The Next Frontier in the Molecular Biology of the Opioid System

The Opioid Receptor
  • Olivier Civelli
  • Curtis Machida
  • James Bunzow
  • Paul Albert
  • Eric Hanneman
  • John Salon
  • Jean Bidlack
  • David Grandy
Part of the Molecular Neurobiology book series (MN)

Abstract

The analgesic and euphoric properties of some plant alkaloids such as morphine have been known and exploited for centuries. In contrast, only during the last twenty years have we begun to unravel the molecular basis by which opiates exert their effects, mechanisms important to our general understanding of the nervous system. The analgesic response to opiates is the result of a cascade of biochemical events that are triggered by the interaction of the opiate with specific macromolecular components found on the membranes of nervous system tissues, the opioid receptors. The endogenous ligands of these receptors are small peptides, the opioid peptides. Although much has been learned about the structures and the mode of synthesis of the opioid peptides, little is understood about the structure of their receptors. The application of molecular genetic techniques was of great importance to the studies of the opioid peptides. It is now expected that this same technology will unravel the physical mysteries of the opioid receptors.

Index Entries

Opioid receptors molecular biology physical characteristics of the different types of opioid receptors 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Amano T., Richelson E., and Nirenberg M. (1972) Neurotransmitter synthesis by neuroblastoma clones. Proc. Natl. Acad. Sci. USA 69, 258–263.PubMedCrossRefGoogle Scholar
  2. Attali B., Gouarderes C., Mazaguil H., Audigier Y., and Cros J. (1982) Evidence of multiple “kappa” binding sites by use of opioid peptides in the guinea pig lumbro-sacral spinal cord. Neuropeptides 3, 53–64.PubMedCrossRefGoogle Scholar
  3. Atweh S. F. and Kuhar M. J. (1983) Distribution of physiological significance of opioid receptors in the brain. Br. Med. Bull. 39, 47–52.PubMedGoogle Scholar
  4. Bidlack J. M., Abood L. G., Osei-Guinah P., and Archer S. (1981) Purification of the opiate rceptor from rat brain. Proc. Natl Acad. Sci. USA 78, 636–639.PubMedCrossRefGoogle Scholar
  5. Blume A. J. (1978) Opiate binding to membrane preparations of neuroblastoma X glioma hybrid cells NG108–15: effects of ions and nucleotides. Life Sci. 22, 1843–1852.PubMedCrossRefGoogle Scholar
  6. Bonner T. I., Buckle N. J., Young A. C, and Brann M. R. (1987) Identification of a family of muscarinic acetylcholine receptor genes. Science 237, 527–532.PubMedCrossRefGoogle Scholar
  7. Bowen W. D., Gentleman S., Herkenham M., and Pert C. B. (1981) Interconverting mu and delta forms of the opiate receptor in rat stiatal patches. Proc. Natl. Acad. Sci. USA 78, 4818–4822.PubMedCrossRefGoogle Scholar
  8. Chang K.-J., Cooper B. R., Hazum E., and Cuatrecasas P. (1979) Multiple opiate receptors: Different regional distribution in the brain and differential binding of opiates and opioid peptides. Mol. Pharmacol. 16, 91–104.PubMedGoogle Scholar
  9. Chang K.-J., Hazum E., and Cuatrecasas P. (1981) Novel opiate binding sites selective for benzomorphan drugs. Proc. Natl. Acad. Sci. USA 78, 4141–4145.PubMedCrossRefGoogle Scholar
  10. Cheng Y. C. and Prusoff W. H. (1973) Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099–3108.PubMedCrossRefGoogle Scholar
