Introduction to Opioid Receptor

Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function.

Though it is well known that G protein-coupled receptor kinase 2 [GRK2] is involved in regulation of mu opioid receptor [MOR] desensitization and morphine-related behaviors, the potential role of GRK2 in regulation of kappa opioid receptor [KOR] functions in vivo has not been established yet.

Examples include the opioids––deaths increasing during overprescribing, diminishing with wider availability of the opioid receptor antagonist naloxone, increasing again during COVID-19; the barbiturates––until largely supplanted by the benzodiazepines; propofol; and other central nervous system depressants.

Background: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.

Pharmacological treatments involve the use of traditional laxatives and newer agents like peripherally acting mu-opioid receptor agonists (PAMORAs), including naldemedine, naloxegol, and methylnaltrexone.

Naloxegol, an oral once-daily peripherally acting mu-opioid receptor antagonist, is indicated for the treatment of opioid-induced constipation (OIC) with inadequate response to laxative(s), in cancer and non-cancer patients.

Peripherally acting μ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor®) are indicated for the treatment of opioid-induced constipation (OIC).

Peripherally acting μ-opioid receptor antagonists (PAMORAs) have recently emerged as new effective drugs for OIC management due to their specific binding to enteric μ-receptors.

Here, we investigated the role of β-arrestin-2 in the mechanism of opioid tolerance in dorsal root ganglia nociceptive neurons using β-arrestin-2 knockout mice and the G-protein-biased μ-opioid receptor agonist, TRV130.

The cellular pharmacodynamics of three selected formulations were evaluated by applying DAMGO, a synthetic opioid peptide agonist to a μ-opioid receptor, to recruit β-arrestin 2.

Finally, potential future therapeutics aimed at reversing or avoiding opioid-induced respiratory depression through non-opioid receptor targets are in development and could provide certain advantages over naloxone.

Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBötC).

Furthermore, relative gene expression analyses of tyrosine hydroxylase (Th), mu-opioid receptor (Oprm1) and 5-hydroxitryptamine transporter (Slc6a4) were performed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) and dorsal raphe nucleus (DR), respectively.

The authors then paired these behavioral measures with assessment of dopamine release in the nucleus accumbens shell using fast-scan cyclic voltammetry and muopioid receptor expression in the ventral tegmental area and nucleus accumbens.

Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia.

Objectives Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) for treatment of opioid-induced constipation (OIC).

Strategies for treating opioid use disorder can be divided those that target the opioid receptor system and those that target non-opioid receptor systems, including the dopamine and glutamate receptor systems.

Rs678849, an intronic variant in the delta-opioid receptor gene (OPRD1), has been found to predict regional brain volume, addiction risk, and the efficacy of buprenorphine/naloxone in treating opioid use disorder.

Naldemedine is the newest orally available, peripherally selective μ-opioid receptor antagonist blocker approved for opioid-induced constipation (OIC) treatment in adult patients.

Opioid-induced constipation (OIC) is a distressing side effect during opioid analgesia and is mainly mediated by gastrointestinal μ-opioid receptors.

The sigma-1 receptor (σ1R), a unique Ca2+-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB1R).

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ1R) antagonists and mu opioid receptor (MOR) agonists.

Possible involvement of μ1- and κ-opioid receptors and cannabinoid type 1 receptors (CB1) into the mechanism of analgesic activity of the experimental drug product "Thiowurtzine, (capsule 120 mg)" synthesized on the basis of active pharmaceutical substance 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo [5,5,0,03,11,05,9]dodecane was studied in vivo using the hot plate test and acetic acid writhing test.

For mechanism investigation, it was used hot plate test to induce opioid receptors, a histamine and serotonin test to induce oedema paw, finally, for the TRPV1 receptor, it was used the capsaicin test.

Using a knock-in transgenic mouse model with a mutation in Gao that does not bind RGS proteins (RGS-insensitive), we determined the effect of RGS proteins on presynaptic mu opioid receptor (MOR)-mediated inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG).

Using a knock-in transgenic mouse model with a mutation in Gαo that does not bind RGS proteins (RGS-insensitive), we determined the effect of RGS proteins on presynaptic μ opioid receptor (MOR)-mediated inhibition of GABA release in the ventrolateral periaqueductal gray (vlPAG).

Over the past several years, studies have highlighted the δ-opioid receptor (DOPr) as a promising therapeutic target for chronic pain management.

Background: D,L-Methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management.

