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Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ‐opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ‐opioid receptor (κ receptor), δ‐opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole‐based cebranopadol and a compound class with a piperidin‐4‐yl‐1,3‐dihydroindol‐2‐one backbone (SR16835/AT‐202 and SR14150/AT‐200). In addition, the ornivol BU08028 is an analogue of the clinically well‐established buprenorphine. Moreover, the morphinan‐based nalfurafine exerts its effect with a dominant κ receptor‐component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi‐receptor opioid ligand in that it binds to μ, κ and δ receptors. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of particular multi‐opioid receptor ligands, but not on their medicinal chemistry and design. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc

Hippocampal slices of mouse brain were used to estimate how selective agonist and antagonist of opioid receptors alter Low-Mg+2 artificial cerebrospinal fluid (LM-ACSF)-induced epileptiform activities in normal and morphine-dependent mice. Brain slices were obtained from control and morphine-dependent mice. The morphine-dependent group received morphine once a day for 5 consecutive days, and the control group received saline. All injections were administered subcutaneously (s.c) in a volume of 0.1mL on postnatal days 14-18. Brain slices were perfused with LM-ACSF along with selective agonist and antagonist of μ, κ and δ opioid receptors. Changes in spike count per unit of time were used as indices to quantify the effects of LM-ACSF exposure in the slices. In both groups, DAMGO (selective μ opioid receptor agonist) and DPDPE (selective δ opioid receptor agonist) suppressed while Dyn-A (selective κ opioid receptor agonist) potentiated the epileptiform activity. Meanwhile, BFN-A (selective μ opioid receptor antagonist) recovered epileptiform activity in normal brain slices but not in morphine-dependent ones. NTI (selective δ opioid receptor antagonist) and nor-BNI (selective κ opioid receptor antagonist) decreased epileptiform activity. It seems that the excitatory effect of morphine on epileptiform activity was mediated through kappa receptors and its inhibitory effect was mediated via the mu receptor and, to a lesser degree, through the delta receptor. The pattern of effect was similar in normal and morphine-dependent slices, but the intensity of the effect was significantly stronger in normal mice. Finding of this study might be considered for further research and attention in epilepsy treatment.

We previously demonstrated that a single treatment of a non-peptidic delta opioid receptor agonist, KNT-127, has an antidepressant-like effect in rodents in the forced swim test. Here we evaluated the effect of repeated administration of the potential antidepressant KNT-127 in an olfactory-bulbectomized (OBX) rat model. Male Wistar rats (8-12 weeks old) underwent olfactory bulbectomy. From 14days after surgery each was weighed and administered either KNT-127 (3mgkg-1/day), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10mgkg-1/day), or vehicle, daily for 14 days. Hyperemotionality was measured on days 3, 5, 7, 10, and 14. Repeated administration of KNT-127 significantly decreased total and individual hyperemotionality scores (attack, startle, struggle and fight) over the entire period. Conversely, fluoxetine did not show any significant effect on days 3, 5, 7, or 14 but significantly reduced the total score on day 10. The inhibitory effects of KNT-127 were greater than those of fluoxetine. The KNT-127 and control groups both gained weight, while the fluoxetine group lost weight. Our results suggest that KNT-127 is a potential lead compound for antidepressant therapy, with high efficacy, a relatively rapid onset of therapeutic effect, and without the possible adverse effects of weight loss caused by SSRIs.

