Mu Opioids and Their Receptors: Evolution of a Concept
Reads0
Chats0
TLDR
Understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years, which now reveals a complexity of the morphine- like agents andtheir receptors that had not been previously appreciated.Abstract:
Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes—primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.read more
Citations
More filters
Journal ArticleDOI
Structure-based discovery of opioid analgesics with reduced side effects
Aashish Manglik,Henry Lin,Dipendra K. Aryal,John D. McCorvy,Daniela Dengler,Gregory Corder,Anat Levit,Ralf C. Kling,Ralf C. Kling,Viachaslau Bernat,Harald Hübner,Xi Ping Huang,Maria F. Sassano,Patrick M. Giguère,Stefan Löber,Da Duan,Grégory Scherrer,Brian K. Kobilka,Peter Gmeiner,Bryan L. Roth,Brian K. Shoichet +20 more
TL;DR: PZM21 is a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses.
Journal ArticleDOI
Structural insights into µ-opioid receptor activation
Weijiao Huang,Aashish Manglik,AJ Venkatakrishnan,Toon Laeremans,Evan N. Feinberg,Adrian L. Sanborn,Hideaki E. Kato,Kathryn E. Livingston,Thor S. Thorsen,Ralf C. Kling,Sébastien Granier,Peter Gmeiner,Stephen M. Husbands,John R. Traynor,William I. Weis,Jan Steyaert,Ron O. Dror,Brian K. Kobilka +17 more
TL;DR: A 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment is reported, revealing 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.
Journal ArticleDOI
Opioid-induced hyperalgesia: Cellular and molecular mechanisms.
TL;DR: The molecular actors identified include the Toll-like receptor 4 and the anti-opioid systems as well as some other excitatory molecules, receptors, channels, chemokines, pro-inflammatory cytokines or lipids, which contribute to OIH.
Journal ArticleDOI
Breaking barriers to novel analgesic drug development
TL;DR: Recent advances in the understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.
Journal ArticleDOI
Transition-Metal-Catalyzed Selective Functionalization of C(sp3 )-H Bonds in Natural Products.
TL;DR: Advances in the transition-metal-catalyzed functionalization of C(sp3 )-H bonds have allowed natural product derivatives to be created selectively and strategies to achieve such transformation are reviewed.
References
More filters
Journal ArticleDOI
Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests
TL;DR: A large degree of genetically‐determined variability in sensitivity to painful stimuli is demonstrated, and inherent differences in sensitive stimuli may be responsible, in part, for individual differences in the potency of morphine's antinociceptive effects.
Journal ArticleDOI
Spinal analgesic activity of orphanin FQ/nociceptin and its fragments
TL;DR: Antisense probes targeting the second and third coding exons, but not the first exon, of the cloned mouse OFQ/nociceptin receptor (KOR-3) partially block OfQ/N analgesia.
Journal ArticleDOI
Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice.
José Manuel Entrena,Enrique J. Cobos,Francisco R. Nieto,Cruz Miguel Cendán,Georgia Gris,Esperanza Del Pozo,Daniel Zamanillo,José M. Baeyens +7 more
TL;DR: It is suggested that σ1 receptors are essential for capsaicin‐induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.
Journal ArticleDOI
Interaction of endogenous opioid peptides and other drugs with four kappa opioid binding sites in guinea pig brain.
Richard B. Rothman,Victor Bykov,Brian R. de Costa,Arthur E. Jacobson,Kenner C. Rice,Linda S. Brady +5 more
TL;DR: Quantitative autoradiographic studies demonstrated that kappa 2a and kapp 2b binding sites are heterogeneously distributed in guinea pig brain, and that the anatomical distribution of kappa 1 binding sites reported in the literature is different from that observed in this study for the kappa2 binding sites.
Journal ArticleDOI
Double in situ hybridization study on coexistence of μ-, δ- and κ-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia
TL;DR: The results suggest that mu- and kappa-OPRs exist on most of and a part of the primary afferent terminals containing SP, respectively, and suggest the possibility that OPRs co-exist with other neurotransmitters and/or neuromodulators than SP in thePrimary afferent neurons.
Related Papers (5)
Structural insights into µ-opioid receptor activation
Weijiao Huang,Aashish Manglik,AJ Venkatakrishnan,Toon Laeremans,Evan N. Feinberg,Adrian L. Sanborn,Hideaki E. Kato,Kathryn E. Livingston,Thor S. Thorsen,Ralf C. Kling,Sébastien Granier,Peter Gmeiner,Stephen M. Husbands,John R. Traynor,William I. Weis,Jan Steyaert,Ron O. Dror,Brian K. Kobilka +17 more
Structure-based discovery of opioid analgesics with reduced side effects
Aashish Manglik,Henry Lin,Dipendra K. Aryal,John D. McCorvy,Daniela Dengler,Gregory Corder,Anat Levit,Ralf C. Kling,Ralf C. Kling,Viachaslau Bernat,Harald Hübner,Xi Ping Huang,Maria F. Sassano,Patrick M. Giguère,Stefan Löber,Da Duan,Grégory Scherrer,Brian K. Kobilka,Peter Gmeiner,Bryan L. Roth,Brian K. Shoichet +20 more