Delta Opioid Receptor Expression Research Articles

Mu and Delta Opioid Receptors Modulate Inhibition within the Prefrontal Cortex Through Dissociable Cellular and Molecular Mechanisms.

The endogenous opioid system regulates behaviors that rely on prefrontal cortex (PFC) function. Previous studies have described Mu and Delta opioid receptor expression within cortical GABAergic interneurons, but a detailed understanding of how opioids regulate different interneuron subtypes and cortical microcircuits has not been reported. We use whole-cell patch-clamp electrophysiology, genetically engineered mice, and optogenetics to assess MOR and DOR regulation of PFC inhibitory transmission, demonstrating that MOR and DOR inhibition of interneurons display qualitative and quantitative variation across GABAergic circuits within mouse prelimbic PFC.

Voluntary Exercise Ameliorates Chronic Ethanol Withdrawal-Induced Adaptations of Opioid Receptor Expression in the Nucleus Accumbens, Dopamine Release, and Ethanol Consumption.

Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors. In this study, we investigated the impact of voluntary exercise in EtOH-dependent mice on EtOH consumption, KOR and delta opioid receptor (DOR) expression in the NAc and VTA, and functional effects on EtOH-induced alterations in DA release in the NAc. Our findings reveal that voluntary exercise reduces EtOH consumption, reduces KOR and enhances DOR expression in the NAc, and modifies EtOH-induced adaptations in DA release, suggesting a competitive interaction between exercise-induced and EtOH-induced alterations in KOR expression. We also found changes to DOR expression in the NAc and VTA with voluntary exercise but no significant changes to DA release. These findings elucidate the complex interplay of AUD-related neurobiological processes, highlighting the potential for exercise as a therapeutic intervention for AUD.

Morphine Analgesia, Cannabinoid Receptor 2, and Opioid Growth Factor Receptor Cancer Tissue Expression Improve Survival after Pancreatic Cancer Surgery.

Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine (n = 48) or piritramide (n = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; p = 0.038). This finding was supported by multivariate modelling (p < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; p = 0.029, resp. p = 0.01). Conversely, high delta opioid receptor gene expression shortened OS (p = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, p = 0.011, resp. HR = 0.435, p = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, p = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.

Activation of Delta-Opioid Receptor Protects ARPE19 Cells against Oxygen-Glucose Deprivation/Reoxygenation-Induced Necroptosis and Apoptosis by Inhibiting the Release of TNF-α.

Retinal ischemia-reperfusion injury (RIRI) is the basis of the pathology that leads to many retinal diseases and induces necroptosis and apoptosis. Tumor necrosis factor-α (TNF-α) is critically involved in necroptosis and apoptosis. Delta-opioid receptor (DOR) activation inhibits TNF-α release in our previous studies, it might prevent necroptosis and apoptosis by inhibiting the release of TNF-α. However, the role of TNF-α and DOR in necroptosis and apoptosis of retinal pigment epithelial (RPE) cells remains largely unknown. Here, we explored the mechanisms of TNF-α and DOR in necroptosis and apoptosis using an oxygen-glucose deprivation/reoxygenation (OGD/R) model of adult retinal pigment epithelial cell line-19 (ARPE19) cells. ARPE19 cells were exposed to OGD/R conditions to mimic RIRI in vitro. Cell viability was quantified using the Cell Counting Kit-8 (CCK-8) assay. Morphological changes were observed by inverted microscopy. TNF-α protein levels in cell lysates were measured by enzyme-linked immunosorbent assay (ELISA). The DOR agonist TAN-67 and antagonist naltrindole (NTI) were used to pretreat cells for 1 or 2 hours before OGD24/R36 administration. Calcein acetoxymethylester/propidium iodide (Calcein-AM/PI) and Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining were used to detect necroptotic and apoptotic ARPE19 cells, respectively. The protein expression of DOR, p-RIP1 (RIP1), p-RIP3 (RIP3), p-MLKL (MLKL), and cleaved Caspase3 (Caspase3) was measured by western blotting. OGD severely damaged ARPE19 cells. Prolonged reoxygenation significantly increased TNF-α level and decreased DOR expression in ARPE19 cells. Pretreatment with the DOR agonist TAN-67 (10 µM) significantly improved ARPE19 cell viability after OGD24/R36 by reducing the number of necroptotic and apoptotic cells. Furthermore, DOR activation significantly inhibited TNF-α release and suppressed the expression of proteins related to necroptosis and apoptosis, including p-RIP1, p-RIP3, p-MLKL, and cleaved Caspase3, after OGD24/R36. This effect was reversed by the DOR antagonist NTI. These results strongly suggest that DOR activation inhibits necroptosis and apoptosis by decreasing TNF-α release, leading to the prevention of OGD/R-induced injury in ARPE19 cells. This study provides an innovative idea for clinical treatment strategies for retinal damage and vision loss due to RIRI.