METHODS We evaluated body weight, food intake of standard and palatable diet, and mRNA expression of dopamine receptor D1 (DDR1), dopamine receptor (DDR2), melanocortin 4 receptor (MC4R), the μ-opioid receptor (MOR), neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine-and amphetamine-regulated transcript (CART), serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT), 5-hydroxytryptamine receptor 1B (5-HT1B), 5-hydroxytryptamine receptor 2C receptor (5-HT2C), Clock (CLOK), cryptochrome protein 1 (Cry1) and period circadian protein homolog 2 (Per2) in the striatum, hypothalamus and brainstem of male rats at post-natal days (PND) 22 and 60.

This review summarizes the pathogenesis of depression from six of the most related receptors and their associated genes, including N-methyl-D-aspartate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glucocoricoid receptor, 5-hydroxytryptamine receptor, GABAA receptor α2, and dopamine receptor; and several "non-classic" receptors, such as metabotropic glutamate receptor, opioid receptor, and insulin receptor.

Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), have been shown to mediate downstream signals of δ opioid receptor (δOR) activation through the metalloproteinase (MMP)-dependent EGF-like growth factor (HB-EGF) excretion pathway, which is called transactivation.

Several proteins targets including Kappa Opioid receptor, Mu opioid receptor, delta-opioid receptor, Cannabinoid receptor 2, Phosphodiesterase 10A (by homology), Platelet-derived growth factor receptor-beta, Stem cell growth factor receptor, Vascular endothelial growth factor receptor 2, Proteinase-activated receptor 1, and Epoxide hydratase were identified as target candidates for mexicanolide.

It has been demonstrated that TGF-β1 and opioid receptors signalling crosstalk results in an improvement of endogenous opioid analgesia, but it is not known whether mu opioid peptide receptor (MOPr) or delta opioid peptide receptor (DOPr) agonists can positively modulate TGF-β1 pathway.

MATERIALS AND METHODS Rats had intracerebroventricularly (icv) received nonspecific opioid peptide receptor antagonist, naloxone (50 ?g/10 ?l in saline) and ?-opioid receptor-selective antagonist naltrindole (50 ?g/10 ?l in saline) and then exercised till exhaustion.

Studies of pharmacological agents acting on various aspects of pain pathways including μ-opioid receptor agonist- norepinephrine reuptake inhibitor (MONRI), cannabinoid receptor, dual serotonin-nor-adrenergic (SNRI)-and triple dopamine reuptake inhibitor (SNDRI), purinergic receptors and sodium channel v1.

: Tapentadol is an analgesic agent that acts as both a µ-opioid receptor agonist and a norepinephrine reuptake inhibitor.

This study demonstrates that activation of opioid receptors (MORs), but not δ opioid receptors (DORs) or κ opioid receptors (KORs), inhibits tonic activation of adenosine A1Rs via a cyclic adenosine monophosphate (cAMP) dependent mechanism in both male and female mice.

Stressed-mice also showed significant increase in TLR4, Nuclear Factor-Kappa B (NF-kB), inducible nitric oxide synthase (iNOS), dopamine receptor D2 (DRD2), cyclic adenosine monophosphate (cAMP) response element binding protein-1 (CREB-1) and opioid receptor MU-1 (OPRM-1) genes expression compared with control and LPS-RS treated stressed-mice.

Spinal estrogenic signaling via membrane estrogen receptors (mERs), in combination with multiple other signaling molecules [spinal dynorphin, kappa-opioid receptors (KOR), glutamate and metabotropic glutamate receptor 1 (mGluR1)], appears to function as a master coordinator, parsing functionality between pronociception and antinociception.

Glial fibrillary acidic protein (GFAP), mu-opioid receptor (MOR), glutamate receptor 1 (GluR1), and glutamic acid decarboxylase (GAD65/67) protein level expression were analyzed in the ACC of diabetic rats treated with PBM.

The mu opioid receptor (MOR) antagonist naloxone was administered as a pre-treatment (1 mg/kg, IV) 5 min prior to fentanyl (25 μg/kg) or a post-treatment (1 and 2 mg/kg) 1 min after fentanyl (25 μg/kg).

Rats were then given injections of the preferential mu opioid receptor antagonist naltrexone (1 mg/kg, s.

Therefore, we observe the effect of kappa opioid receptor (KOR) agonist on cognitive disorders of rats after cardiopulmonary bypass (CPB) and investigate the mechanism of the Ca2+/calmodulin-dependent protein kinase (CaMKII)/cAMP responsive element-binding protein (CREB) pathway.