Introduction:Choreaform movements provoked by opiates is an infrequent adverse event. Buprenorphine induction of chorea has not heretofore been described. Such a case is presented.METHOD:Case Study: A 38-year-old female presented with a decade long history of alcohol, cocaine, benzodiazepine, and heroin abuse. The patient was insufflating 1.5 grams of heroin daily. On presentation, she was actively withdrawing, scoring 17 on the Clinical Opioid Withdrawal Scale. Urine toxicology screening was positive for opiates, cocaine, and cannabinoids. Buprenorphine 4 mg sublingual was initiated. Within one hour, she observed, “My legs were moving uncontrollably as if I was a marionette.” These dance-like movements were isolated to both legs and gradually resolved after discontinuation of buprenorphine: most of the movements manifested in the first 8 hours, and dissipated over the next 2 days. She did have similar movements after treatment with quetiapine during a previous hospitalization, years earlier.RESULTS:Abnormalities in physical examination: General: goiter, bilateral palmar erythema. Neurological examination: Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 2 (anosmia). Motor Examination: Drift testing: mild right pronator drift. Reflexes: 3+ bilateral lower extremities. Neuropsychiatric Examination: Clock Drawing Test: 3 (abnormal). Animal Fluency Test: 18 (normal). Go-No-Go Test 6/6 (normal).DISCUSSION:Buprenorphine induced chorea could be a result of partial mu-opioid agonism, or kappa and delta receptor antagonism (Burke, 2018; Cowan, 1977). Mu-opioid receptor activation causes increased dopamine turnover in the nigrostriatum, which is responsible for locomotor sensitization (Campos-Jurado, 2017). With the addition of mu-opioid receptor modulation of dopamine release, kappa-opioid receptor alters various neurotransmitters in the basal ganglia, potentiating hyperkinetic movements. Buprenorphine’s choreiformogenic action may be due to kappa-opioid receptors ability to augment neurotransmission in the striatum (Escobar, 2017; Bonnet, 1998). The combination of simultaneous activity of these three opioid receptors may cause chorea, since they act to modulate dopamine, glutamate, and GABA in the direct and indirect pathways within the basal ganglia (Abin, 1989; Cui, 2013; Allouche, 2014; Trifilieff, 2013). This patient’s history of heroin and cocaine use may have caused supersensitization of dopamine receptors (Memo, 1981), provoking hyperkinesia. Involvement of substance-induced sensitization with concurrent kappa-opioid receptor neurotransmitter augmentation in direct and indirect pathways in the basal ganglia may have primed our patient to the development of chorea after buprenorphine administration. Further investigation for the presence of extrapyramidal movements in those undergoing buprenorphine treatment is warranted.

In recent years, the delta opioid receptor has attracted increasing interest as a target for the treatment of chronic pain and emotional disorders. Due to their therapeutic potential, numerous tools have been developed to study the delta opioid receptor from both a molecular and a functional perspective. This review summarizes the most commonly available tools, with an emphasis on their use and limitations. Here, we describe (1) the cell-based assays used to study the delta opioid receptor. (2) The features of several delta opioid receptor ligands, including peptide and non-peptide drugs. (3) The existing approaches to detect delta opioid receptors in fixed tissue, and debates that surround these techniques. (4) Behavioral assays used to study the in vivo effects of delta opioid receptor agonists; including locomotor stimulation and convulsions that are induced by some ligands, but not others. (5) The characterization of genetically modified mice used specifically to study the delta opioid receptor. Overall, this review aims to provide a guideline for the use of these tools with the final goal of increasing our understanding of delta opioid receptor physiology.

Endorphins are endogenous morphine, neuropeptides produced from pituitary gland in response to stress and pain. These are of three types- beta-endorphins, dynorphins, enkephalins, binds to mu, kappa, delta receptors found on immune cells and nervous system. Beta-endorphins is the most abundant endorphin synthesized and stored in the anterior pituitary gland. It has got various activities such as Immune stimulatory activity, anti-inflammatory activity, analgesic activity, stress buster, and anti-aging activity. Immune stimulatory activity by activation of NK cells, macrophages, T-lymphocytes, anti-inflammatory activity by production of cytokines, such as IL-18, 1L-10, analgesic activity by inhibiting substance-p, anti-ageing by suppressing ROS, RNS, free radicals and lengthening telomeres, stress buster activity by decreasing cortisol and nor-adrenaline, dopamine release involved in holistic, preventive, promotive, therapeutic and palliative treatment of cancer without any adverse affects and inexpensive. This article brief about the current concept of novel actions of endorphins in holistic treatment of cancer .

The opioid receptors modulate a variety of biological functions, including pain, mood, and reward. As a result, opioid ligands are being explored as potential therapeutics for a variety of indications. Multifunctional opioid ligands, which act simultaneously at more than one type of opioid receptor, show promise for use in the treatment of addiction, pain, and other conditions. Previously, we reported the creation of bifunctional kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) partial agonist ligands from the classically delta opioid receptor (DOR) antagonist selective dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold through the addition of a 7-benzyl pendant on the tetrahydroisoquinoline ring. This study further explores the structure&ndash, activity relationships surrounding 7-position pendants on the Dmt-Tiq scaffold. Some analogues maintain a KOR agonist/MOR partial agonist profile, which is being explored in the development of a treatment for cocaine addiction. Others display a MOR agonist/DOR antagonist profile, which has potential to be used in the creation of a less addictive pain medication. Ultimately, we report the synthesis and in vitro evaluation of novel opioid ligands with a variety of multifunctional profiles.

Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures and in vivo. We established ligand selective mu-delta co-internalization upon activation by exogenous ligands and provide evidence for mu-delta co-internalization by the endogenous opioid peptide met-enkephalin, but not β-endorphin. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors and led to sorting to the lysosomal compartment. This alteration in the mu opioid receptor intracellular fate was accompanied by sustained ERK1/2 phosphorylation. In addition, increased mu-delta neuronal co-localization in the rostral ventromedial medulla in a chronic neuropathic state suggests that mu-delta heteromers are involved in the regulation of nociceptive transmission

Background Cocaine withdrawal activates stress systems. Females are more vulnerable to relapse to cocaine use and more sensitive to withdrawal-induced negative affect. Delta opioid receptors modulate anxiety-like behavior during cocaine withdrawal in rats. This study measured the time course of gene regulation of one of the main stress peptides, corticotropin-releasing factor (CRF), and its type 1 receptor in male and female rats as well as the ability of the delta opioid receptor agonist SNC80 to normalize cocaine withdrawal-induced changes in CRF mRNA. Methods Rats were injected with cocaine or saline 3 times daily for 14 days. Brains were collected 30 minutes, 24 hours, 48 hours, 7 days, and 14 days following the last injection. The paraventricular nucleus of the hypothalamus, central amygdala, and bed nucleus of the stria terminalis were processed for quantitative reverse transcriptase PCR measurement of CRF and CRFR1 mRNA. Additional rats received SNC80 during early cocaine withdrawal, and CRF mRNA was measured in the central amygdala. Results CRF mRNA was elevated in the central amygdala at 24 hours and the paraventricular nucleus at 48 hours of cocaine withdrawal in males and females. Significant sex differences in cocaine-induced CRF upregulation were found in the bed nucleus of the stria terminalis at 30 minutes and 24 hours. SNC80 administration attenuated the increase in CRF mRNA in the central amygdala of female rats only. Conclusions CRF mRNA regulation during cocaine withdrawal is sex, time, and brain region dependent. Administration of a delta opioid receptor agonist during early withdrawal may ameliorate stress-related negative affect in females by abrogating the induction of CRF mRNA.

Following oxycodone conditioned place preference (CPP) in naive female and male Sprague Dawley rats, delta- and mu-opioid receptors (DORs and MORs) redistribute in hippocampal CA3 pyramidal cells and GABAergic interneurons in a manner that would promote opioid-associative learning processes, particularly in females. MORs and DORs similarly redistribute in CA3 and hilar neurons following chronic immobilization stress (CIS) in females, but not males, essentially "priming" the opioid system for oxycodone-associative learning. Following CIS, only females acquire oxycodone CPP. The present study determined whether sex and CIS differentially affect the levels of phosphorylated MORs and DORs (pMORs and pDORs) in the hippocampus following oxycodone CPP as phosphorylation is important for opioid receptor internationalization and trafficking. In naive oxycodone-injected (Oxy) female rats, the density of pMOR-immunoreactivity (ir) was increased in CA1 stratum oriens and CA3a,b strata lucidum and radiatum compared to saline-injected (Sal)-females. Additionally, the density of pDOR-ir increased in the pyramidal cell layer and stratum radiatum of CA2/3a in Oxy-males compared to Sal-males. In CIS females that acquire CPP, pDOR-ir levels were increased in the CA2/3a. These findings indicate only rats that acquire oxycodone CPP have activated MORs and DORs in the hippocampus but that the subregion containing activated opioid receptors differs in females and males. These results are consistent with previously observed sex differences in the hippocampal opioid system following Oxy-CPP.

