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Tsutomu Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Regulations of Opioid dependence by Opioid Receptor types
Pharmacology & Therapeutics, 2020Co-Authors: Minoru Narita, Masahiko Funada, Tsutomu SuzukiAbstract:Abstract Three major types of Opioid Receptors, designated μ, δ, and κ, are widely expressed in the CNS. Development of selective Receptor ligands and recent cloning of each Receptor have contributed greatly to our increasing knowledge of the neuropharmacological profile of each Opioid Receptor type. It is of interest to note that they include noncompetitive and allosteric interactions among their types. This review focuses on the functional interaction among these Opioid Receptor types that contribute to Opioid dependence. Various studies provide arguments to support substantial roles for μ-Opioid Receptors and the possible involvement of δ-Opioid Receptors in the development of physical and psychological dependence on morphine. Noradrenergic transmission originating in the locus coeruleus is most likely to play the primary causal role in the expression of physical dependence on morphine. In contrast, many studies have pointed to the mesolimbic dopaminergic pathway projecting from the ventral tegmental area to the nucleus accumbens as a critical site for the initiation of psychological dependence on Opioids. It is noteworthy as the broad existence of opposing interactions between μ/δ- and κ-Receptors in the brain. The activation of κ-Receptors leads to the suppression of unpleasant μ/δ-mediated side effects such as the rewarding effect. Considering the functional interaction among Opioid Receptor types, the co-administration of morphine-like compounds with κ-Receptor agonists may constitute a preferable and superior approach to the treatment of pain with fewer side effects.
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Effect of chronic ethanol treatment on μ-Opioid Receptor function, interacting proteins and morphine-induced place preference
Psychopharmacology, 2013Co-Authors: Masahiro Shibasaki, Minoru Narita, Tomohisa Mori, Toshimasa Itoh, Kenjiro Watanabe, Kotaro Takeda, Tomohisa Tsuyuki, Tsutomu SuzukiAbstract:Rationale Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-Opioid Receptor system is involved in the reinforcing/rewarding effects of ethanol. Objectives The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-Opioid Receptor and the development of morphine-induced rewarding effects. Methods Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w / v ethanol. The direct involvement of μ-Opioid Receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [^35S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm. Results The function of μ-Opioid Receptor was increased by treatment with ethanol in the lower midbrain using [^35S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic Receptor kinase 1 inhibitor. Conclusions The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-Opioid Receptor, mediated by GRK2.
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Involvement of supraspinal and peripheral naloxonazine-insensitive Opioid Receptor sites in the expression of μ-Opioid Receptor agonist-induced physical dependence.
European journal of pharmacology, 2013Co-Authors: Tomohisa Mori, Sachiko Komiya, Naoki Uzawa, Koichi Inoue, Toshimasa Itoh, Shiyou Aoki, Masahiro Shibasaki, Tsutomu SuzukiAbstract:Withdrawal syndrome after the cessation of μ-Opioid Receptor agonists remains an obstacle in the clinical treatment of pain. There is limited information available on the mechanisms that underlie the expression of the withdrawal signs of Opioids, and especially regarding the involvement of μ-Opioid Receptor subtypes and the location of the responsible Opioid Receptors. Therefore, the present study was designed to determine the mechanism of the expression of withdrawal signs in μ-Opioid Receptor agonist-dependent mice. Morphine-, oxycodone- and fentanyl-dependent mice showed a marked loss of body-weight and other signs of withdrawal after a naloxone challenge. Interestingly, the phenotype of the withdrawal signs for morphine and oxycodone was different from that of fentanyl. Furthermore, pretreatment with naloxonazine (so-called μ1-Opioid Receptor antagonist), did not significantly alter the withdrawal signs precipitated by naloxone in these μ-Opioid Receptor agonist-dependent mice, whereas the peripherally limited Opioid Receptor antagonist naloxone methiodide significantly increased the loss of body-weight accompanied by diarrhea, indicating that a peripheral naloxonazine-insensitive site for Opioid Receptors, as an adaptation mechanism, plays an important role in the expression of at least the loss of body-weight. On the other hand, i.c.v. treatment with naloxone methiodide potently induced jumping behavior and trembling in morphine-dependent mice. These results indicate that the prolonged activation of supraspinal μ-Opioid Receptors plays a role in most of the physical dependence induced by μ-Opioid Receptor agonists in mice. Thus, the withdrawal symptoms observed after the cessation of μ-Opioid Receptor agonists are distinctly regulated though supraspinal and peripheral naloxonazine-insensitive sites of μ-Opioid Receptors.