The mechanism includes various signal pathways, such as extracellular regulated protein kinases-mitogen activated protein kinase-cAMP-response element binding protein pathway, adenylate cyclase 1 protein kinase Mζ- glutamate receptor 1 pathway, contains many biomolecules, such as opioid receptors, neuropeptide S and its receptor, and refers to microglia at the cellular level.

The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS.

Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected.

The mechanism of action for C20:0-5HT and C22:0-5HT was evaluated using naloxone (opioid receptor antagonist, 1 mg/kg), atropine (muscarinic receptor antagonist, 1 mg/kg), AM251 (cannabinoid CB1 receptor antagonist, 1 mg/kg), or ondansetron (5-HT3 serotoninergic receptor antagonist, 0.

Four articles investigated sodium channels, 1 investigated a sodium channel and nerve growth factor receptor, 2 investigated potassium channels, 1 investigated calcium channels, 1 investigated the downstream regulatory element antagonist modulator protein, 1 investigated the dynorphin-kappa opioid receptor system, 1 investigated TRPA1, 1 investigated the Nrg1/ErbB3/ErbB2 signaling complex, 1 investigated a serotonin transporter and 1 investigated potassium channels, sodium channels, calcium channels, chloride channels, TRP channels and gap junctions.

Frequently used premedication protocols included an α2-adrenergic agonist and ketamine combined with either midazolam (group α2−adrenergic agonist, midazolam, ketamine, AMK; n = 34), a μ-opioid receptor agonist (group α2−adrenergic agonist, μ-opioid receptor agonist, ketamine, AOK; n = 13), or a μ−opioid receptor agonist and midazolam (group α2−adrenergic agonist, midazolam, μ-opioid receptor agonist, ketamine, AMOK; n = 10).

To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signaling mediated by mu opioid receptors (MOR).

However, some exogenous GPCRs, including the mu opioid receptor, are non-functional in yeast, which may be due to the presence of the fungal sterol ergosterol instead of the animal sterol cholesterol.

In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin.

VOMA-exposed female mice exhibited increased kappa opioid receptor (κOR) expression in the hippocampus compared to male mice, suggesting a vulnerability toward abstinence-induced dysphoria.

The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes.

Although delta opioid receptors (DOP) are now known to play a major role in modulating chronic pain and controlling emotional processes, unfortunately, some DOP agonists, such as SNC80, reportedly produced convulsive-like behaviors manifesting as tremor-like behaviors in a preclinical study.

Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via μ opioid receptor (μOR) stimulation.

KATP channels are downstream targets of the μ opioid receptor and contribute to morphine-induced antinociception.

TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels.

The analgesic effect is associated with the recruitment of T lymphocytes within the inflamed mucosa and is reversed by naloxone-methiodide, a peripheral opioid receptor antagonist.

We showed that both SLL-039 and SLL-1206 produced potent and long-lasting antinociceptive actions in three different rodent models of pain via activation of κ opioid receptor.

In HFD rats, nanoinjections of the κ opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), in the MnPO rescued the impaired BAT SNA and thermogenic responses to cold.

In addition, we detected expression of Oprm1mRNA (encoding µ opioid receptors, MOR) in VGluT2+ VGaT− and VGluT2− VGaT+ neurons, and that the MOR agonist DAMGO hyperpolarized neurons with these phenotypes.

DS21980956 had potent analgesic activity in the mouse acetic acid writhing test or tail flick test without agonistic activity at the µ opioid receptor (MOR).

Notably, pretreatment with naloxone, a non-selective opioid receptor antagonist, markedly reversed the antinociceptive effect induced by curcumin.

The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a selective sigma 1 (σ1) antagonist with antinociceptive effect, able to increase selective opioid receptor agonist-mediated analgesia.

Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism.

The network of intercalated cells (ITC) which surrounds the lateral and basolateral amygdala and serves to modulate information flow from the lateral amygdala to the central nucleus, express a very high local concentration of mu-type opioid receptors.

Naltrexone (NTX) is a nonspecific opioid antagonist that exerts pharmacological effects on the opioid axis by blocking opioid receptors distributed in cytoplastic and nuclear regions.

Blocking opioid receptor activation with naltrexone selectively reduced wanting of rewards, which on a neural level was reflected by stronger coupling between dorsolateral prefrontal cortex and the striatum under naltrexone compared with placebo.

