Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs

The safe disposal of unused opioid drugs is an area of regulatory concern. While toilet flushing is recommended for some drugs to prevent accidental exposure, there is a need for data that can support a more consistent disposal policy based on an assessment of relative risk. For drugs acting at the Mu-opioid receptor (MOR), published measurements of binding affinity (K(i)) are incomplete and inconsistent due to differences in methodology and assay system, leading to a wide range of values for the same drug thus precluding a simple and meaningful relative ranking of drug potency. Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). The drugs were separated into three categories based upon their K(i) values: K(i) > 100 nM (tramadol, codeine, meperidine, propoxyphene and pentazocine), K(i)=1-100 nM (hydrocodone, oxycodone, diphenoxylate, alfentanil, methadone, nalbuphine, fentanyl and morphine) and K(i) < 1 nM (butorphanol, levorphanol, oxymorphone, hydromorphone, buprenorphine and sufentanil). These data add to the understanding of the pharmacology of opioid drugs and support the development of a more consistent labeling policies regarding safe disposal.     

Non-peptide δ opioid agonists and antagonists

Following a flurry of medicinal chemistry activity in the late 1980s, a number of non-peptide pharmacological tools, selective for the δ opioid receptors, became available to challenge the pre-eminent position occupied by the existing peptide δ ligands. The first non-peptide δ antagonist NTI (1) represented a breakthrough in this field. Several analogues have been subsequently synthesised and are currently being used to clarify the pharmacology associated with the δ opioid receptors. The discovery of the selective δ agonists TAN-67 (50), BW373U86 (56) and SNC 80 (62) represented another step towards the understanding of the involvement of the δ opioid receptor in a number of possible pathophysiological conditions. This review addresses the recent highlights and developments that have been made by several research groups in the design of potent and selective non-peptide δ ligands. Focus has been given to the different pharmacological actions of δ agonists and antagonists. Analgesia can be considered the historical target for drugs acting through the opioidergic system. However, contrary to existing μ opioid narcotic drugs, there is substantial evidence to suggest that selective δ opioid agonists may be safe and effective analgesics. Beside this very important therapeutic target, recent studies have revealed that such drugs may elicit a variety of other beneficial pharmacological effects. They may also positively modulate some activities of μ agonists such as morphine. Animal models have demonstrated that δ antagonists may also play an important pharmacological role per se having possible clinical applications in preventing drug abuse, in organ transplantation and as antitussive agents.     

Binding properties of C-truncated delta opioid receptors

目的：研究δ阿片受体Ｃ末端在受体结合配体的亲和力及选择性中的作用．方法：在中国苍鼠卵巢细胞（ＣＨＯ细胞）中分别稳定表达Ｃ末端截短３１个氨基酸残基及野生型δ阿片受体，用受体结合分析法研究表达产物与配体的结合特征．结果：表达得到典型突变受体克隆ＣＨＯＴ及野生型受体克隆ＣＨＯＷ．ＣＨＯＴ结合［３Ｈ］ｄｉｐｒｅｎｏｒｐｈｉｎｅ（Ｄｉｐ）及［３Ｈ］［ＤＡｌａ２，ＤＬｅｕ５］ｅｎｋｅｐｈａｌｉｎ（ＤＡＤＬＥ）的Ｋｄ值与ＣＨＯＷ一致，δ选择性激动剂对二者与［３Ｈ］Ｄｉｐ的结合均有很强的抑制作用，且Ｋｉ相似；而μ及κ选择性激动剂则对二者均无抑制作用．结论：δ阿片受体的Ｃ末端与受体结合配体的亲和力及选择性无关．     

Novel approaches for the treatment of psychostimulant and opioid abuse – focus on opioid receptor-based therapies

Introduction: Psychostimulant and opioid addiction are poorly treated. The majority of abstinent users relapse back to drug-taking within a year of abstinence, making ‘anti-relapse’ therapies the focus of much current research. There are two fundamental challenges to developing novel treatments for drug addiction. First, there are three key stimuli that precipitate relapse back to drug-taking: stress, presentation of drug-conditioned cue, taking a small dose of drug. The most successful novel treatment would be effective against all three stimuli. Second, a large number of drug users are poly-drug users: taking more than one drug of abuse at a time. The ideal anti-addiction treatment would, therefore, be effective against all classes of drugs of abuse.