  11. Cho T. M., Hasegawa J. I., Ge B. L., and Loh H. H. (1986) Purification to apparent homogeneity of a mu-type opioid receptor from rat brain. Proc. Natl. Acad. Sci. USA 83, 413–4142.CrossRefGoogle Scholar
  12. Civelli O., Douglass J., Goldstein A., and Herbert E. (1985) Sequence and expression of the rat pro-dynorphin gene. Proc. Natl. Acad. Sci. USA 82, 4291–4295.PubMedCrossRefGoogle Scholar
  13. Comb M., Seeburg P. H., Adelman J., Eiden L., and Herbert E. (1982) Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. Nature 295, 663–666.PubMedCrossRefGoogle Scholar
  14. Dixon R. A., Koblika B. K., Strader D. J., Benovic J. L., Dohlman H. G., Frielle T., Bolanowski M. A., Bennett C. D., Rands E., Diehl R. E., Mumford R. A., Slater E. E., Sigal I. S., Caron M. G., Lefkovitz R. J., and Strader C. D. (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321, 75–79.PubMedCrossRefGoogle Scholar
  15. Dole V. P., Cuatrecasas P., and Goldstein A. (1975) Criteria for receptors in Opiate receptor mechanisms, Snyder S. H., and Matthysse E., eds., MIT Press, Camgbride, MA, pp. 24–26.Google Scholar
  16. Frederickson R. C. A., Smithwick E. L., and Shuman R. (1981) Metkephamid, a systemically active analog of methionine enkephalin with potent opioid delta-receptor activity. Science 221, 603–605.CrossRefGoogle Scholar
  17. Gilbert P. E. and Martin W. R. (1976) The effects of morphine- and nalorphine-like drugs in the non-dependent, morphine-dependent and cyclazoc-ine-dependent chronic spinal dog. J. Pharmacol Exp. Ther. 198, 66–82.Google Scholar
  18. Gioannini T., Howard A. D., Hiller J. M., and Simon E. J. (1985) Purification of an active opioid-bind-ing protein from bovine striatum. J. Biol Chem. 260, 15117–15121.Google Scholar
  19. Goldstein A., Tachibana S., Lowney L. I., Hunkapiller M., and Hood L. (1979) Dynorphin (1–13), an extraordinarily potent opioid peptide. Proc. Natl. Acad. Sci. USA 76, 6666–6670.PubMedCrossRefGoogle Scholar
  20. Grenningloh G., Rienitz A., Schmitt B., Methfessel C., Zensen M., Beyreuther K., Gundelfinge E. D., and Betz H. (1987) The strychnine-binding sub-unit of the glycine receptor shows homology with nicotine acetylcholine receptors. Nature 328, 215–220.PubMedCrossRefGoogle Scholar
  21. Grevel J., Yu V., and Sadee W. (1985) Characterization of a labile naloxone binding site (lambda site) in rat brain. J. Neurochem. 44, 1647–1656.CrossRefGoogle Scholar
  22. Gross R. A. and MacDonald R. L. (1987) Dynorphin A selectively reduces a large transient (N-type) calcium current of mouse dorsal root ganglion neurons in cell culture. Proc. Natl. Acad. Sci. USA 84, 5469–5473.PubMedCrossRefGoogle Scholar
  23. Grundersen C. B., Miledi R., and Parker I. (1984) Messenger RNA from human brain induces drug- and voltage-operated channels in Xenopus oocytes. Nature 308, 421–424.CrossRefGoogle Scholar
  24. Gubler U., Seeburg P. H., Gage L. P., and Udenfriend S. (1982) Molecular cloning establishes pro-enkephalin as precursor of enkephalin-contain-ing peptides. Nature 295, 206–209.PubMedCrossRefGoogle Scholar
  25. Hall Z. A. (1987) Three of a kind: the beta-adrenergic receptor, the muscarinic acetylcholine receptor, and rhodopsin. Trends in Neuro Sci. 10, 99–100.CrossRefGoogle Scholar
  26. Hedrick S. M., Cohen D. I., Nielsen E. A., and Davis M. M. (1984) Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149–153.PubMedCrossRefGoogle Scholar
  27. Herbert E., Birnberg N., Lissitsky J. C., Civelli O., and Uhler M. (1981) Proopiomelanocortin: A model for the regulation of expression of neuropeptides in pituitary and brain. Neurosa. News-lett. 1, 16–27.Google Scholar
