µ Opioid Receptors

Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor antagonists (PAMORAs) which are effective for the management of OIC. We report on a case in the palliative care setting where a patient with established OIC had an inadequate response to naloxegol but an effective and immediate response to methylnaltrexone at the dose recommended for her weight. This is the first reported case of two PAMORAs used concomitantly...

BACKGROUND: The misuse of opioids stems, in part, from inadequate knowledge of molecular interactions between opioids and opioid receptors. It is still unclear why some opioids are far more addictive than others. The κ-opioid receptor (KOR) plays a critical role in modulating pain, addiction, and many other physiological and pathological processes. Butorphanol, an opioid analgesic, is a less addictive opioid with unique pharmacological profiles. In this study, we investigated the interaction between butorphanol and KOR to obtain insights into the safe usage of this medication...

Several epidemiological studies support the protective role of breastfeeding in reducing the risk for type 1 diabetes. Human breast milk is the perfect nutrition for infants and contains many complex proteins, lipids and carbohydrates. In this study, we examined the physiological effects of human milk-derived opioid peptides, β-casomorphins (BCM), and compared them with bovine-milk-derived opioid peptides on pancreatic hormone regulation and β-cell regeneration. Exposure of wild-type zebrafish embryos to 50 µg/ml of human BCM-5 and -7 from 3 days post fertilisation until 6 days post fertilisation resulted in an increased insulin domain of expression while exposure to bovine BCM-5 and -7 significantly reduced the insulin domain of expression as analysed by whole-mount in situ hybridisation...

Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine precursor L-DOPA, but its prolonged usage causes dyskinesias referred to as L-DOPA induced dyskinesia (LID). Several studies in animal models of PD have suggested that dyskinesias are associated with a heightened opioid co-transmitter tone, observations that have led to the notion of a LID-related hyperactive opioid transmission that should be corrected by µ opioid receptor antagonists. Reports that both antagonists and agonists of the µ opioid receptor may alleviate LID severity in primate models of PD and LID, together with the failure of non-specific antagonist to improve LID in pilot clinical trials in patients, raises doubt about the reliability of the available data on the opioid system in PD and LID...

BACKGROUND: Nuclei located in the dorsal midline thalamus, such as the paraventricular nucleus of the thalamus (PVT), are crucial to modulate fear and aversive behaviour. In addition, the PVT shows a dense expression of µ-opioid receptors (MORs) and could mediate the anxiolytic effects of opioids. METHODS: We analysed the contribution of MORs in the dorsal midline thalamus (i.e. the PVT) to the performance of mice in a classical fear conditioning paradigm. We locally injected a specific agonist (DAMGO), an antagonist (CTAP) of MOR or saline as a control into the dorsal midline thalamus of male mice, prior to fear extinction training...

Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classic opioids-in particular the µ -opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been attributed to the preferential activation of β -arrestin over G proteins, make methadone a standard-of-care maintenance medication for opioid addiction. Although a recent biophysical study suggests that methadone stabilizes different MOR active conformations from those stabilized by classic opioid drugs or G protein-biased agonists, how this drug modulates the conformational equilibrium of MOR and what specific active conformation of the receptor it stabilizes are unknown...

BACKGROUND: The delta opioid receptor (DOR) has been identified as a therapeutic target for migraine, with DOR agonists exhibiting low abuse potential compared with conventional µ-opioid agonists. TRV250 is a novel small molecule agonist of the DOR that is preferentially selective for G-protein signaling, with relatively little activation of the β-arrestin2 post-receptor signaling pathway. This selectivity provides reduced susceptibility to proconvulsant activity seen with non-selective DOR agonists...

Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe...

The interactions between TRPV1 and µ-opioid receptors (MOR) have recently attracted much attention because these two receptors play important roles in pain pathways and can apparently modulate each other's functioning. However, the knowledge about signaling interactions and crosstalk between these two receptors is still limited. In this study, we investigated the mutual interactions between MOR and TRPV1 shortly after their activation in HEK293 cells expressing these two receptors. After activation of one receptor we observed significant changes in the other receptor's lateral mobility and vice versa...

The interplay between G protein-coupled receptors (GPCRs) is critical for controlling neuronal activity that shapes neuromodulatory outcomes. Recent evidence indicates that the orphan receptor GPR139 influences opioid modulation of key brain circuits by opposing the actions of the µ-opioid receptor (MOR). However, the function of GPR139 and its signaling mechanisms are poorly understood. In this study, we report that GPR139 activates multiple heterotrimeric G proteins including members of the Gq/11 and Gi/o families...