Characterizing the influence of Toxoplasma infection on opioid receptor expression using human neuroblastoma cells (SKNSH)

BackgroundToxoplasma gondii is an obligate intracellular parasite that has permanently infected billions of people. The parasite can convert to a latent form that is found preferentially in the brain and heart. Recent serological studies have linked Toxoplasma infection to many brain disorders including schizophrenia, depression, substance abuse and Alzheimer’s. However, the molecular mechanism by which Toxoplasma influences these brain disorders remains unclear. Previous studies have shown that Toxoplasmaincreases dopamine synthesis, and dopamine is an important neurotransmitter in the reward pathway, where the opioid system has been shown to play a major role in modulating this pathway. We aim to further explore these mechanisms by studying the influence of Toxoplasmainfection on opioid receptor expression.ObjectivesThe goal of our project is to elucidate the influence of Toxoplasma gondiion brain physiology through studying the impact of Toxoplasma infection on opioid receptor expression. The aim of this study is to determine the effect of Toxoplasma infection on opioid receptor expression in neuroblastoma cells (SKNSH) in the presence or absence of morphine.MethodsTo evaluate the potency of morphine against Toxoplasma, a doubling assay was performed. Briefly, Human foreskin fibroblasts (HFF) were infected with Toxoplasma. Six‐hours post‐infection, the uninvaded parasites were removed and the media was replaced with media containing 10 µM morphine, 10 µM pyrimethamine, or DMSO. The flasks were fixed with ice‐cold methanol and the number of parasites per vacuole were enumerated at 24‐ and 48‐hours post‐treatment. To evaluate the expression of opioid receptors, the neuroblastoma cell SKNSH, which has been shown to express functional mu and delta opioid receptors, was infected with Toxoplasma type 1. Four hours post‐infection, uninvaded parasites were removed and the medium was replaced with media containing DMSO or 1 µM morphine or 10 µM morphine. Thirty‐two hours post‐treatment, the cells were harvested and protein was isolated. The expression of mu and delta opioid receptors was evaluated using western blot analysis.ResultsWe observed changes in the morphology of SKNSH upon infection with Toxoplasma type 1. The results from our doubling assay demonstrate the lack of potency for morphine against Toxoplasma type 1 at 24 hours and 48 hours post treatment with the highest morphine concentration we have been using for these experiments. Preliminary results suggest that the expression of the delta opioid receptor is downregulated in the presence of Toxoplasma, independent of morphine administration. In addition, the expression of delta opioid receptor is increased in the presence of morphine alone. When pyrimethamine was added to cells containing both Toxoplasma and morphine, delta receptor expression was comparable to its expression in the presence of morphine alone.ConclusionWe have confirmed the expression of muand delta opioid receptors in SKNSH, as reported previously. In addition, we were able to successfully infect this cell line with Toxoplasma. Additionally, we have found that morphine lacks potency against Toxoplasma, unlike previously reported. Preliminary data suggest that the collective the presence of Toxoplasma can negatively influence the expression of delta opioid receptors. Future experiments are being designed to elucidate the molecular mechanism of these findings, as well as observing similar findings in the animal model of Toxoplasmosis.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Hair Growth Promotion by δ-Opioid Receptor Activation.