The circadian rhythmicity of critical skin cell functions related to homeostasis, regeneration and aging has recently been highlighted. In this study, we suggest an important link between cutaneous opioid receptor (OPr) activity and circadian rhythmicity. We find that activation of the Delta-opioid receptor (DOPr) by its endogenous agonist Met-enkephalin in N/TERT-1 keratinocytes results in a phase shift in the expression of the core clock gene Per2 and in the nuclear localization of the DOPr - β-arrestin 1 complex. Furthermore, DOPr activation enhances and induces a phase shift in the rhythmic binding of β-arrestin1 to the Per2 promoter. Coupled with this finding, β-arrestin1 was found to regulate the transcription of its target genes, including Per2, by facilitating histone 4 acetylation. Taken together, we propose that activation of DOPr leads to a phase shift in Per2 expression via β-arrestin1 facilitated chromatin remodelling. We believe our results have potential implications in wound healing, DNA repair and chronopharmacology. Doctor of Philosophy

As tool compounds to study cardiac ischemia, the endogenous &delta, opioid receptors (&delta, OR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the &delta, OR&rsquo, s protective role during ischemic events. Thus, a need remains for &delta, OR peptides with improved selectivity and unique signaling properties for investigating the specific roles for &delta, OR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to &delta, ORs and &micro, opioid receptors (&micro, ORs) and potency to inhibit cAMP signaling and to recruit &beta, arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the &delta, OR and &micro, OR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties.

Delta opioid delta receptor (DOP) agonists were expected to be analgesics and many researchers tried to develop the SNC80 derivatives. However, the derivatives were dropped at the stage of early clinical trials because of undesirable side effects and weak analgesia. On the other hand, DOP agonists have been proposed as attractive candidates for the novel psychotropic drugs. We recently succeeded in synthesizing a novel selective DOP agonist KNT-127. KNT-127 produced neither catalepsy nor convulsive effects. We have demonstrated that KNT-127 has potent anxiolytic-like effect in rat models of innate anxiety. This anxiolytic-like effect was independent from known adverse effect of benzodiazepine, such as memory impairment, motor coordination deficits, and ethanol interactions. We have also demonstrated that KNT-127 showed potent and rapid antidepressant-like effects in rat models of depression. This antidepressant-like effect was independent from known adverse effect of selective serotonin reuptake inhibitor (SSRI), such as digestive symptoms. Therefore, we propose that DOP should be considered as an attractive target for the development of novel psychotropic drugs, without producing the adverse effects associated with benzodiazepine anxiolytics and SSRI antidepressants. Very recently, we developed another delta agonist NC-2800 with a different structure. NC-2800 is now in the preclinical stage using the CiCLE fund supported by AMED (Japanese Agency for Medical Research and Development).

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

Opiate addiction develops as a chronic relapsing disorder upon drug recreational use or following misuse of analgesic prescription. Mu opioid (MOP) receptors are the primary molecular target of opiates but increasing evidence support in vivo functional heteromerization with the delta opioid (DOP) receptor, which may be part of the neurobiological processes underlying opiate addiction. Here, we used double knock-in mice co-expressing fluorescent versions of the MOP and DOP receptors to examine the impact of chronic morphine administration on the distribution of neurons co-expressing the two receptors. Our data show that MOP/DOP neuronal co-expression is broader in morphine-dependent mice and is detected in novel brain areas located in circuits related to drug reward, motor activity, visceral control and emotional processing underlying withdrawal. After four weeks of abstinence, MOP/DOP neuronal co-expression is still detectable in a large number of these brain areas except in the motor circuit. Importantly, chronic morphine administration increased the proportion of MOP/DOP neurons in the brainstem of morphine-dependent and abstinent mice. These findings establish persistent changes in the abstinent state that may modulate relapse and opiate-induced hyperalgesia and also point to the therapeutic potential of MOP/DOP targeting. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.

Oxycodone, a widely prescribed and very potent oral opioid analgesic agent, is highly addictive and has many side effects, including troublesome constipation. Our studies in mice indicated that pretreatment of naltrindole did not significantly affect the analgesic efficacy of oxycodone but attenuated the tolerance and withdrawal induced by chronic oxycodone administration. Naltrindole also attenuated the oxycodone-induced rewarding and re-instatement behaviors, as shown by the conditioned place preference test. Further, oxycodone-induced decrease in intestinal transit (i.e., constipation) was reduced by naltrindole. However, naltrindole did not block the respiratory depression produced by oxycodone. Taken together, these data suggest that naltrindole can attenuate some major side effects while retaining the analgesic efficacy of oxycodone in mice. Naltrindole and oxycodone may have the potential to be a potent analgesic combination with much lower levels of oxycodone's side effects of addictive liability and constipation.

