A5044097175- Neuropeptides and Animal Physiology
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Neurotransmitter Receptor Influence on Behavior
- Pain Mechanisms and Treatments
- Pharmacological Receptor Mechanisms and Effects
- Cancer, Stress, Anesthesia, and Immune Response
- Substance Abuse Treatment and Outcomes
- Opioid Use Disorder Treatment
- Stress Responses and Cortisol
- Palliative Care and End-of-Life Issues
- Neuroendocrine regulation and behavior
- Nicotinic Acetylcholine Receptors Study
- Lipid Membrane Structure and Behavior
- Ion channel regulation and function
- Neural dynamics and brain function
- Photoreceptor and optogenetics research
- Treatment of Major Depression
- Cholinesterase and Neurodegenerative Diseases
- Pain Management and Opioid Use
- Family and Patient Care in Intensive Care Units
- Pharmacological Effects and Assays
- Cancer survivorship and care
- Childhood Cancer Survivors' Quality of Life
- Cannabis and Cannabinoid Research
University of Bath
2015-2025
Royal Prince Alfred Hospital
2020
University of Bristol
2004-2019
Gomal University
2019
University of Pecs
2019
University of Washington
2015
National University of Ireland, Maynooth
2015
University of Southampton
2006-2015
Virginia Commonwealth University Medical Center
2013
Virginia Commonwealth University
2013
We have compared the ability of a number μ-opioid receptor (MOPr) ligands to activate G proteins with their abilities induce MOPr phosphorylation, promote association arrestin-3 and cause internalization. For model protein-coupled (GPCR) activation where all agonists stabilize single active conformation receptor, close correlation between signaling outputs might be expected. Our results show that overall there is very good efficacy for protein recruitment, whereas few agonists, in particular...
Background and Purpose GPCRs can signal through both G proteins β‐arrestin2. For the μ‐opioid receptor, early experimental evidence from a single study suggested that protein signalling mediates analgesia, whereas β‐arrestin2 respiratory depression constipation. Consequently, for more than decade, much research effort has been focused on developing biased agonists preferentially target over β‐arrestin signalling, as it was believed such drugs would be analgesics devoid of depressant...
PZM21 is a novel μ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic classical μ ligands such as morphine. We have re-examined signalling profile its ability depress respiration.
The ability of two opioid agonists, [d-Ala<sup>2</sup>,<i>N</i>-Me-Phe<sup>4</sup>,Gly<sup>5</sup>-ol]-enkephalin (DAMGO) and morphine, to induce μ-opioid receptor (MOR) phosphorylation, desensitization, internalization was examined in human embryonic kidney (HEK) 293 cells expressing rat MOR1 as well G protein-coupled inwardly rectifying potassium channel (GIRK) subunits. Both DAMGO morphine activated GIRK currents, but the maximum response greater than that indicating is a partial agonist....
Background and purpose: The ability of an agonist to induce desensitization the µ‐opioid receptor (MOR) depends upon used. Furthermore, previous data suggest that intracellular mechanisms underlying may be agonist‐specific. We investigated MOR desensitization, in adult mammalian neurons, caused by morphine (a partial this system) DAMGO high‐efficacy agonist). Experimental approach: function was measured locus coeruleus using whole‐cell patch‐clamp electrophysiology, rat mouse brain slices...
Previously we correlated the efficacy for G protein activation with that arrestin recruitment a number of agonists at μ-opioid receptor (MOPr) stably expressed in HEK293 cells. We suggested endomorphins (endomorphin-1 and -2) might be biased toward recruitment. In present study, investigated this phenomenon more detail endomorphin-2, using endogenous MOPr rat brain as well For neurons brainstem locus ceruleus slices, peptide...
Abstract In morphine tolerance a key question that remains to be answered is whether μ‐opioid receptor (MOPr) desensitization contributes tolerance, and if so by what cellular mechanisms. Here we demonstrate MOPr can observed in single rat brainstem locus coeruleus (LC) neurons following either prolonged (> 4 h) exposure vitro or treatment of animals with vivo for 3 days. Analysis function an operational model indicated could induce profound degree (70–80%) loss function. Ongoing PKC...