Literature has revealed that the delta opioid receptor (DOR) exhibited diverse pharmacological effects on neuron and skin. In the present study, we have investigated whether the activation of DOR has hair-growth promotion effects. Compared with other opioid receptor, DOR was highly expressed in epidermal component of hair follicle in human and rodents. The expression of DOR was high in the anagen phase, but it was low in the catagen and telogen phases during mouse hair cycle. Topical application of UFP-512, a specific DOR agonist, significantly accelerated the induction of the anagen in C3H mice. Topical application of UFP-512 also increased the hair length in hair organ cultures and promoted the proliferation and the migration of outer root sheath (ORS) cells. Similarly, pharmacological inhibition of DOR by naltrindole significantly inhibited the anagen transition process and decreased hair length in hair organ cultures. Thus, we further examined whether Wnt/β-catenin pathway was related to the effects of DOR on hair growth. We found that Wnt/β-catenin pathway was activated by UFP-512 and siRNA for β-catenin attenuated the UFP-512 induced proliferation and migration of ORS cells. Collectively, result established that DOR was involved in hair cycle regulation, and that DOR agonists such as UFP-512 should be developed for novel hair-loss treatment.

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In DOR loxP controls SNC80 blocked the development of acute and chronic cephalic allodynia in the chronic nitroglycerin model, an effect that was lost in Dlx-DOR mice. In addition, the anti-allodynic effects of SNC80 were lost in a model of opioid induced hyperalgesia/medication overuse headache in Dlx-DOR conditional knockouts. In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.

Peripheral Deltorphin II Inhibits Nociceptors Following Nerve Injury.

Clinical and preclinical studies have revealed that local administration of opioid agonists into peripheral tissue attenuates inflammatory pain. However, few studies have examined whether peripherally restricted opioids are effective in reducing mechanical allodynia and hyperalgesia that usually follows nerve injury. The aim of the present study was to determine whether the mechanical responsiveness of C-fiber mechanical nociceptors innervating skin under neuropathic pain conditions is depressed by direct activation of delta opioid receptors (DORs) on their peripheral terminals. A murine model of peripheral neuropathic pain was induced with a spared nerve (tibial) injury, in which mice survived 7 or 28 days after surgery before electrophysiological testing began. Control groups comprised naïve and sham-operated animals. An ex vivo preparation of mouse plantar skin with attached tibial nerve was used to examine electrophysiologically the effects of the selective DOR agonist, deltorphin II, on the response properties of individual cutaneous C-fiber nociceptors. In contrast to naïve and sham-operated animals, deltorphin II induced an inhibition of the mechanical responsiveness of C-fiber mechanical nociceptors innervating skin under neuropathic conditions. The effects of deltorphin II were concentration-dependent and prevented by pretreatment with naltrindole indicating DOR-mediated inhibitory effects of deltorphin II. Our results provide the first direct evidence for expression of functional DORs on mechanical nociceptors innervating skin in an animal model of neuropathic pain.

Delta opioid receptor activation modulates affective pain and modality-specific pain hypersensitivity associated with chronic neuropathic pain.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.

Mu and Delta Opioid Receptors Are Coexpressed and Functionally Interact in the Enteric Nervous System of the Mouse Colon.

Background & AimsFunctional interactions between the mu opioid receptor (MOR) and delta opioid receptor (DOR) represent a potential target for novel analgesics and may drive the effects of the clinically approved drug eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome. Although the enteric nervous system (ENS) is a likely site of action, the coexpression and potential interaction between MOR and DOR in the ENS are largely undefined. In the present study, we have characterized the distribution of MOR in the mouse ENS and examined MOR-DOR interactions by using pharmacologic and cell biology techniques.MethodsMOR and DOR expression was defined by using MORmCherry and MORmCherry–DOR-eGFP knockin mice. MOR-DOR interactions were assessed by using DOR-eGFP internalization assays and by pharmacologic analysis of neurogenic contractions of the colon.ResultsAlthough MOR was expressed by approximately half of all myenteric neurons, MOR-positive submucosal neurons were rarely observed. There was extensive overlap between MOR and DOR in both excitatory and inhibitory pathways involved in the coordination of intestinal motility. MOR and DOR can functionally interact, as shown through heterologous desensitization of MOR-dependent responses by DOR agonists. Functional evidence suggests that MOR and DOR may not exist as heteromers in the ENS. Pharmacologic studies show no evidence of cooperativity between MOR and DOR. DOR internalizes independently of MOR in myenteric neurons, and MOR-evoked contractions are unaffected by the sequestration of DOR.ConclusionsCollectively, these findings demonstrate that although MOR and DOR are coexpressed in the ENS and functionally interact, they are unlikely to exist as heteromers under physiological conditions.