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Functional interaction among Opioid Receptor types: up-regulation of μ- and δ-Opioid Receptor functions after repeated stimulation of κ-Opioid Receptors
Neuropharmacology, 2004Co-Authors: Junaidi Khotib, Minoru Narita, Masami Suzuki, Yoshinori Yajima, Tsutomu SuzukiAbstract:It has been widely accepted that repeated administration of kappa-Opioid Receptor agonists leads to the development of antinociceptive tolerance. The present study was designed to investigate the effect of repeated administration of a selective kappa-Opioid Receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride ((-)U-50,488H) on the mu- and delta-Opioid Receptor agonist-induced antinociception and G-protein activation in mice. The mice were injected either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) pretreated with saline or (-)U-50,488H once a day for seven consecutive days. Two hours after the last injection, the mice were challenged by either mu- or delta-Opioid Receptor agonist for the antinociceptive assay. Repeated treatment with (-)U-50,488H (s.c. or i.c.v.) significantly enhanced antinociceptive effect of both mu-Opioid Receptor agonist (morphine) and delta-Opioid Receptor agonists ([d-Ala2]deltorphin (DELT) and (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dime thyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) compared to saline-treated groups. Under these conditions, repeated s.c. injection of (-)U-50,488H significantly enhanced both mu- and delta-Opioid Receptor agonist-stimulated [35S]GTPgammaS binding in the membrane of the thalamus. On the contrary, either repeated administration of morphine (s.c. or i.c.v.) or SNC-80 failed to affect the kappa-Opioid Receptor agonist-induced antinociception and G-protein activation. Taken together, these results suggest that repeated stimulation of kappa-Opioid Receptor markedly increases the functional mu- and delta-Opioid Receptors, whereas repeated stimulation of either mu- or delta-Opioid Receptor had no direct effect on kappa-Opioidergic function in mice.
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Opioid Receptor types and dependence
Folia Pharmacologica Japonica, 1997Co-Authors: Tsutomu Suzuki, Miwa MisawaAbstract:The existence of mu, delta and kappa Opioid Receptors in the central nervous system is well documented. The present review focuses on the relationships between Opioid Receptor types and physical and psychic dependences. Mu and delta, but not kappa Opioid Receptor agonists produce physical dependence. From behavioral, biochemical and molecular biological studies, it is suggested so far that development of physical dependence on morphine results predominantly from an activation of mu 1 and mu 2 Opioid Receptors which causes functional changes in Gi/o, adenylate cyclase, protein kinases A and C, beta-adrenoceptor and NMDA Receptor in the locus coeruleus. Recently, there have been significant advances in studies on psychic dependence. Mu and delta Opioid Receptor agonists produce psychic dependence, but kappa Opioid Receptor agonists rather produce an aversive effect. Activation of the mesolimbic dopamine system may lead to psychic dependence on Opioids. Mu and delta 1 Opioid Receptor agonists activate the mesolimbic dopamine system to induce a rewarding effect, whereas the rewarding effect of delta 2 Opioid Receptor agonists may be produced through a non-dopaminergic system. There are complicated interactions among Opioid Receptor types. The activation of kappa Opioid Receptor suppresses physical and psychic dependences on mu and delta Opioid Receptor agonists, but the activation of delta Opioid Receptor potentiates the dependence on mu Opioid Receptor agonists. The clinical use of morphine in patients with cancer pain won't develop dependence probably due to the balance of the Opioid system coming from these interactions.
Minoru Narita - One of the best experts on this subject based on the ideXlab platform.
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Regulations of Opioid dependence by Opioid Receptor types
Pharmacology & Therapeutics, 2020Co-Authors: Minoru Narita, Masahiko Funada, Tsutomu SuzukiAbstract:Abstract Three major types of Opioid Receptors, designated μ, δ, and κ, are widely expressed in the CNS. Development of selective Receptor ligands and recent cloning of each Receptor have contributed greatly to our increasing knowledge of the neuropharmacological profile of each Opioid Receptor type. It is of interest to note that they include noncompetitive and allosteric interactions among their types. This review focuses on the functional interaction among these Opioid Receptor types that contribute to Opioid dependence. Various studies provide arguments to support substantial roles for μ-Opioid Receptors and the possible involvement of δ-Opioid Receptors in the development of physical and psychological dependence on morphine. Noradrenergic transmission originating in the locus coeruleus is most likely to play the primary causal role in the expression of physical dependence on morphine. In contrast, many studies have pointed to the mesolimbic dopaminergic pathway projecting from the ventral tegmental area to the nucleus accumbens as a critical site for the initiation of psychological dependence on Opioids. It is noteworthy as the broad existence of opposing interactions between μ/δ- and κ-Receptors in the brain. The activation of κ-Receptors leads to the suppression of unpleasant μ/δ-mediated side effects such as the rewarding effect. Considering the functional interaction among Opioid Receptor types, the co-administration of morphine-like compounds with κ-Receptor agonists may constitute a preferable and superior approach to the treatment of pain with fewer side effects.