Pain is a common feature of most rheumatic diseases and it is often the main reason for the patient to seek for a clinical appointment. Chronic pain has a major impact on patient's quality of life, being frequently associated with functional incapacity, sleep and mood disorders. This leads to absenteeism and heavy consumption of health resources, both representing huge burdens on national economy. Managing musculoskeletal pain is pivotal but can be challenging. The use of the available pharmaceutical armamentarium should be parsimonious...

Luminal distention and abdominal pain are major clinical hallmarks of obstructive bowel disorders and functional bowel disorders linked to gut dysbiosis. Our recent studies found that chronic lumen distention increased visceral sensitivity and decreased abundance of gut commensal Lactobacillus reuteri in a rodent model of partial colon obstruction (OB). To establish causation, we performed precision microbial therapy to assess whether recolonization of L. reuteri prevents visceral hypersensitivity in lumen distention, and if so, to identify the gut-microbiota mechanism...

BACKGROUND: Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling. METHODS: The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling...

OBJECTIVE: The objective of this study was to provide an overview of opioid-induced constipation (OIC) and its influence on disease burden and quality of life (QOL). METHODS: This is a narrative review. RESULTS: For many patients, opioid-related side effects, the most common being OIC, have the potential to significantly impair patients' QOL. Patients with OIC often experience substantial overall burden (ie, increases in anxiety and depression, impairments in activities of daily living, low self-esteem, feelings of embarrassment) and economic burden (ie, higher health care costs, more frequent doctor visits, increased out-of-pocket medication costs), which often causes patients to modify or discontinue opioid treatment despite the analgesic benefits...

The role of the different components of the respiratory network in the mediation of opioid-induced respiratory depression is still unclear. We investigated the contribution of the preBötzinger Complex (preBötC) and the neighbouring Bötzinger Complex (BötC) and inspiratory portion of the ventral respiratory group (iVRG) in anesthetized, vagotomized, paralyzed and artificially ventilated adult rabbits making use of bilateral microinjections (30-50 nl) of the μ-opioid receptor agonist [D-Ala2 , N-Me-Phe4 , Gly5 -ol]-enkephalin (DAMGO)...

G-protein-coupled receptors (GPCRs) are key signaling proteins that mostly function as monomers, but for several receptors constitutive dimer formation has been described and in some cases is essential for function. Using single-molecule microscopy combined with super-resolution techniques on intact cells, we describe here a dynamic monomer-dimer equilibrium of µ-opioid receptors (µORs), where dimer formation is driven by specific agonists. The agonist DAMGO, but not morphine, induces dimer formation in a process that correlates both temporally and in its agonist- and phosphorylation-dependence with β-arrestin2 binding to the receptors...

Hybrid analogues of the µ opioid agonists endomorphin and [Dmt1 ]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 , Dmt = 2',6'-dimethyltyrosine) containing cis-4-amino-Pro, trans-4-amino-Pro, cis-4-aminoethyl-Pro or cis-4-guanidinylethyl-Pro in the 2-position of the peptide sequence were synthesized. None of the compounds retained high µ opioid agonist activity and, unexpectedly, substitution of cis-4-amino-Pro resulted in a novel class of potent µ opioid antagonists. In particular, the compound H-Dmt-cis-4-amino-Pro-Trp-Arg-NH2 (CZ-1) turned out to be a highly selective µ opioid antagonist with ~ 1 nM µ receptor binding affinity...

Since both morphine and tadalafil have been proven to exert some of their analgesic activity through modulation of the NO-cGMP pathway, the aim of the current study is to evaluate the pharmacologic interaction between tadalafil and morphine in order to decrease the dose of morphine and subsequently its side effects. The assessment was carried out through isobolographic analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c mice. Morphine and tadalafil ED50s calculated from the dose-response curves were 8303 µg/kg and 2080 µ/kg, respectively...

Reducing the well-known side effects of opioids prescribed to treat chronic pain remains unresolved, despite extensive research in this field. Among several options to tackle this problem the synthesis of multifunctional compounds containing hybridized structures gained a lot of interest. Recently, extensively investigated are combinations of opioid agonist and antagonist pharmacophores embodied in a single molecule. To this end, agonism at the µ opioid receptor (MOR) with simultaneous antagonism at the δ opioid receptor (DOR) emerged as a promising avenue to obtaining novel analogs devoid of serious adverse effects associated with morphine-based analgesics...

There is a growing concern related to the use of opioid maintenance treatment (OMT) during pregnancy. Studies in both humans and animals have reported reduced cognitive functioning in offspring prenatally exposed to methadone or buprenorphine; however, little is known about the neurobiological mechanisms underlying these impairments. To reveal possible neurobiological effects of such in utero exposure, we examined brain tissue from methadone- and buprenorphine-exposed rat offspring previously shown to display impaired learning and memory...