Areas covered: In this review, the authors discuss the clinical need and animal models used to uncover potential novel treatments. There is a very broad range of potential treatment approaches and targets currently being examined as potential anti-relapse therapies. These broadly fit into two categories: ‘memory-based’ and ‘receptor-based’ and the authors discuss the key targets here within.

Expert opinion: Opioid receptors and ligands have been widely studied, and research into how different opioid subtypes affect behaviours related to addiction (reward, dysphoria, motivation) suggests that they are tractable targets as anti-relapse treatments. Regarding opioid ligands as novel ‘anti-relapse’ medication targets, research suggests that a ‘non-selective’ approach to targeting opioid receptors will be the most effective.     

New development of drugs against opioid addiction

Opioid addiction has been a big trouble for human being for several centuries. In China, it also has become a main direct threat against national safety, society advancement, economic development and public health. Based on the national report in 2002, the number of addicts registered in due form is over 1 million, which are distributed in 2148 counties and cities in China. The real number of addicts, however, is much more than those as mentioned above. Money used for buying opioids each year in China might be over 10 billion except for other payment. Base on the statistics, 20 - 50% crimes are commited by addicts. On the other hand, drug abuse often induces contagion spread, such as tuberculosis, hepatitis and HIV disease. About 70% HIV positive subjects in China are related to drug abuse. We are very happy to see more andmore attention has been paid to the problem in our country. Recently, a program on neurobiological basis and medical biological measures of addiction has been supported by National Science and Technology Ministry as a 973 program.     

The gut–brain interaction in opioid tolerance

1. Download : Download high-res image (139KB)
2. Download : Download full-size image

     

Analgesic synergy between opioid and α2-adrenoceptors

Opioid and α₂-adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. These supra-additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α₂-adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α₂-adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α₂-adrenoceptor agonists and that α₂-adrenoceptor agonists can mediate synergy through either the α_2A or the α_2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid–adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Modulation of gastrointestinal function by MuDelta,a mixed μ opioid receptor agonist/ μ opioid receptor antagonist

BACKGROUND & PURPOSE

Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation.

EXPERIMENTAL APPROACH

MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified.

KEY RESULTS

δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model.

CONCLUSIONS AND IMPLICATIONS

MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.     

Aminothiazolomorphinans with mixed κ and μ opioid activity

A series of N-substituted and N'-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower than their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [(35)S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N'-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications.     

The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the μ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.     

β-endorphin-sensitive opioid receptors in the rat tail artery

Summary Isolated tail arteries of rats were perfused and field-stimulated every 2 min with 2 pulses at 1 Hz. Different opioid peptides depressed the contractile responses to stimulation; their concentration-response curves showed a maximum at about 40% inhibition. The rank order of potency of the peptides was -endorphin (IC₅₀ = 97 nmol/1) BAM-22P > FK-33824 > DAGO > [d-Ala²,d-Leu⁵]-enkephalin metorphamide > dynorphin A-(1-13) [Met⁵]enkephalin. All these substances have in common a certain activity at opioid -receptors, although the enkephalins are preferential -, and the dynorphins preferential -agonists. However, the selective -agonist [d-Pen²,l-Pen⁵]enkephalin was ineffective at up to 10 mol/l, and the -agonists ethylketocyclazocine and U-50488 acted only at concentrations higher than 3 mol/l. Whereas the effects of -endorphin, DAGO and [d-Ala²,d-Leu⁵]enkephalin could be reduced by the -preferential antagonist naloxone, the effects of ethylketocyclazocine and U-50488 were not changed. The -selective antagonist ICI 174864 did not influence the action of [d-Ala²,d-Leu⁵]enkephalin. Naloxone in a concentration (1 mol/l) which nearly abolished the effect of DAGO 3 mol/l, slightly enhanced responses to stimulation. Neither -endorphin nor DAGO influenced vasoconstriction evoked by the application of noradrenaline or adenosine triphosphate; U-50488 reduced it. In arteries preincubated with [³H]noradrenaline DAGO depressed, whereas naloxone enhanced the tritium overflow and vasoconstriction evoked by field stimulation (0.4 Hz, 24 pulses every 14 min). In addition, naloxone antagonized the effect of DAGO. We suggest that the axon terminals of postganglionic sympathetic neurones in the rat tail artery possess -endorphin-sensitive opioid receptors of the -type. The activation of these receptors by exogenous or endogenous opioids inhibits the release of the neuroeffector transmitter.This work was supported by the Deutsche Forschungsgemeinschaft (SFB 325) Send offprint requests to P. Illes at the above address     