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Effect of chronic ethanol treatment on μ-Opioid Receptor function, interacting proteins and morphine-induced place preference
Psychopharmacology, 2013Co-Authors: Masahiro Shibasaki, Minoru Narita, Tomohisa Mori, Toshimasa Itoh, Kenjiro Watanabe, Kotaro Takeda, Tomohisa Tsuyuki, Tsutomu SuzukiAbstract:Rationale Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-Opioid Receptor system is involved in the reinforcing/rewarding effects of ethanol. Objectives The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-Opioid Receptor and the development of morphine-induced rewarding effects. Methods Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w / v ethanol. The direct involvement of μ-Opioid Receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [^35S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm. Results The function of μ-Opioid Receptor was increased by treatment with ethanol in the lower midbrain using [^35S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic Receptor kinase 1 inhibitor. Conclusions The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-Opioid Receptor, mediated by GRK2.
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Functional interaction among Opioid Receptor types: up-regulation of μ- and δ-Opioid Receptor functions after repeated stimulation of κ-Opioid Receptors
Neuropharmacology, 2004Co-Authors: Junaidi Khotib, Minoru Narita, Masami Suzuki, Yoshinori Yajima, Tsutomu SuzukiAbstract:It has been widely accepted that repeated administration of kappa-Opioid Receptor agonists leads to the development of antinociceptive tolerance. The present study was designed to investigate the effect of repeated administration of a selective kappa-Opioid Receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride ((-)U-50,488H) on the mu- and delta-Opioid Receptor agonist-induced antinociception and G-protein activation in mice. The mice were injected either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) pretreated with saline or (-)U-50,488H once a day for seven consecutive days. Two hours after the last injection, the mice were challenged by either mu- or delta-Opioid Receptor agonist for the antinociceptive assay. Repeated treatment with (-)U-50,488H (s.c. or i.c.v.) significantly enhanced antinociceptive effect of both mu-Opioid Receptor agonist (morphine) and delta-Opioid Receptor agonists ([d-Ala2]deltorphin (DELT) and (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dime thyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) compared to saline-treated groups. Under these conditions, repeated s.c. injection of (-)U-50,488H significantly enhanced both mu- and delta-Opioid Receptor agonist-stimulated [35S]GTPgammaS binding in the membrane of the thalamus. On the contrary, either repeated administration of morphine (s.c. or i.c.v.) or SNC-80 failed to affect the kappa-Opioid Receptor agonist-induced antinociception and G-protein activation. Taken together, these results suggest that repeated stimulation of kappa-Opioid Receptor markedly increases the functional mu- and delta-Opioid Receptors, whereas repeated stimulation of either mu- or delta-Opioid Receptor had no direct effect on kappa-Opioidergic function in mice.
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Absence of G-protein activation by μ-Opioid Receptor agonists in the spinal cord of μ-Opioid Receptor knockout mice
British Journal of Pharmacology, 1999Co-Authors: Minoru Narita, Ichiro Sora, Hirokazu Mizoguchi, Michiko Narita, Leon F. TsengAbstract:1. The ability of mu-Opioid Receptor agonists to activate G-proteins in the spinal cord of mu-Opioid Receptor knockout mice was examined by monitoring the binding to membranes of the non-hydrolyzable analogue of GTP, guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS). 2. In the Receptor binding study, Scatchard analysis of [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin ([3H]DAMGO; mu-Opioid Receptor ligand) binding revealed that the heterozygous mu-knockout mice displayed approximately 40% reduction in the number of mu-Receptors as compared to the wild-type mice. The homozygous mu-knockout mice showed no detectable mu-binding sites. 3. The newly isolated mu-Opioid peptides endomorphin-1 and -2, the synthetic selective mu-Opioid Receptor agonist DAMGO and the prototype of mu-Opioid Receptor agonist morphine each produced concentration-dependent increases in [35S]GTPgammaS binding in wild-type mice. This stimulation was reduced by 55-70% of the wild-type level in heterozygous, and virtually eliminated in homozygous knockout mice. 4. No differences in the [35S]GTPgammaS binding stimulated by specific delta1- ([D-Pen2,5]enkephalin), delta2-([D-Ala2]deltorphin II) or kappa1-(U50,488H) Opioid Receptor agonists were noted in mice of any of the three genotypes. 5. The data clearly indicate that mu-Opioid Receptor gene products play a key role in G-protein activation by endomorphins, DAMGO and morphine in the mouse spinal cord. They support the idea that mu-Opioid Receptor densities could be rate-limiting steps in the G-protein activation by mu-Opioid Receptor agonists in the spinal cord. These thus indicate a limited physiological mu-Receptor reserve. Furthermore, little change in delta1-, delta2- or kappa1-Opioid Receptor-G-protein complex appears to accompany mu-Opioid Receptor gene deletions in this region.