Involvement of opioid system in behavioral despair induced by social isolation stress in mice

Social isolation stress (SIS) as a type of chronic stress could induce depressive- and anxiety-like behaviors. Our study evaluates the role of opioid system on negative behavioral impacts of SIS in male NMRI mice. We investigated effects of morphine, a nonselective opioid receptor (OR) agonist, naltrexone (NLX), an OR antagonist, naltrindole (NLT), a delta opioid receptor (DOR) antagonist, SNC80, a DOR agonist, U-69593, a kappa opioid receptor (KOR) agonist, nor-Binaltorphimine, a selective KOR antagonist and cyprodime hydrochloride a selective mu opioid receptor (MOR) antagonist on depressive- and anxiety-like behaviors. Using RT-PCR we evaluated ORs gene expression in mice brain. Our findings showed that SIS induced anxiety- and depressive-like behavior in the forced swimming test, open field test, splash test and hole-board test. Moreover, administration of SNC-80 significantly mitigated anxiety- and depressive-like behaviors. NLT decreased grooming-activity in the splash test. Excitingly, administration of agents affecting KOR failed to alter the negative effects of SIS. RT-PCR demonstrated that MOR and KOR gene expression decreased in socially isolated mice; however, SIS did not affect DORs expression. Our findings suggest that SIS at least in part, probably via altering endogenous opioids particularly MORs and KORs but not DORs mediated negative impacts on behavior; also, it could be concluded that DORs might be considered as a novel target for studying depression and anxiety.

SNC80 and naltrindole modulate voltage-dependent sodium, potassium and calcium channels via a putatively delta opioid receptor-independent mechanism.

SNC80 was designed as a highly selective nonpeptide delta opioid receptor (DOR) agonist. Antidepressant-like and antinociceptive effects of this compound were demonstrated in animal models. Naltrindole was synthetized as a highly selective DOR antagonist. Its antitussive and antinociceptive effects were reported. Observed effects of SNC80 and naltrindole may be accompanied by changes in neuronal excitability including modulation of voltage-dependent ion channels. We investigated possible DOR-independent modulation of neuronal sodium, calcium and potassium currents by both agents. NG108-15 cells lacking expression of DOR protein were used as model of neuronal cells. Cells were differentiated into neuronal phenotype by exposure to dibutyryl cyclic-AMP (dbcAMP). Lack of DORs expression in NG108-15 cells and the presence of DOR expression in brain and neuronal cultures were demonstrated by Western blot analysis. Both SNC80 and naltrindole exerted low to moderate modulatory effects on voltage-dependent ion currents. SNC80 weakly inhibited sodium current, potentiated calcium current, and did not act on potassium channels. Naltrindole inhibited sodium current, did not act on calcium current and inhibited potassium current at a high concentration. Such effects should be taken into account when these compounds are used for investigation of DOR-mediated signaling pathways.

Effect of Sinomenine on the Morphine-Dependence and Related Neural Mechanisms in Mice.

Evidence suggests that the dopamine receptor rate-limiting enzyme, tyrosine hydroxylase (TH), and the glutamate receptor, N-methyl-D-aspartate receptor 2B (NR2B), contribute to morphine dependence. Previous studies show that chronic exposure to morphine changes the expression of opioid receptors. In this study, we focus on the effects of sinomenine on morphine-dependent mice and its related neural mechanisms. Conditioned place preference (CPP) mouse model was established using morphine (9mg/kg, s.c.), and their expression levels of TH and NR2B were observed by immunohistochemistry. Moreover, their mu opioid receptor (MOR) and delta opioid receptor (DOR) contents were assessed using quantitative reverse transcription polymerase chain reaction. Results showed that high sinomenine dose (80mg/kg) effectively attenuated the behavior of CPP mice and reversed increased expression levels of TH and NR2B induced by morphine. Moreover, compared with the morphine group, sinomenine up-regulated the content of MOR to a normal level but did not significantly affect the DOR expression. In summary, these data indicate that sinomenine can inhibit morphine dependence by increasing the expression levels of TH, NR2B, and MOR in the mouse brain; however, DOR may not contribute to this effect.