Prolonged morphine treatment alters δ opioid receptor post-internalization trafficking

BACKGROUND AND PURPOSE

The δ opioid receptor (DOP receptor) undergoes internalization both constitutively and in response to agonists. Previous work has shown that DOP receptors traffic from intracellular compartments to neuronal cell membranes following prolonged morphine treatment. Here, we examined the effects of prolonged morphine treatment on the post-internalization trafficking of DOP receptors.

EXPERIMENTAL APPROACH

Using primary cultures of dorsal root ganglia neurons, we measured the co-localization of endogenous DOP receptors with post-endocytic compartments following both prolonged and acute agonist treatments.

KEY RESULTS

A departure from the constitutive trafficking pathway was observed following acute DOP receptor agonist-induced internalization by deltorphin II. That is, the DOP receptor underwent distinct agonist-induced post-endocytic sorting. Following prolonged morphine treatment, constitutive DOP receptor trafficking was augmented. SNC80 following prolonged morphine treatment also caused non-constitutive DOP receptor agonist-induced post-endocytic sorting. The μ opioid receptor (MOP receptor) agonist DAMGO induced DOP receptor internalization and trafficking following prolonged morphine treatment. Finally, all of the alterations to DOP receptor trafficking induced by both DOP and MOP receptor agonists were inhibited or absent when those agonists were co-administered with a DOP receptor antagonist, SDM-25N.

CONCLUSIONS AND IMPLICATIONS

The results support the hypothesis that prolonged morphine treatment induces the formation of MOP–DOP receptor interactions and subsequent augmentation of the available cell surface DOP receptors, at least some of which are in the form of a MOP/DOP receptor species. The pharmacology and trafficking of this species appear to be unique compared to those of its individual constituents.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

Social and environmental influences on opioid sensitivity in rats: importance of an opioid’s relative efficacy at the mu-receptor

Rationale Evidence indicates that social and environmental enrichment can influence the functional maturation of the central nervous system and may affect an organism’s sensitivity to centrally acting drugs. Objective The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to mu-opioids possessing a range of relative efficacies at the mu-receptor. Methods Rats were obtained at weaning (21 days) and divided into two groups immediately upon arrival. Isolated rats were housed individually in opaque laboratory cages with no visual or tactile contact with other rats; enriched rats were housed socially in groups of four in large cages and given various novel objects on a daily basis. After 6 weeks under these conditions, the effects of morphine, levorphanol, buprenorphine, butorphanol, and nalbuphine were examined in the warm-water, tail-withdrawal procedure and the place-conditioning procedure. Results In the tail-withdrawal procedure, isolated and enriched rats did not differ in sensitivity to morphine (1.0–30 mg/kg) and levorphanol (0.3–10 mg/kg), but enriched rats were more sensitive to buprenorphine (0.03–3.0 mg/kg), butorphanol (0.3–30 mg/kg), and nalbuphine (0.3–30 mg/kg). In drug combination tests, butorphanol and nalbuphine antagonized the effects of morphine in isolated rats under conditions in which they produced high levels of antinociception in enriched rats. In the place-conditioning procedure, doses of 10 morphine and 3.0 levorphanol established a place preference in both groups of rats, whereas doses of 0.3 buprenorphine, 3.0 butorphanol, and 10 nalbuphine established a place preference only in enriched rats. Conclusions These findings may be taken as evidence that enriched rats are more sensitive than isolated rats to the effects of lower-efficacy mu-opioids and that social and environmental enrichment leads to functional alterations in opioid receptor populations.     