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Pretreatment with β-endorphin facilitates the attenuation of δ-Opioid Receptor-mediated antinociception caused by δ-Opioid Receptor antisense oligodeoxynucleotide
European Journal of Pharmacology, 1995Co-Authors: Leon F. Tseng, Minoru Narita, John P. KampineAbstract:Abstract Intracerebroventricular (i.c.v.) pretreatment of male ICR mice with β-endorphin (0.6 nmol) or intrathecal (i.t.) pretreatment with antisense oligodeoxynucleotide to δ-Opioid Receptor mRNA (163 pmol) alone given 24 h earlier did not have any effect on i.t. administered δ-Opioid Receptor agonist [ d -Ala 2 ]deltorphin II (6.4 nmol)-induced antinociception. However, a concomitant i.c.v. pretreatments with β-endorphin (0.08–0.6 nmol) and i.t. pretreatment with δ-Opioid Receptor antisense oligodeoxynucleotide (163 pmol) for 24 h dose-dependently attenuated i.t. challenged [ d -Ala 2 ]deltorphin II-induced antinociception. A concomitant i.c.v. pretreatment with μ-Opioid Receptor agonist [ d -Ala 2 , N MePhe 4 ,Gly(ol) 5 ]enkephalin (DAMGO) or κ-Opioid Receptor agonist U50,488H and i.t. pretreatment with δ-Opioid Receptor antisense oligodeoxynucleotide for 24 h did not affect i.t. challenged [ d -Ala 2 ]deltorphin II-induced antinociception. β-Endorphin given supraspinally has been documented to release [Met 5 ]enkephalin acting on δ-Opioid Receptors in the spinal cord. Our results indicate that supraspinal pretreatment with β-endorphin selectively causes a loss of spinal δ-Opioid Receptor-mediated antinociception in mice receiving δ-Opioid Receptor antisense oligodeoxynucleotide.
Sebastien Granier - One of the best experts on this subject based on the ideXlab platform.
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structure of the δ Opioid Receptor bound to naltrindole
Nature, 2012Co-Authors: Sebastien Granier, Aashish Manglik, Andrew C Kruse, Tong Sun Kobilka, Foon Sun Thian, William I Weis, Brian K KobilkaAbstract:The X-ray crystal structure of the mouse δ-Opioid Receptor in complex with the subtype-selective antagonist naltrindole is reported. Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known Opioid Receptors in ligand-bound conformations. These G-protein-coupled Receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-Opioid Receptor bound to a morphinan antagonist and the δ-Opioid Receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-Opioid Receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ Receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying Receptor function and drug development. The Opioid Receptor family comprises three members, the µ-, δ- and κ-Opioid Receptors, which respond to classical Opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled Receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-Opioid Receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood1. The structures of the µ-OR and κ-OR have recently been solved2,3. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the µ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of Opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of Opioid Receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among Opioid Receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of Opioid Receptor pharmacology4,5, in which distinct ‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.
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crystal structure of the µ Opioid Receptor bound to a morphinan antagonist
Nature, 2012Co-Authors: Aashish Manglik, Andrew C Kruse, Tong Sun Kobilka, Foon Sun Thian, William I Weis, Brian K Kobilka, Jesper Mosolff Mathiesen, Roger K Sunahara, Leonardo Pardo, Sebastien GranierAbstract:Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical Opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-Opioid Receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled Receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into Opioid Receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction. The crystal structure of the mouse μ-Opioid Receptor bound to an antagonist is described, with possible implications for the future development of analgesics. Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known Opioid Receptors in ligand-bound conformations. These G-protein-coupled Receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-Opioid Receptor bound to a morphinan antagonist and the δ-Opioid Receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-Opioid Receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ Receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying Receptor function and drug development.
Brian K Kobilka - One of the best experts on this subject based on the ideXlab platform.
