The Efficacy of Peripheral Opioid Antagonists in Opioid-Induced Constipation and Postoperative Ileus: A Systematic Review of the Literature.

Opioid-induced constipation has a negative impact on quality of life for patients with chronic pain and can affect more than a third of patients. A related but separate entity is postoperative ileus, which is an abnormal pattern of gastrointestinal motility after surgery. Nonselective μ-opioid receptor antagonists reverse constipation and opioid-induced ileus but cross the blood-brain barrier and may reverse analgesia. Peripherally acting μ-opioid receptor antagonists target the μ-opioid receptor without reversing analgesia. Three such agents are US Food and Drug Administration approved. We reviewed the literature for randomized controlled trials that studied the efficacy of alvimopan, methylnaltrexone, and naloxegol in treating either opioid-induced constipation or postoperative ileus. Peripherally acting μ-opioid receptor antagonists may be effective in treating both opioid-induced bowel dysfunction and postoperative ileus, but definitive conclusions are not possible because of study inconsistency and the relatively low quality of evidence. Comparisons of agents are difficult because of heterogeneous end points and no head-to-head studies

In vitro and in vivo pharmacological activities of 14-o-phenylpropyloxymorphone, a potent mixed mu/delta/kappa-opioid receptor agonist with reduced constipation in mice

Pain, particularly chronic pain, is still an unsolved medical condition. Central goals in pain control are to provide analgesia of adequate efficacy and to reduce complications associated with the currently available drugs. Opioids are the mainstay for the treatment of moderate to severe pain. However, opioid pain medications also cause detrimental side effects, thus highlighting the need of innovative and safer analgesics. Opioids mediate their actions via the activation of opioid receptors, with the mu-opioid receptor as the primary target for analgesia, but also for side effects. One long-standing focus of drug discovery is the pursuit for new opioids exhibiting a favorable dissociation between analgesia and adverse effects. In this study, we describe the in vitro and in vivo pharmacological profiles of the 14-O-phenylpropyl substituted analog of the mu-opioid agonist 14-O-methyloxymorphone (14-OMO). The consequence of the substitution of the 14-O-methyl in 14-OMO with a 14-O-phenylpropyl group on in vitro binding and functional activity, and in vivo behavioral properties (nociception and gastrointestinal motility) was investigated. In binding studies, 14-O-phenylpropyloxymorphone (POMO) displayed very high affinity at mu-, delta-, and kappa-opioid receptors (Ki values in nM, mu:delta:kappa = 0.073:0.13:0.30) in rodent brain membranes, with complete loss of mu-receptor selectivity compared to 14-OMO. In guinea-pig ileum and mouse vas deferens bioassays, POMO was a highly efficacious and full agonist, being more potent than 14-OMO. In the [35S]GTPγS binding assays with membranes from CHO cells expressing human opioid receptors, POMO was a potent mu/delta-receptor full agonist and a kappa-receptor partial agonist. In vivo, POMO was highly effective in acute thermal nociception (hot-plate test, AD50= 0.7 nmol/kg) in mice after subcutaneous administration, with over 70- and 9000-fold increased potency than 14-OMO and morphine, respectively. POMO-induced antinociception is mediated through the activation of the mu-opioid receptor, and it does not involve delta- and kappa-opioid receptors. In the charcoal test, POMO produced fourfold less inhibition of the gastrointestinal transit than 14-OMO and morphine. In summary, POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses

Placenta ingestion by rats enhances d- and k-opioid antinociception, but suppresses m-opioid antinociception

Ingestion of placenta or amniotic fluid produces a dramatic enhancement of centrally mediated opioid antinociception in the rat. The present experiments investigated the role of each opioid receptor type (m, d, k) in the antinociception-modulating effects of Placental Opioid-Enhancing Factor (POEF—presumably the active substance). Antinociception was measured on a 52 C hotplate in adult, female rats after they ingested placenta or control substance (1.0 g) and after they received an intracerebroventricular injection of a d-specific ([D-Pen2,D-Pen5]enkephalin (DPDPE); 0, 30, 50, 62, or 70 nmol), m-specific ([D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO); 0, 0.21, 0.29, or 0.39 nmol), or k-specific\ud (U-62066; spiradoline; 0, 100, 150, or 200 nmol) opioid receptor agonist. The results showed that ingestion of placenta potentiated d- and k-opioid antinociception, but attenuated m-opioid antinociception. This finding of POEF action as both opioid receptor-specific and complex\ud provides an important basis for understanding the intrinsic pain-suppression mechanisms that are activated during parturition and modified by placentophagia, and important information for the possible use of POEF as an adjunct to opioids in pain management