Buprenorphine – the unique opioid adjuvant in regional anesthesia

Regional anesthesia techniques are commonly used for many surgical procedures alone or as an addition to general anesthesia, because they offer many advantages over general anesthesia. Unfortunately these techniques are partially limited by the time of action of local anesthetics. One of the methods of overcoming this limitation is adding to the local anesthetic solution additional drug – so called adjuvant. Among many adjuvants to local anesthetic drugs tested so far one seems to be particularly interesting – buprenorphine. The aim of this paper is to present pharmacological background for using buprenorphine for regional anesthesia and to review clinical trials of using buprenorphine for all regional anesthesia techniques: spinal and epidural anesthesia, peripheral nerves blocks, local anesthesia and intravenous regional anesthesia.     

Molecular modeling of μ opioid receptor and receptor-ligand interaction

目的：构建μ阿片受体（μＯＲ）的三维结构模型并研究它与芬太尼衍生物的相互作用．方法：以细菌视紫红质为模板，模拟μＯＲ的三维结构；然后，将芬太尼衍生物对接到μＯＲ的七个α螺旋束之内，并计算结合能．结果：（１）得到受体－配基作用模型．（２）模型中，基本结合位点可能是Ａｓｐ１４７和Ｈｉｓ２９７．Ａｓｐ１４７与配基的正电性铵基形成强的静电和氢键相互作用，这种作用在Ｈｉｓ２９７和配基的羰基Ｏ原子之间较弱．受体、配基间还存在某些π－π相互作用．（３）受体配基结合能与芬太尼衍生物的镇痛活性间有良好的相关性．结论：模型有助于理解受体配基的相互作用和设计新的阿片μ选择性配基．     

Kentucky pharmacists’ experiences in dispensing abuse-deterrent opioid analgesics

BackgroundDespite pharmaceutical industry promise and enthusiasm, abuse-deterrent formulation (ADF) opioid use is relatively low. While some barriers to use have been addressed through state laws and policy, pharmacists’ experiences with and opinions of ADF opioids are unclear.ObjectivesThe objective of this study was to evaluate pharmacists’ perceptions of dispensing ADFs.MethodsThis was a cross-sectional survey of community pharmacists licensed and practicing in Kentucky conducted in late 2019. The survey asked about perception, experience dispensing, and insurance coverage of 5 ADF opioids available at the time.ResultsMost respondents (421/629, 67.9%) were familiar or very familiar with ADFs, and 63.1% agreed that all opioids should meet U.S. Food and Drug Administration standards for abuse deterrence. Aside from OxyContin, most ADF opioid formations were not stocked (range: 46.7%–73.6%). Third-party payer claims were occasionally or almost always rejected for most ADFs (range: 56.3%–75.4%). Contrary to intended mechanism of deterrence, ADFs were rated as the least effective strategy to reduce opioid misuse/abuse, with over half (51.2%) of respondents believing ADFs were not effective or somewhat effective. ADFs were rated as effective or very effective at reducing opioid abuse by swallowing intact by 37.4% of respondents.ConclusionPharmacists are familiar with ADFs but do not dispense them frequently. Pharmacists appear skeptical about the effectiveness of ADFs but support policies that could increase ADF uptake.     