There is ongoing debate about the role of G protein–coupled receptor kinases (GRKs) in agonist-induced desensitization <i>μ</i>-opioid (MOPr) brain neurons. In present paper, we have used a novel membrane-permeable, small-molecule inhibitor GRK2 and GRK3, Takeda compound 101 (Cmpd101; 3-[[[4-methyl-5-(4-pyridyl)-4<i>H</i>-1,2,4-triazole-3-yl] methyl] amino]-<i>N</i>-[2-(trifuoromethyl) benzyl] benzamidehydrochloride), to study involvement GRK2/3 acute MOPr desensitization. We observed that...
Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids in development tolerance but degree is thought to vary between different effects drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses overdose deaths have revealed an inverse correlation blood morphine ethanol levels. In present study, we determined whether reduced depressant opioids. Mice were treated...
Postsynaptic alterations are currently believed to be able fully account for NMDA-receptor-dependent long-term depression (LTD) and potentiation of synaptic strength, although there is also evidence supporting changes in presynaptic release. Using dualphoton laser scan microscopy N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide (FM1-43) directly visualize vesicular release at Schaffer collateral-CA1 excitatory synapses hippocampal slices, we demonstrate reduced...
Recent studies have shown that morphine, in contrast to other agonists at the μ-opioid receptor, causes very little rapid receptor desensitization or internalization adult rat mammalian neurons, raising important questions about how morphine tolerance is induced. Here we show can indeed cause marked of receptors mature locus ceruleus neurons when protein kinase C also activated. Thus, activation Gq-coupled M<sub>3</sub> muscarinic application a phorbol ester enhanced receptor-evoked...
ABSTRACT Background We argue for a translational approach to addiction science, using an important current research question as case study. Case study What is the evidence in support of hypothesis that alcohol increases risk heroin/opiate overdose through pharmacological interaction? Findings The positive epidemiological shows opiate deaths rarely involve single drug; most common other drug involved; there negative association between and morphine concentration at post mortem; post‐mortem...
Differences in the mechanisms underlying tolerance and μ-opioid receptor desensitization resulting from exposure to opioid agonists of different efficacy have been suggested previously. The objective this study was determine effects protein kinase C (PKC) G protein-coupled (GRK) inhibition on antinociceptive vivo efficacy. A rapid (8-h) tolerance-induction model used where each repeatedly administered naive mice. Animals were then challenged with after injection a inhibitor its level...
Agonists at the δ opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective of anxiety depression. However, some agonists have proconvulsant properties while tolerance therapeutic effects can develop. Previous evidence indicates that different acting differentially engage signaling regulatory pathways with significant on behavioral outcomes. As such, interest is now growing development biased as a potential means target specific potentially improve profile...
Abstract Background and Purpose The illicit use of fentanyl‐like drugs (fentanyls), which are μ opioid receptor agonists, the many overdose deaths that result, has become a major problem. Fentanyls very potent in vivo, leading to respiratory depression death. However, efficacy possible signalling bias different fentanyls is not clearly known. Here, we compared relative series fentanyls. Experimental Approach For agonist measurements, Bioluminescence Resonance Energy Transfer experiments were...
Abstract Background Co-use of benzodiazepines and/or ‘z-drugs’ along with opioids is linked to the rise in drug related deaths (DRD) UK. Understanding patterns co-use could inform harm reduction strategies for reducing DRDs. This study explored how people co-use, including dosages, timings, methods administration, use other substances and desired effects sought. Methods Forty-eight semi-structured interviews across Glasgow Scotland (n = 28), Bristol 10) Teesside England individuals who...
Mu-opioid receptors (MORs) exhibit rapid desensitization and internalization during exposure to various opioid agonists. In some studies, however, morphine has been observed produce little MOR or internalization. We examined in mature rat locus ceruleus (LC) neurons confirmed that is a very poor desensitizing agent, whereas [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO), high-efficacy agonist, methadone, an agonist we be of equivalent efficacy morphine, produced profound desensitization....
Opiates have been used historically for the treatment of depression. Renewed interest in use opiates as antidepressants has focused on development kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts a partial µ-opioid agonist and κ-receptor antagonist. By combining buprenorphine with antagonist naltrexone, activation receptors will be reduced κ-antagonist properties enhanced. We established that combination dose (1 mg/kg) naltrexone functions short-acting mouse tail withdrawal...