On the G-protein-coupled receptor heteromers and their allosteric receptor-receptor interactions in the central nervous system: focus on their role in pain modulation

The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via beta-arrestin 2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia

Scalable Production of Highly-Sensitive Nanosensors Based on Graphene Functionalized with a Designed G Protein-Coupled Receptor

We have developed a novel, all-electronic biosensor for opioids that consists of an engineered mu opioid receptor protein, with high binding affinity for opioids, chemically bonded to a graphene field-effect transistor to read out ligand binding. A variant of the receptor protein that provided chemical recognition was computationally redesigned to enhance its solubility and stability in an aqueous environment. A shadow mask process was developed to fabricate arrays of hundreds of graphene transistors with average mobility of ~1500 cm2 V-1 s-1 and yield exceeding 98%. The biosensor exhibits high sensitivity and selectivity for the target naltrexone, an opioid receptor antagonist, with a detection limit of 10 pg/mL.Comment: Nano Letters 201

Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives : Ligands with mixed NOP and opioid receptor profile

© 2018 Kumar, Polgar, Cami-Kobeci, Thomas, Khroyan, Toll and Husbands.A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.Peer reviewedFinal Published versio

7‑hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects

Mitragynina speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.</p

Chronic morphine treatment attenuates cell growth of human BT474 breast cancer cells by rearrangement of the ErbB signalling network.

There is increasing evidence that opioid analgesics may interfere with tumour growth. It is currently thought that these effects are mediated by transactivation of receptor tyrosine kinase (RTK)-controlled ERK1/2 and Akt signalling. The growth of many breast cancer cells is dependent on hyperactive ErbB receptor networks and one of the most successful approaches in antineoplastic therapy during the last decade was the development of ErbB-targeted therapies. However, the response rates of single therapies are often poor and resistance mechanisms evolve rapidly. To date there is no information about the ability of opioid analgesics to interfere with the growth of ErbB-driven cancers. Here we demonstrate that ErbB2 overexpressing BT474 human breast cancer cells carry fully functional endogenous µ-opioid receptors. Most interestingly, the acute opioid effects on basal and Heregulin-stimulated ERK1/2 and Akt phosphorylation changed considerably during chronic Morphine treatment. Investigation of the underlying mechanism by the use of protein kinase inhibitors and co-immunoprecipitation studies revealed that chronic Morphine treatment results in rearrangement of the ErbB signalling network leading to dissociation of ERK1/2 from Akt signalling and a switch from ErbB1/ErbB3 to ErbB1/ErbB2-dependent cell growth. In chronically Morphine-treated cells Heregulin-stimulated ERK1/2 signalling is redirected via a newly established PI3K- and metalloproteinase-dependent feedback loop. Together, these alterations result in apoptosis of BT474 cells. A similar switch in Heregulin-stimulated ERK1/2 signalling from an ErbB2-independent to an ErbB2-, PI3K- and metalloproteinase-dependent mechanism was also observed in κ-opioid receptor expressing SKBR3 human mammary adenocarcinoma cells. The present data demonstrate that the ErbB receptor network of human breast cancer cells represents a target for chronic Morphine treatment. Rearrangement of ErbB signalling by chronic Morphine may provide a promising strategy to enhance the sensitivity of breast cancer cells to ErbB-directed therapies and to prevent the development of escape mechanisms

Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation

Mu opioid receptor selective antagonists are highly desirable because of their utility as pharmacological probes for receptor characterization and functional studies. Furthermore, the mu opioid receptors act as an important target in drug abuse and addiction treatment. Previously, we reported NAP as a novel lead compound with high selectivity and affinity towards the mu opioid receptor. Based on NAP, we have synthesized its derivatives and further characterized their binding affinities and selectivity towards the receptor. NMP and NGP were identified as the two most selective MOR ligands among NAP derivatives. In the present study, molecular modeling methods were applied to assess the dual binding modes of NAP derivatives, particularly on NMP and NGP, in three opioid receptors, in order to analyze the effects of structural modifications on the pyridyl ring of NAP on the binding affinity and selectivity. The results indicated that the steric hindrance, electrostatic, and hydrophobic effects caused by the substituents on the pyridyl ring of NAP contributed complimentarily on the binding affinity and selectivity of NAP derivatives to three opioid receptors. Analyses of these contributions provided insights on future design of more potent and selective mu opioid receptor ligands

Morphine activates neuroinflammation in a manner parallel to endotoxin

Opioids create a neuroinflammatory response within the CNS, compromising opioid-induced analgesia and contributing to various unwanted actions. How this occurs is unknown but has been assumed to be via classic opioid receptors. Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors. These results provide an exciting, nonconventional avenue to improving the clinical efficacy of opioids.Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yi