  28. Hill A. V. (1910) A new mathematical treatment of changes of ionic concentration in muscle and nerve under the action of electric currents, with a theory as to their mode of excitation. J. Physiol. (London) 40, iv-viii.Google Scholar
  29. Hiller J. M., Pearson J., and Simon E. J. (1973) Distribution of stereo-specific binding of the potent narcotic analgesic etorphine in the human brain: Predominance in the limbic system. Res. Commun. Chem. Pathol Pharmacol. 6, 1052–1062.Google Scholar
  30. Holaday J. W. (1985) Endogenous opioids and their receptors, Current Concepts, The Upjohn Company, Kalamazoo, MI, pp. 1–64.Google Scholar
  31. Howard A. D., de La Baume S., Gioannini T. L., Hiller J. M., and Simon E. J. (1985) Covalent labeling of opioid receptors with radioiodinated human beta-endorphin. J. Biol Chem. 260, 10833–10839.PubMedGoogle Scholar
  32. Hughes J. and Kosterlitz H. W. (1983) Introduction to the opioid peptide systems. Brit. Med. Bull. 39, 1–3ff.PubMedGoogle Scholar
  33. Hughes J., Smith T. W., Kosterlitz H. W., Fothergill L. A., Morgan B. A., and Morris H. R. (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature (London) 258, 577–579.CrossRefGoogle Scholar
  34. Kakidani H., Furutani Y., Takahashi H., Noda M., Morimoto Y., Hirose T., Asai M., Inayama S., Nakanishi S., and Numa S. (1982) Cloning and sequence analysis of cDNA for porcine beta-neoen-dorphin/dynorphin precursors. Nature 298, 245–249.PubMedCrossRefGoogle Scholar
  35. Klee W. A. and Nirenberg M. (1974) A neuroblastoma X glioma hybrid cell line with morphine receptors. Proc. Natl. Acad. Sci. USA 71, 3474–3477.PubMedCrossRefGoogle Scholar
  36. Klee W. A., Sharman S. K., and Nirenberg M. (1975) Opiate receptors as regulators of adenylate cyclase. Life Sci. 16, 1869–1874.PubMedCrossRefGoogle Scholar
  37. Koski G. and Klee W. A. (1981) Opiates inhibit adenylate cyclase by stimulating GTP hydrolysis. Proc. Natl. Acad. Sci. USA 78, 4185–4186.PubMedCrossRefGoogle Scholar
  38. Kosterlitz H. W. (1985) Opioid peptides and their receptors. Proc. R. Soc. Lond. B 225, 27–40.PubMedCrossRefGoogle Scholar
  39. Kosterlitz H. W. and Waterfield A. A. (1975) In vitro models in the study of structure-activity relationships of narcotic analysis. Ann. Rev. Pharmacol. Toxicol 15, 29–47.Google Scholar
  40. Kubo T., Fukuda K., Mikami A., Maeda A., Takahashi H., Mishina M., Haga T., Haga K., Ichiyama A., Kangawa K., Kojima M., Matsuo H., Hirose T., and Numa S. (1986a) Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature 323, 411–416.PubMedCrossRefGoogle Scholar
  41. Kubo T., Maeda A., Sugimoto K., Akiba I., Mikami A., Takahashi H., Haga T., Haga K., Ichiyama A., Kangawa K., Matsuo H., Hirose T., and Numa S. (1986b) Primary structure of porcine cardiac muscarinic acetylcholine receptor deduced from the cDNA sequence. FEBS Lett 209, 367–372.PubMedCrossRefGoogle Scholar
  42. Kuhar M. J., Pert C. B., and Snyder S. H. (1973) Regional distribution of opiate receptor binding in monkey and human brain. Nature 245, 447–451.PubMedCrossRefGoogle Scholar
  43. Loh H. H., Tseng L. F., Wei E., and Li C. H. (1976) Beta-endorphin is a potent analgesic agent. Proc. Natl. Acad. Sci. USA 73, 2895–2898.PubMedCrossRefGoogle Scholar
  44. Lord J. A. H., Waterfield A. A., Hughes J., and Kosterlitz H. W. (1971) Endogenous opioid peptides: Multiple agonists and receptors. Nature 267, 495–499.CrossRefGoogle Scholar