In previous studies, early-life fibroblast growth factor-2 (FGF2) administration conferred resilience to developing anxiety-like behavior in vulnerable animals in adulthood. To follow up on this work, we administered FGF2 the day after birth to animals that differ in emotional behavior and further explored its long-term effects on affective behavior and circuitry. Selectively-bred “high responder” rats (bHRs) exhibit low levels of anxiety-like and depression-like behavior, whereas selectively-bred “low responders” (bLRs) display high levels of anxiety-like and depression-like behavior. We found that early-life administration of FGF2 decreased negative affect in bLRs during the early post-natal period, as indexed by 40 kHz ultrasonic vocalizations (USVs) in response to a brief maternal separation on PND11. FGF2 also increased positive affect during the juvenile period, as measured by 50 kHz USVs in response to heterospecific hand play (“tickling”) after weaning. In general, we found that bHRs produced more 50 kHz USVs than bLRs. In adulthood, we measured opioid ligand and receptor expression in brain regions implicated in USV production and affect regulation by mRNA in situ hybridization. Within multiple affective brain regions, bHRs had greater expression of the mu opioid receptor than bLRs. FGF2 increased mu opioid expression in bLRs. The bLRs had more kappa and less delta receptor expression than bHRs, and FGF2 increased prodynorphin in bLRs. Our results provide support for further investigations into the role of growth factors and endogenous opioids in the treatment of disorders characterized by altered affect, such as anxiety and depression.

The delta opioid receptor (DOP) belongs to the Class A, rhodopsin-like family of G protein-coupled receptors. Although this receptor has a high level of similarity with the other opioid receptors, it displays unique aspects and functions. Indeed, as opposed to most membrane receptors, DOP is poorly addressed to the plasma membrane. In this chapter, we first review the molecular and cellular mechanisms regulating the expression and the cellular trafficking/sorting of DOP. We then summarize the structural insights of this receptor through the analysis of the existing crystal structures, with a particular focus on the role of the sodium binding site. Finally, we review the current signaling mechanisms mediating receptor function and desensitization.

Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/β-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over β-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.

The impact that β-arrestin proteins have on G protein-coupled receptor trafficking, signaling and physiological behavior has gained much appreciation over the past decade. A number of studies have attributed the side effects associated with the use of naturally occurring and synthetic opioids, such as respiratory depression and constipation, to excessive recruitment of β-arrestin. These findings have led to the development of biased opioid small molecule agonists that do not recruit β-arrestin, activating only the canonical G protein pathway. Similar G protein-biased small molecule opioids have been found to occur in nature, particularly within kratom, and opioids within salvia have served as a template for the synthesis of other G protein-biased opioids. Here, we present the first report of naturally occurring peptides that selectively activate G protein signaling pathways at δ opioid receptors, but with minimal β-arrestin recruitment. Specifically, we find that rubiscolin peptides, which are produced as cleavage products of the plant protein rubisco, bind to and activate G protein signaling at δ opioid receptors. However, unlike the naturally occurring δ opioid peptides leu-enkephalin and deltorphin II, the rubiscolin peptides only very weakly recruit β-arrestin 2 and have undetectable recruitment of β-arrestin 1 at the δ opioid receptor.

Opioid receptors are implicated in alcoholism, other addictions, withdrawal, and depression, and are considered potential pharmacological targets for treatment. Our goal in the present study was to compare the availability of kappa opioid receptors (KOR) between an alcohol-dependent cohort (AD) and a healthy control cohort (HC). Sixty-four participants-36 AD and 28 HC-underwent PET scans with [11C]LY2795050, a selective kappa antagonist tracer. Partial-volume correction was applied to all PET data to correct for atrophy. Volume of distribution (VT) of the tracer was estimated regionally as a measure of KOR availability. VT values of AD versus HC were compared for 15 defined ROIs. Multivariate analysis showed a main effect of group on VT across these 15 ROIs. Post hoc tests showed that AD had significantly lower VT and thus a lower KOR availability than HC in amygdala and pallidum (corrected for multiple comparisons). Exploratory analysis of change in VT with age was conducted; VT was not found to vary significantly with age in any region. Our findings of lower VT in AD versus HC in multiple regions are in contrast to findings in the mu and delta opioid receptor systems of higher VT in AD versus HC. Although age-related decline in receptors has previously been observed in the mu opioid receptor system, we found that KOR availability does not change with age. ispartof: NEUROPSYCHOPHARMACOLOGY vol:43 issue:13 pages:2539-2547 ispartof: location:England status: published