Effect of opioid receptor antagonist naltrindole on transplantation rejection

In our previous work, naltrexone, a common opioid receptor antagonist was found to be able to inhibit transplantation rejection. The purpose of present study is to investigate the subtype of the opioid receptors involved in transplantation rejection.The in vivo experiment:Cardiac tissue of the newborn C57 mice was transplanted into the ear of Balb/c mice.The survival of the transplanted tissue was tested with the ECG of transplanted tissue. Naltrexone or naltrindole (a selective opioid receptor antagonist) 5 mg-kg~(-1) was injected ip twice per day for 10 d, respectively.The in vitro experiment: Lymphocytes from two different strain mice were mixed and cultured together. Naltrexone, naltrindole or enkephalin (a selective opioid receptor agonist) was added into the culture fluid, respectively.~3H-TdR uptake (cpm) was measured to show the mixed lymphocyte reaction.The mean     

Interaction models of 3-methylfentanyl derivatives with μ opioid receptors

研究３-甲基芬太尼衍生物与μ阿片受体的作用模型．方法：经过系统构象搜寻，用比较分子力场分析法（ＣｏＭＦＡ）研究三维定量构效关系．结果：①６种ＣｏＭＦＡ模型具有良好的预测活性，且每种模型均对应于１３个被研究化合物的低能构象；②μ药效基团的几何参数ｄ１（），ｄ２（），ｄ３（），ｄ４（），ｄ５（）和ｄ６（）分别为模型Ａ：５２，５４，４９，１０．６，１０２和５８；模型Ｂ：５２，６５，３６，１０６，１１６和５８；模型Ｃ：５２，４６，４９，１１６，９２和６５；模型Ｄ：５２，５４，４９，１０５，１０３和５８；模型Ｅ：３６，５４，４９，５７，７５和５７；模型Ｆ：５２，４７，４９，１１２，９５和６４．结论：可能存在几种活性构象与μ受体相互作用，并且不一定是最低能量构象．     

Increment of endogenous opioid peptides contents and μ- opioid receptor mRNA expression in immuno- suppressive rat induced by intrathecal injection of morphine

Endogenous opioid peptides (EOP) and opioid receptors are important factors in the neuroimmunology.As earlier work from our laboratory demonstrated that intrathecal injection of morphine (0.8 μg/μL) markedly decreased the lymphocyte proliferation, IL-2 production, and NK cell activity in rat spleen, our task was to recognize whether EOP and opioid receptors were involved in the immunosuppression induced by intrathecal morphine.Using in vivo push pull perfusion technique and radioimmunoaassay, it was found that the release of β-endorphin and dynorphin in rat increased in perfusate from hippocampus after inwathecal morphine.With the method of in situ hybridization     

Is opioid substitution treatment beneficial if injecting behaviour continues?

Background

Opioid substitution treatment (OST) is recognised as an effective treatment for opioid dependence. Still, a subgroup of OST users continues to inject drugs. This study examines health risks and criminal activity in a population of needle exchange programme (NEP) participants by comparing those identified as current OST users to (i) those identified as former OST users and (ii) those with no OST experience.

Methods

This was a semi-annual cross-sectional study conducted from 2002 to 2011. NEP participants were interviewed in Oslo, Norway (n = 1760); 341 were identified as current OST users, 356 as former OST users and 1063 had no OST experience. The associations between OST status and health risk and criminal activity were assessed through univariate and multiple logistic regression analyses.

Results

Among NEP participants, those currently in OST had fewer non-fatal overdoses (OR = 0.5 [95% CI 0.3, 0.9]) compared to former OST users and those never in OST. Additionally, they were less likely to have injected frequently (OR = 0.4 [95% CI 0.3, 06]), to have used heroin daily or almost daily (OR = 0.3 [95% CI 0.2, 0.4]), and to have committed theft (OR = 0.6 [95% CI 0.4, 1.0]) and engaged in drug dealing (OR = 0.7 [95% CI 0.5, 0.9]) in the past month. Overall, there was a high level of polysubstance use and no group differences on this measure.

Conclusions

NEP participants who are currently in OST have substantially reduced health risks and criminal activity than other NEP participants. The high level of polysubstance use nevertheless poses a public health challenge.