  45. Lubbert H., Hoffman B. J., Snutch T. P., van Dyke T., Levine A. J., Hartig P. R., Lester H. A., and Davidson N. (1987) cDNA cloning of a serotonin 5-HTAC receptor by electrophysiological assays of mRNA-injected Xenopus oocytes. Proc. Natl Acad. Sci. USA, 84, 4332–4336.PubMedCrossRefGoogle Scholar
  46. Malfroy B., Swerts J. P., and Guyan A. (1978) High affinity enkephalin-degrading peptidase in brain is increased after morphine. Nature 276, 523–526.PubMedCrossRefGoogle Scholar
  47. Maneckjee R., Zukin R. S. Archer S., Michael J., and Osei-Gyimah P. (1985) Purification and characterization of the mu opiate receptor from rat brain using affinity chromatography. Proc. Natl. Acad. Sci. USA 82, 594–598.PubMedCrossRefGoogle Scholar
  48. Mansour A., Khachaturian H., Lewis M. E., Akil H., and Watson S. J. (1987) Autoradiographic differentiation of mu, delta and kappa opioid receptors in the rat forebrain and midbrain. J. of Neurose. 7, 2445–2464.Google Scholar
  49. Martín W. R., Eades C. G., Thompson J. A., Huppler R. E., and Gilbert P. E. (1976) The effects of morphine- and nalorphine-like drugs in the nonde-pendent and morphine-dependent chronic spinal dog. J. Pharmacol Exp. Ther. 197, 517–532.PubMedGoogle Scholar
  50. McKnight A. T., Corbett A. D., and Kosterlitz H. W. (1983) Increase in potencies of opioid peptides after peptidase inhibition. Eur. J. Pharmacol. 86, 393–402.PubMedCrossRefGoogle Scholar
  51. Morley J. E., Levine A. S., Yim G. K., and Lowy M. T. (1983) Opioid modulation of appetite. Neurosci. Biobehav. Rev. 7, 281–305.PubMedCrossRefGoogle Scholar
  52. Nakanishi S., Inoue A., Kita T., Nakamura M., Chang A. C. Y., Cohen S. N., and Numa S. (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-beta-lipotropin precursor. Nature 278, 423–427.PubMedCrossRefGoogle Scholar
  53. Nathans J. and Hogness D. S. (1983) Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin. Cell 34, 807–814.PubMedCrossRefGoogle Scholar
  54. Newman E. L. and Barnard E. A. (1984) Identification of an opioid receptor subunit carrying the mu binding site. Biochemistry 23, 5385–5389.PubMedCrossRefGoogle Scholar
  55. Ninkovic M., Hunt S. P., Emson P. C., and Iversen L. L. (1981) The distribution of multiple opiate receptors in bovine brain. Brain Res. 214, 163–167.PubMedCrossRefGoogle Scholar
  56. Noda M., Furutani Y., Takahashi H., Toyosato M., Hirose T., Inayama S., Nakanishi S., and Numa S. (1982) Cloning and sequence analysis of cDNA for bovine adrenal preproenkephalin. Nature 295, 202–206.PubMedCrossRefGoogle Scholar
  57. Noda M., Takahashi H., Tanabe T., Toyosato M., Furutani Y., Hirose T., Asai M., Inayama S., Miyata T., and Numa S. (1982) Primary structure of alpha-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence. Nature 299, 793–797.PubMedCrossRefGoogle Scholar
  58. Noda M., Takahashi H., Tanabe T., Toyosato M., Kikyotani S., Hirose T., Asai M., Takashima H., Inayawa S., Miyata T., and Numa S. (1983) Primary structures of beta- and delta-subunit precursors of Torpedo californica acetylcholine receptor deduced from cDNA sequences. Nature 301, 251–255.PubMedCrossRefGoogle Scholar
  59. North R. A. (1979) Minireview: Opiates, opioid peptides and single neurons. Life Sci. 24, 1527–1546.PubMedCrossRefGoogle Scholar
  60. North R. A. and Williams J. T. (1983) Opiate activation of potassium conductance inhibits calcium action potentials in rat locus coeruleus neurons. Br. J. Pharmacol 80, 225–228.PubMedGoogle Scholar