In this study dibenzylidene ketone derivatives (2E,5E)-2-(4-methoxybenzylidene)-5-(4-nitrobenzylidene) cyclopentanone (AK-1a) and (1E,4E)-4-(4-nitrobenzylidene)-1-(4-nitrophenyl) oct-1-en-3-one (AK-2a) were newly synthesized, inspired from curcuminoids natural origin. Novel scheme was used for synthesis of AK-1a and AK-2a. The synthesized compounds were characterized by spectroscopic techniques. AK-1a and AK-2a showed high computational affinities (E-value > − 9.0 kcal/mol) against cyclooxygenase-1, cyclooxygenase-2, proteinase-activated receptor 1 and vitamin K epoxide reductase. AK-1a and AK-2a showed moderate docking affinities (E-value > − 8.0 kcal/mol) against mu receptor, kappa receptor, delta receptor, human capsaicin receptor, glycoprotein IIb/IIIa, prostacyclin receptor I2, antithrombin-III, factor-II and factor-X. AK-1a and AK-2a showed lower affinities (E-value > − 7.0 kcal/mol) against purinoceptor-3, glycoprotein-VI and purinergic receptor P2Y12. In analgesic activity, AK-1a and AK-2a decreased numbers of acetic acid-induced writhes (P

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. Therefore, these induced convulsions limit the progress of the clinical development of DOP agonists. However, mechanisms underlying DOP-induced convulsant activity remain unclarified. Thus, the study aimed to elucidate mechanisms that could cause tremor-like behaviors of SNC80. These drugs were microinjected into the ventral hippocampus CA3 (vCA3), amygdala (AMY), and insular cortex (IC) of mice. In addition, we examined the extracellular glutamate levels after DOP agonist local treatment. Microinjection of SNC80 into the vCA3 increased the number of tremor-like behaviors and extracellular glutamate levels but did not cause tremor-like behaviors in mice when microinjected into IC and AMY. Pretreatment with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainite receptor antagonist CNQX into vCA3 totally inhibited the SNC80-induced increases in tremor-like behaviors. In contrast, another DOP agonist, KNT-127, did not cause tremor-like behaviors in any of the tested brain areas. Further, the extracellular glutamate levels in the hippocampus were significantly lower in the KNT-127-treated mice than in the SNC80-treated mice. Our results showed that the administration of SNC80, but not KNT-127, into vCA3 induced tremor-like behaviors by activating glutamatergic neurons in mice. We propose that KNT-127 should be further studied clinically as a DOP agonist that is expected to have a low risk for convulsions than those resulting in antinociceptive and antidepressant effects.

Opioid signaling controls the activity of the brain's reward system. It is involved in signaling the hedonic effects of rewards and has essential roles in reinforcement and motivational processes. Here, we focused on opioid signaling through mu and delta receptors on dopaminoceptive neurons and evaluated the role these receptors play in reward-driven behaviors. We generated a genetically modified mouse with selective double knockdown of mu and delta opioid receptors in neurons expressing dopamine receptor D1. Selective expression of the transgene was confirmed using immunostaining. Knockdown was validated by measuring the effects of selective opioid receptor agonists on neuronal membrane currents using whole-cell patch clamp recordings. We found that in the nucleus accumbens of control mice, the majority of dopamine receptor D1-expressing neurons were sensitive to a mu or delta opioid agonist. In mutant mice, the response to the delta receptor agonist was blocked, while the effects of the mu agonist were strongly attenuated. Behaviorally, the mice had no obvious impairments. The mutation did not affect the sensitivity to the rewarding effects of morphine injections or social contact and had no effect on preference for sweet taste. Knockdown had a moderate effect on motor activity in some of the tests performed, but this effect did not reach statistical significance. Thus, we found that knocking down mu and delta receptors on dopamine receptor D1-expressing cells does not appreciably affect some of the reward-driven behaviors previously attributed to opioid signaling.