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

Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci Signal. 2020 Mar 31;13(625): Authors: Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzw.er S, Schmidel F, Katte TA, Reekie T, Grimsey NL, Kassiou M, Kellam B, Krasel C, Halls ML, Connor M, Lane JR, Schulz S, Christie MJ, Canals M Abstract 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 windo...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research

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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
Abstract 1. INTRODUCTION Hemorrhoids are vascular cushions underlying the distal rectal mucosa and contributing for approximately 15-20% of the resting anal pressure with a complete closure of the anal canal. They can become pathological (hemorrhoidal disease, HD) being the most common cause of painless rectal bleeding during defecation with or without prolapsing anal tissue1 . In this case the blood is bright red, not mixed with faeces but instead coated on their outer surface, or dropping after bowel movement. HD is generally classified by its location in internal (originated above the dentate line and covered b...
Source: Reviews on Recent Clinical Trials - Category: Cancer & Oncology Authors: Tags: Rev Recent Clin Trials Source Type: research
Bacillus coagulans (PROBACI) bacteria have been examined for efficacy against infectious or inflammatory bowel diseases. The aim of this observational and cross-sectional study was to evaluate the effects of PROBACI against various functional bowel symptoms. Thirty-eight enrolled patients (36.5 ± 12.6 years) with functional bowel disorders in a gastrointestinal clinic were administered PROBACI (300-mg formulation containing 1 × 109 colony-forming units of B coagulans) twice/day over a 4-week period. Abdominal pain, abdominal distention, and global assessment were evaluated using a 5-point visual analo...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
CONCLUSION: As a common result of the studies conducted with different sample groups, it is possible that reflexology had positive effects on children. However, the absence of standardization related to reflexology, inadequate use of a study protocol and guidelines, the heterogeneity of the data, and the determination that half the studies were conducted with high-risk groups according to the bias analysis with RoB 2.0 indicate that it is too soon to generalize the results. Well-structured, randomized controlled double-blind trials are required. PMID: 32444044 [PubMed - as supplied by publisher]
Source: Complementary Therapies in Medicine - Category: Complementary Medicine Authors: Tags: Complement Ther Med Source Type: research
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