  61. North R. A., Williams J. T., Surprenant A., and Christie M. J. (1987) Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc. Natl Acad. Sci. USA 84, 5487–5491.PubMedCrossRefGoogle Scholar
  62. Okayama M. and Berg P. (1982) High-efficiency cloning of full-length cDNA. Mol. Cell. Biol. 2, 161–170.PubMedGoogle Scholar
  63. Pasternak G. W., Gintzler A. R., Houghton R. A., Ling G. S. F., Goodman R. R., Spiegel K., Nishmura S., Johnson N., and Recht L. D. (1983) Biochemical and pharmacological evidence for opioid receptor multiplicity in the central nervous system. Life Sci. (Suppl. 1) 33, 167–173.Google Scholar
  64. Paterson S. J., Robson L. E., and Kosterlitz H. W. (1984) Opioid receptors in the peptides, vol. 6, Udenfriend S. and Meinhofer J., eds., Academic London, pp. 147–187.Google Scholar
  65. Peralta E. G., Winslow J. W., Peterson G. L., Smith D. H., Ashkenazi A., Ramachandran J., Schimerlik M. I., and Capon D. J. (1987) Primary structure and biochemical properties of an M2 muscarnic receptor. Science 236, 600–605.PubMedCrossRefGoogle Scholar
  66. Pert C. B. and Snyder S. H. (1973) Opiate receptor: Demonstration in nervous tissue. Science 179, 1011–1014.PubMedCrossRefGoogle Scholar
  67. Pfeiffer A., Pasi A., Mehraein P., and Herz A. (1982) Opiate receptor binding sites in human brain. Brain REs. 248, 87–96.PubMedCrossRefGoogle Scholar
  68. Portoghese P. S. (1965) A new concept on the mode of interaction of narcotic analgesics with receptors. J. Med. Chem. 8, 609–619.CrossRefGoogle Scholar
  69. Robson L. E. and Kosterlitz H. W. (1979) Specific protection of the binding site of D-Ala2-D-Leu2-enkephalin (delta receptors) and dihydromor-phine (mu receptors). Proc. R. Soc. Lond. (Biol) 205, 425–432.CrossRefGoogle Scholar
  70. Sasahi K. and Sato M. (1987) A single GTP-binding protein regulates K+-channels coupled with dopamine, histamine and acetylcholine receptors. Nature 328, 221–227.CrossRefGoogle Scholar
  71. Scatchard G. (1949) The attractions of proteins for small molecules and ions. Ann. NY Acad. Sci. 51, 660–674.CrossRefGoogle Scholar
  72. Schofield P. R., Darlison M. G., Fujita N., Burt D. R., Stephenson F. A., Rodriguez H., Rhee L. M., Ramachandran J., Reale V., Glencourse T. A., Seeburg P. H., and Barnard E. A. (1987) Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor superfamily. Nature 328, 221–227.PubMedCrossRefGoogle Scholar
  73. Schulz R., Wuster M., and Herz A. (1981) Pharmacological characterization of the Epsilon-opiate receptor. J. Pharmacol Exp. Ther. 216, 604–606.Google Scholar
  74. Schwyzer R., Karlaganis G., and Lang U. (1980) Hormone-receptor interactions: A study of the molecular mechanism of receptor stimulation in isolated fat cells by the partial agonist corti-cotropin-(5–24)-icosapeptide. Frontiers of Bioor-ganic Chemistry and Molecular Biology, Ananchenko S. N., ed., Pergamon, Oxford and NY, pp. 277–283.Google Scholar
  75. Simon E. J., Bonnet K. A., Crain S. M., Groth J., Hiller J. M., and Smith J. R. (1980) Recent studies on interaction between opioid peptides and their receptors. Neural Peptides and Neuronal Communication, Costa E., and Trabucchi M., eds., pp. 335–346.Google Scholar
  76. Simon E. J. and Groth J. (1975) Kinetic of opiate receptors, inactivation by sulfhydryl reagents: Evidence for conformational change in presence of sodium ions. Proc. Natl Acad. Sci. USA 72, 2404–2407.PubMedCrossRefGoogle Scholar