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structure of the δ Opioid Receptor bound to naltrindole
Nature, 2012Co-Authors: Sebastien Granier, Aashish Manglik, Andrew C Kruse, Tong Sun Kobilka, Foon Sun Thian, William I Weis, Brian K KobilkaAbstract:The X-ray crystal structure of the mouse δ-Opioid Receptor in complex with the subtype-selective antagonist naltrindole is reported. Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known Opioid Receptors in ligand-bound conformations. These G-protein-coupled Receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-Opioid Receptor bound to a morphinan antagonist and the δ-Opioid Receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-Opioid Receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ Receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying Receptor function and drug development. The Opioid Receptor family comprises three members, the µ-, δ- and κ-Opioid Receptors, which respond to classical Opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled Receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-Opioid Receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood1. The structures of the µ-OR and κ-OR have recently been solved2,3. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the µ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of Opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of Opioid Receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among Opioid Receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of Opioid Receptor pharmacology4,5, in which distinct ‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.
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crystal structure of the µ Opioid Receptor bound to a morphinan antagonist
Nature, 2012Co-Authors: Aashish Manglik, Andrew C Kruse, Tong Sun Kobilka, Foon Sun Thian, William I Weis, Brian K Kobilka, Jesper Mosolff Mathiesen, Roger K Sunahara, Leonardo Pardo, Sebastien GranierAbstract:Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical Opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-Opioid Receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled Receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into Opioid Receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction. The crystal structure of the mouse μ-Opioid Receptor bound to an antagonist is described, with possible implications for the future development of analgesics. Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known Opioid Receptors in ligand-bound conformations. These G-protein-coupled Receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-Opioid Receptor bound to a morphinan antagonist and the δ-Opioid Receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-Opioid Receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ Receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying Receptor function and drug development.
Aashish Manglik - One of the best experts on this subject based on the ideXlab platform.
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structural insights into µ Opioid Receptor activation
Nature, 2015Co-Authors: Weijiao Huang, Aashish Manglik, A J Venkatakrishnan, Toon Laeremans, Evan N Feinberg, Adrian L Sanborn, Hideaki E Kato, Kathryn E Livingston, T S Thorsen, Ralf C KlingAbstract:Activation of the μ-Opioid Receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 A X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic Receptor (β2AR) and the M2 muscarinic Receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled Receptors. X-ray crystallography and molecular dynamics simulations of the μ-Opioid Receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled Receptor that are associated with its activation. The μ-Opioid Receptor is a G-protein-coupled Receptor (GPCR) activated by various analgesics, endogenous endorphins and drugs of abuse such as heroin and opium. Our understanding of the mechanism by which agonist binding leads to recognition, coupling, and activation of a particular G protein subtype is incomplete. In two papers in this issue of Nature, the authors used X-ray crystallography, molecular dynamics simulations, and NMR spectroscopy to probe the structural basis for Receptor activation. As well as revealing the conformational changes in the extracellular and intracellular domains of this GPCR associated with Receptor activation, these studies help explain why the allosteric coupling between the agonist-binding pocket and the cytoplasmic G-protein-coupling interface of this Receptor is relatively weak.
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structure of the δ Opioid Receptor bound to naltrindole
Nature, 2012Co-Authors: Sebastien Granier, Aashish Manglik, Andrew C Kruse, Tong Sun Kobilka, Foon Sun Thian, William I Weis, Brian K KobilkaAbstract:The X-ray crystal structure of the mouse δ-Opioid Receptor in complex with the subtype-selective antagonist naltrindole is reported. Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known Opioid Receptors in ligand-bound conformations. These G-protein-coupled Receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-Opioid Receptor bound to a morphinan antagonist and the δ-Opioid Receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-Opioid Receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ Receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying Receptor function and drug development. The Opioid Receptor family comprises three members, the µ-, δ- and κ-Opioid Receptors, which respond to classical Opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled Receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-Opioid Receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood1. The structures of the µ-OR and κ-OR have recently been solved2,3. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the µ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of Opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of Opioid Receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among Opioid Receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of Opioid Receptor pharmacology4,5, in which distinct ‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.
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crystal structure of the µ Opioid Receptor bound to a morphinan antagonist
Nature, 2012Co-Authors: Aashish Manglik, Andrew C Kruse, Tong Sun Kobilka, Foon Sun Thian, William I Weis, Brian K Kobilka, Jesper Mosolff Mathiesen, Roger K Sunahara, Leonardo Pardo, Sebastien GranierAbstract:Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical Opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-Opioid Receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled Receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into Opioid Receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction. The crystal structure of the mouse μ-Opioid Receptor bound to an antagonist is described, with possible implications for the future development of analgesics. Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known Opioid Receptors in ligand-bound conformations. These G-protein-coupled Receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-Opioid Receptor bound to a morphinan antagonist and the δ-Opioid Receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-Opioid Receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ Receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying Receptor function and drug development.