One-step generation of mice carrying a conditional allele together with an HA-tag insertion for the delta opioid receptor

G protein-coupled receptors (GPCRs) are important modulators of many physiological functions and excellent drug targets for many diseases. However, to study the functions of endogenous GPCRs is still a challenging task, partially due to the low expression level of GPCRs and the lack of highly potent and selective GPCR antibodies. Overexpression or knock-in of tagged GPCRs, or knockout of specific GPCRs in mice, are common strategies used to study the in vivo functions of these receptors. However, generating separate mice carrying tagged GPCRs or conditional alleles for GPCRs is labor intensive, and requires additional breeding costs. Here we report the generation of mice carrying an HA-tagged DOR (delta opioid receptor) flanked by LoxP sequences at the endogenous DOR locus using a single recombination step, aided by the TALEN system. These animals can be used directly to study the expression, localization, protein-protein interaction and signal transduction of endogenous DOR using anti-HA antibodies. By crossing with mice expressing tissue-specific Cre, these mice can also generate offspring with DOR knockout within specific tissues. These mice are powerful tools to study the in vivo functions of DOR. Furthermore, the gene modification strategy could also be used to study the functions of many other GPCRs.

Delta Opioid Receptor Expression and Function in Primary Afferent Somatosensory Neurons.

The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory experiences, from shooting pain to pleasant touch. In recent years, the identification of dozens of genetic markers specifically expressed by subpopulations of DRG neurons has dramatically improved our understanding of this diversity and provided the tools to manipulate their activity and uncover their molecular identity and function. Opioid receptors have long been known to be expressed by discrete populations of DRG neurons, in which they regulate cell excitability and neurotransmitter release. We review recent insights into the identity of the DRG neurons that express the delta opioid receptor (DOR) and the ion channel mechanisms that DOR engages in these cells to regulate sensory input. We highlight recent findings derived from DORGFP reporter mice and from in situ hybridization and RNA sequencing studies in wild-type mice that revealed DOR presence in cutaneous mechanosensory afferents eliciting touch and implicated in tactile allodynia. Mechanistically, we describe how DOR modulates opening of voltage-gated calcium channels (VGCCs) to control glutamatergic neurotransmission between somatosensory neurons and postsynaptic neurons in the spinal cord dorsal horn. We additionally discuss other potential signaling mechanisms, including those involving potassium channels, which DOR may engage to fine tune somatosensation. We conclude by discussing how this knowledge may explain the analgesic properties of DOR agonists against mechanical pain and uncovers an unanticipated specialized function for DOR in cutaneous mechanosensation.

Involvement of the coatomer protein complex I in the intracellular traffic of the delta opioid receptor.

The delta opioid receptor (DOPr) is known to be mainly expressed in intracellular compartments. It remains unknown why DOPr is barely exported to the cell surface, but it seems that a substantial proportion of the immature receptor is trapped within the endoplasmic reticulum (ER) and the Golgi network. In the present study, we performed LC-MS/MS analysis to identify putative protein partners involved in the retention of DOPr. Analysis of the proteins co-immunoprecipitating with Flag-DOPr in transfected HEK293 cells revealed the presence of numerous subunits of the coatomer protein complex I (COPI), a vesicle-coating complex involved in recycling resident proteins from the Golgi back to the ER. Further analysis of the amino acid sequence of DOPr identified multiple consensus di-lysine and di-arginine motifs within the intracellular segments of DOPr. Using cell-surface ELISA and GST pulldown assays, we showed that DOPr interacts with COPI through its intracellular loops 2 and 3 (ICL2 and ICL3, respectively) and that the mutation of the K164AK166 (ICL2) or K250EK252 (ICL3) putative COPI binding sites increased the cell-surface expression of DOPr in transfected cells. Altogether, our results indicate that COPI is a binding partner of DOPr and provide a putative mechanism to explain why DOPr is highly retained inside the cells.

