Loss of neuropeptide signalling alters temporal expression of mouse suprachiasmatic neuronal state and excitability.

Individual neurons of the hypothalamic suprachiasmatic nuclei (SCN) contain an intracellular molecular clock that drives these neurons to exhibit day-night variation in excitability. The neuropeptide vasoactive intestinal polypeptide (VIP) and its cognate receptor, VPAC, are synthesized by SCN neurons and this intercellular VIP-VPAC receptor signal facilitates coordination of SCN neuronal activity and timekeeping. How the loss of VPAC receptor signalling affects the electrophysiological properties and states of SCN neurons as well as their responses to excitatory inputs is unclear.

Biased signalling in analgesic research and development.

Ligand bias offers a novel means to improve the therapeutic profile of drugs. With regard to G protein-coupled receptors involved in analgesia, it could be advantageous to develop such drugs if the analgesic effect is mediated by a different cellular signalling pathway than the adverse effects associated with the drug. Whilst this has been explored over a number of years for the μ receptor, it remains unclear whether this approach offers significant benefit for the treatment of pain.

Biased Agonism: Lessons from Studies of Opioid Receptor Agonists.

In ligand bias different agonist drugs are thought to produce distinct signaling outputs when activating the same receptor. If these signaling outputs mediate therapeutic versus adverse drug effects, then agonists that selectively activate the therapeutic signaling pathway would be extremely beneficial. It has long been thought that μ-opioid receptor agonists that selectively activate G protein- over β-arrestin-dependent signaling pathways would produce effective analgesia without the adverse effects such as respiratory depression.

Role of Acetaldehyde in Ethanol Reversal of Tolerance to Morphine-Induced Respiratory Depression in Mice.

Background: Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption.

A novel G protein-biased agonist at the μ opioid receptor induces substantial receptor desensitisation through G protein-coupled receptor kinase.

Background And Purpose: G protein-biased μ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased μ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones.

Experimental Approach: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells.

A Novel G Protein-Biased Agonist at the Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain.

Agonists at the opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective in models of anxiety and depression. However, some opioid agonists have proconvulsant properties while tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the opioid receptor differentially engage signaling and regulatory pathways with significant effects on behavioral outcomes.

A Biased View of -Opioid Receptors?

The field of biased agonism has grown substantially in recent years and the -opioid receptor has been one of the most intensively studied receptor targets for developing biased agonists. Yet, despite extensive research efforts, the development of analgesics with reduced adverse effects remains a significant challenge. In this review we discuss the evidence to support the prevailing hypothesis that a G protein-biased agonist at the -opioid receptor would be an effective analgesic without the accompanying adverse effects associated with conventional -opioid agonists.

Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor.

Ticagrelor is a potent antagonist of the P2Y receptor (P2YR) and consequently an inhibitor of platelet activity effective in the treatment of atherothrombosis. Here, we sought to further characterize its molecular mechanism of action. Initial studies showed that ticagrelor promoted a greater inhibition of adenosine 5'-diphosphate (ADP)-induced Ca release in washed platelets vs other P2YR antagonists.