  77. Simon E. J., Hiller J. M., and Edelman I. (1973) Stere-ospecific binding of the potent narcotic analgesic 3H-etorphine to rat brain homogenate. Proc. Natl. Acad. Sci. USA 70, 1947–1949.PubMedCrossRefGoogle Scholar
  78. Simonds W. F., Burke T. R., Rice K. C., Jacobson A. E., and Klee W. A. (1985) Purification of the opiate receptor of NG108–15 neuroblatoma-glioma hybrid cells. Proc. Natl. Acad. Sci. USA 82, 4974–4978.PubMedCrossRefGoogle Scholar
  79. Smith, J. R. and Simon E. J. (1980) Selective protection of stereospecific enkephalin and opiate binding against inactivation by N-ethylmaleimide evidence for two classes of receptors. Proc. Natl. Acad. Sci. USA 77, 281–284.PubMedCrossRefGoogle Scholar
  80. Southern P. J. and Berg P. (1982) Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J. Mol Appl. Genet. 1, 327–341.PubMedGoogle Scholar
  81. Stevens C. F. (1987) Channel families in the brain. Nature 328, 198–199.PubMedCrossRefGoogle Scholar
  82. Terenius L. (1973) Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol. Toxicol. Copen. 32, 317–320.CrossRefGoogle Scholar
  83. Teschemacher H. and Schweigerer L. (1985) Opioid Peptides: do they have immunological significance. Trends in Pharmacol. Sci. 12, 368–370.CrossRefGoogle Scholar
  84. Weber E., Esch F. S., Bohlen P., Paterson S., Corbett A. D., McKnight A. T., Kosterlitz H. W., Barchas J. D., and Evans C. J. (1983) Metorphamide: Isolation, structure, and biological activity of an ami-dated opioid octapeptide from bovine brain. Proc. Natl Acad. Sci. USA 80, 7362–7366.PubMedCrossRefGoogle Scholar
  85. Wei E. and Loh H. H. (1976) Physical dependence on opiate-like peptides. Science 193, 1262–1263.PubMedCrossRefGoogle Scholar
  86. Werz M. A. and MacDonald R. L. (1982) Heterogeneous sensitivity of cultured dorsl root ganglian neurons to opioid peptides selective for mu- and delta-opiate receptors. Nature (London) 299, 730–733.CrossRefGoogle Scholar
  87. Werz M. A. and MacDonald R. L. (1983) Opioid peptides with differential affinity for mu- and delta-receptors decrease sensory neuron calcium-dependent action optentials. J. Pharmacol Exp. Ther. 227, 394–402.PubMedGoogle Scholar
  88. West R. E. and Miller R. J. (1983) Opiates, second messengers and cell response. Br. Med. Bull 39, 53–58.PubMedGoogle Scholar
  89. Williams J. T., Egan T. M., and North R. A. (1982) Enkephalin opens potassium channels on mammalian central neurons. Nature 299, 74–77.PubMedCrossRefGoogle Scholar
  90. Yatani A., Codina J., Brown A. M., and Birnbaumer L. (1987) Direct activation of mammalian atrial muscarinic potassium channels by GTP regulatory protein Gk. Science 235, 207–211.PubMedCrossRefGoogle Scholar
  91. Young D., Waitches G., Birchmeier C., Fasno O., and Wigler M. (1986) Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell 45, 711–719.PubMedCrossRefGoogle Scholar
  92. Zukin R. S. and Maneckjee R. (1986) Solubilization and characterization of opiate receptors. Meth. in Enzymol 124, 172–190.CrossRefGoogle Scholar

Copyright information

© The Humana Press Inc. 1988

Authors and Affiliations

  • Olivier Civelli
    • 1
    • 2
  • Curtis Machida
    • 1
    • 2
  • James Bunzow
    • 1
    • 2
  • Paul Albert
    • 1
    • 2
  • Eric Hanneman
    • 1
    • 2
  • John Salon
    • 1
    • 2
  • Jean Bidlack
    • 1
    • 2
  • David Grandy
    • 1
    • 2
  1. 1.Vollum Institute for Advanced Biomedical ResearchThe Oregon Health Sciences UniversityPortlandUSA
  2. 2.Department of PharmacologyUniversity of RochesterRochesterUSA

Personalised recommendations