Research delta opioid receptor and its association with hepatocellular carcinoma

Opioid receptors have drawn highly attention to scientists since they were founded in the 1990s. As a member of G protein-coupled receptor family, opioid peptides are the endogenous ligands. It is well known to us that the basic structure consists of extracellular amino residues, seven transmembrane region and the hydroxyl residues of the cell. In recent years, the progress of science laid the foundation for further studies on the function of delta receptor. Aberrant expression of delta opioid receptor in a variety of tumors, and it plays an important role of the occurrence and development of tumors. This review describes the recent research advances on delta opioid receptor and its association with hepatocellular carcinoma. Key words: Delta opioid receptor(DOR); Receptor structure; Hepatocellular carcinoma

Delta Opioid Pharmacology in Relation to Alcohol Behaviors.

Delta opioid receptors (DORs) are heavily involved in alcohol-mediated processes in the brain. In this chapter we provide an overview of studies investigating how alcohol directly impacts DOR pharmacology and of early studies indicating DOR modulation of alcohol behavior. We will offer a brief summary of the different animal species used in alcohol studies investigating DORs followed by a broader overview of the types of alcohol behaviors modulated by DORs. We will highlight a small set of studies investigating the relationship between alcohol and DORs in analgesia. We will then provide an anatomical overview linking DOR expression in specific brain regions to different alcohol behaviors. In this section, we will provide two models that try to explain how endogenous opioids acting at DORs may influence alcohol behaviors. Next, we will provide an overview of studies investigating certain new aspects of DOR pharmacology, including the formation of heteromers and biased signaling. Finally, we provide a short overview of the genetics of the DORs in relation to alcohol use disorders (AUDs) and a short statement on the potential of using DOR-based therapeutics for treatment of AUDs.

Intermittent access to a sucrose solution impairs metabolism in obesity-prone but not obesity-resistant mice

Consumption of sugar-sweetened beverages is associated with overweight and obesity. In this study, we hypothesized that obesity-prone (OP) mice fed a high-fat high-sucrose diet (HFHS) are more sensitive to consumption of sucrose-sweetened water (SSW) than obesity-resistant (OR) mice.After 3weeks of ad libitum access to the HFHS diet (7.5h/day), 180 male mice were classified as either OP (upper quartile of body weight gain, 5.2±0.1g, n=45) or OR (lower quartile, 3.2±0.1g, n=45). OP and OR mice were subsequently divided into 3 subgroups that had access to HFHS (7.5h/day) for 16weeks, supplemented with: i) water (OP/water and OR/water); ii) water and SSW (12.6% w/v), available for 2h/day randomly when access to HFHS was available and for 5 randomly-chosen days/week (OP/SSW and OR/SSW); or iii) water and SSW for 8weeks, then only water for 8weeks (OP/SSW-water and OR/SSW-water).OR/SSW mice decreased their food intake compared to OR/water mice, while OP/SSW mice exhibited an increase in food and total energy intake compared to OP/water mice. OP/SSW mice also gained more body weight and fat mass than OP/water mice, showed an increase in liver triglycerides and developed insulin resistance. These effects were fully reversed in OP/SSW-water mice. In the gut, OR/SSW mice, but not OP/SSW mice, had an increase GLP-1 and CCK response to a liquid meal compared to mice drinking only water. OP/SSW mice had a decreased expression of melanocortin receptor 4 in the hypothalamus and increased expression of delta opioid receptor in the nucleus accumbens compared to OP/water mice when fasted that could explain the hyperphagia in these mice. When access to the sucrose solution was removed for 8weeks, OP mice had increased dopaminergic and opioidergic response to a sucrose solution.Thus, intermittent access to a sucrose solution in mice fed a HFHS diet induces changes in the gut and brain signaling, leading to increased energy intake and adverse metabolic consequences only in mice prone to HFHS-induced obesity.