autopsy can definitively confirm the disease. Motor deficits generally appear when 50–60% of dopaminergic neurons in the substantia nigra are already lost, limiting the effectiveness of potential neuroprotective therapies. Today, we consider PD to be not just a movement disorder...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Authors: Selvy M, Cuménal M, Kerckhove N, Courteix C, Busserolles J, Balayssac D Abstract Introduction: Peripheral neuropathic pain is highly disabling conditions for patients and a challenge for neurologists and pain physicians. Although many drugs have been assessed in scientific studies, few have demonstrated a clear clinical efficacy against neuropathic pain. Moreover, the paucity of data regarding their safety raised the question on the benefit-risk ratio when used in patients experiencing peripheral neuropathies.Areas covered: The authors conducted a review of double-blind, placebo-controlled, randomiz...
Source: Expert Opinion on Drug Safety - Category: Drugs & Pharmacology Tags: Expert Opin Drug Saf Source Type: research
Purpose of review Opioids are potent drugs for the treatment of severe pain, but they are burdened by detrimental side-effects, such as respiratory depression, addiction, sedation and constipation. Their clinical application is undisputed in acute (e.g. perioperative) and cancer pain, but their use in chronic nonmalignant pain has met increasing scrutiny and has contributed to the opioid crisis. Thus, novel analgesics with reduced side-effects are badly needed. Recent findings Current research topics include enkephalinase inhibitors, allosteric and multivalent ligands, biased opioid receptor signaling and selective ac...
Source: Current Opinion in Supportive and Palliative Care - Category: Palliative Care Tags: PAIN: NON-MALIGNANT DISEASES: Edited by Anthony H. Dickenson and Kirsty Bannister Source Type: research
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