We describe a successful sustained rescue of a difficult 2-year-long PLP case with sublingual buprenorphine/naloxone using the drug’s potent multimodal mechanisms of action: potent long-acting mu agonist/antagonist, kapa receptor antagonist, delta receptor antagonist and novel opioid receptor-like 1 (OR-L1) agonist effects.

Oliceridine is a novel opioid receptor agonist which is thought to have less risk of adverse events, such as postoperative nausea and vomiting (PONV) and respiratory depression.

Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), have been shown to mediate downstream signals of δ opioid receptor (δOR) activation through the metalloproteinase (MMP)-dependent EGF-like growth factor (HB-EGF) excretion pathway, which is called transactivation.

05) by non-selective opioid antagonist naloxone or δ opioid receptor antagonist ICI 154129, but not the μ opioid receptor antagonist CTAP (P > 0.

Such compounds can also bind and activate opioid receptors in the fetal brain, which could lead to long-term brain and behavioral disruptions.

Dual enkephalinase inhibitors (DENKIs) are pain medications that indirectly activate opioid receptors and can be used as an alternative to traditional opioids.

In total, 49 models developed for 14 bioassays were selected based on the criteria and were identified to be mainly associated with binding affinities to different opioid receptors.

Methadone, buprenorphine, and naloxone have proven their effectiveness in treating addicted individuals, and each of them has different effects on different opioid receptors.

This analgesic effect is reversed by intrathecal naloxone, suggesting that IFN-β produces an analgesic effect through central opioid receptor-mediated signaling.

Purpose Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia.

SIGNIFICANCE STATEMENT Chemically diverse agonist ligands at the nociceptin opioid receptor G protein–coupled receptor showed differential efficacy for activating downstream events after receptor binding, in a suite of functional assays measuring guanosine 5'-O-[gamma-thio]triphosphate binding, cAMP inhibition, G protein–coupled inwardly rectifying protein channel activation, β-arrestin recruitment, receptor internalization and receptor phosphorylation.

The nociceptin opioid receptor (NOP), the fourth member of the opioid receptor family, and its endogenous peptide ligand, nociceptin or orphanin FQ (N/OFQ), play a vital role in several central nervous system pathways regulating pain, reward, feeding, anxiety, motor control and learning/memory.

Peripherally acting opioid receptor agonists promise to mitigate the more serious centrally mediated side effects of opioids, and the goal of this paper is to identify and elaborate on recent advances in these peripheral opioid receptor therapeutics.

Purpose Alvimopan is a peripherally acting opioid receptor antagonist indicated to accelerate gastrointestinal (GI) recovery following surgery, but its benefits past GI recovery are unknown and evidence suggests that it may increase risk for myocardial infarction.

Herein, we probe a few minor indole and oxindole based alkaloids, reporting the receptor affinity, G-protein activity, and βarrestin-2 signaling of corynantheidine, corynoxine, corynoxine B, mitraciliatine, and isopaynantheine at mouse and human opioid receptors.

Tissue samples from tails were assessed for two well-known allelic variations of the human opioid receptor gene, OPRM1, known to affect mu opioid sensitivity: The C17T and A118G single nucleotide polymorphisms.

The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D2 receptor antagonist), D2D3 shRNA, and naloxone (nonselective opioid receptor antagonist) on RoMS-mediated antinociceptive efficacy.

, a nonselective opioid receptor antagonist).

Naloxone is an opioid receptor antagonist that counteracts the effects of an opioid overdose.

Naltrexone is an opioid receptor antagonist, which reduces central opioidergic tone, believed to be raised in patients with cholestatic pruritus.

TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels.

Finally, the intrathecal delivery of various pharmacologic agents, such as quinoxaline-based kappa-opioid receptor agonists, can be utilized for neuropathic pain relief.

The human μ-opioid receptor gene (OPRM1 ), due to its genetic and structural variation, has been a target of interest in several pharmacogenetic studies.

Here, we computationally investigated two such mutations, A6V and N40D, found in the mu opioid receptor gene OPRM1.

In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin.

These results suggest that morphine may activate EGFR via δ-opioid receptor activation.

While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction.

Lactoferrin is an iron-binding, anti-inflammatory glycoprotein that displays analgesic activities associated, in part, by interacting with the low-density lipoprotein receptor-related protein (LRP), which may result in the regulation of the DAMP–TRAF6–NFκB, NO–cGMP–ATP K+-sensitive channel and opioid receptor signaling pathways.