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The excitatory response of in vitro hippocampal pyramidal cells to normorphine and methionine-enkephalin may be mediated by different receptor populations


As shown previously, opiate agonists increase the excitability of hippocampal pyramidal cells in a naloxone-reversible manner. In the present study, the degree of excitability was measured by population spike size recorded from hippocampus slices (CA1) obtained from naive or chronically morphinized rats. Cross tolerance could not be demonstrated to occur between met-enkephalin and normorphine in hippocampal cells made tolerant to morphine: the potent stimulatory effect of metenkephaline remains when applied to hippocampal slices removed from chronically morphinized rats, whereas normorphine was no longer effective. When these slices are washed or exposed to naloxone a diminution of the population spike occurs. These results suggest that while both opiate agonists increase neuronal excitability of hippocampal pyramidal cells, this effect is most likely mediated via different receptor populations.

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  1. Andersen P, Bliss TVP, Skeede KK (1971) Unit analysis of the hippocampal population spike. Exp Brain Res 13: 208–221

  2. Bläsig J, Herz A, Reinhold K, Zieglgänsberger S (1973) Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 33: 19–38

  3. Bläsig J, Meyer G, Höllt V, Hengstenberg J, Dum J, Herz A (1979) Non-competitive nature of the antagonistic mechanism responsible for the tolerance development to opiate-induced analgesia. Neuropharmacology 18: 473–481

  4. Bloom FE, Bayon A, Battenberg E, French E, Koda L, Koob G, LeMoal M, Rossier J, Shoemaker W (1980) Endorphins: Developmental, cellular and behavioural aspects. In: Costa E, Trabucchi M (eds) Advances in biochemical psychopharmacology. Raven Press, New York, pp 619–632

  5. Bowen WD, Gentleman S, Herkenham M, Pert CB (1981) Interconverting mu and delta forms of the opiate receptor in rat striatal patches. Proc Natl Acad Sci USA 78: 4818–4822

  6. Chang K-J, Cuatrecasas P (1979) Multiple opiate receptors. J Biol Chem 254: 2610–2618

  7. Corrigall WA, Linseman MA (1980a) GABA and hippocampal inhibition. Br J Pharmacol 40: 881–883

  8. Corrigall WA, Linseman MA (1980b) A specific effect of morphine on evoked activity in the rat hippocampal slice. Brain Res 192: 227–238

  9. Corrigall WA, Linseman MS, Lucato R, Elliott M (1981) Differential tolerance to the effects of morphine on evoked activity in the hippocampal slice. Life Sci 28: 1613–1620

  10. Deadwyler SA, Robinson JH (1979) Effects of morphine or hippocampal cells recorded in vitro. Brain Res Bull 4: 609–613

  11. Duka T, Wüster M, Schubert P, Stoiber R, Herz A (1981) Selective localization of different types of opiate receptors in hippocampus as revealed by in vitro autoradiography. Brain Res 205: 181–186

  12. Dunwiddie TA, Mueller M, Palmer J, Stewart J, Hoffer B (1980) Electrophysiological interactions of enkephalins with neuronal circuitry in the rat hippocampus. I. Effects on pyramidal cell activity. Brain Res 184: 311–330

  13. Fry JP, Herz A, Zieglgänsberger W (1980) A demonstration of naloxone-precipitated opiate withdrawal on single neurones in the morphine tolerant/dependent rat brain. Br J Pharmacol 68: 585–592

  14. Gähwiler BH (1980) Excitatory action of opioid peptides and opiates on cultured hippocampal pyramidal cells. Brain Res 194: 193–203

  15. Gall C, Brecha N, Karten HJ, Chang KJ (1981) Localization of enkephalin-like immunoreactivity to identified axonal and neuronal population of the rat hippocampus. J Comp Neurol 198: 335–350

  16. Gillan MGC, Kosterlitz HW, Paterson SJ (1980) Comparison of the binding characteristics of tritiated opiates and opioid peptides. Br J Pharmacol 70: 481–490

  17. Goodman RR, Snyder SH, Kuhar MJ, Young WS (1980) Differentiation of delta and mu opiate receptor localization by light microscopic autoradiography. Proc Natl Acad Sci USA 77: 6239–6243

  18. Gorenstein C, Snyder SH (1979) Characterization of enkephalinases. In: Way EL (ed) Endogenous and exogenous opiate agonists and antagonistis. Raven Press, New York, pp 345–348

  19. Guyon A, Rocques BP, Guyon F, Foucault A, Perdrisot R, Swerts JP, Schwartz JC (1979) Further characterization and kinetics of appearance of hydrolysis products of met-enkephalin. In: Way EL (ed) Endogenous and exogenous opiate agonists and antagonists. Raven Press, New York, pp 349–352

  20. Henriksen SJ, Bloom FE, McCoy F, Ling N, Guillemin R (1978) Beta-endorphin induced nonconvulsive limbic seizures. Proc Natl Acad Sci USA 75: 5221–5225

  21. Herkenham M, Pert CB (1980) In vitro autoradiography of opiate receptors in rat brain suggest loci of “opiatergic” pathways. Proc Natl Acad Sci USA 77: 5532–5536

  22. Hill RG, Mitchell JF, Pepper CM (1977) The excitation and depression of hippocampal neurones by iontophoretically applied enkephalins. J Physiol (Lond) 272: 50–51

  23. Hökfelt T, Elde R, Johansson O, Terenius L, Stein L (1977) The distribution of enkephalin immunoreactive cell bodies in the rat central nervous system. Neurosci Lett 5: 25–31

  24. Hughes J, Smith TW, Kosterlitz H, Fothergill L, Morgan B, Morris H (1975) Identification of two related pentapetides from the brain with potent opiate agonist activity. Nature 258: 577–579

  25. Hutchinson M, Kosterlitz HW, Leslie FM, Waterfield AA, Terenius L (1975) Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey. Br J Pharmacol 55: 541–546

  26. Kosterlitz HW, Waterfield AA, Gillan MGC, Paterson SJ (1978) Assessment of analogues of opioid peptides in four parallel assays. Bull Problems Drug Dependence 40: 139–150

  27. Lee HK, Dunwiddie T, Hoffer B (1980) Electrophysiological interactions of enkephalins with neuronal circuitry in the rat hippocampus. II. Effects on interneuron excitability. Brain Res 184: 331–342

  28. Leslie FM, Kosterlitz HW (1979) Comparison of binding of 3H- methionine-enkephalin, 3H-naltrexone and 3H-dihydromor phine in the mouse vas deferens and the myenteric plexus and brain of the guinea-pig. Eur J Pharmacol 56: 379–383

  29. Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1976) Multiple opiate receptors. In: Kosterlitz HW (ed) Opiates and endogenous opioid peptides. North Holland, Amsterdam, pp 275–280

  30. Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: Multiple agonists and receptors. Nature 267: 495–499

  31. Lynch G, Schubert P (1980) The use of in vitro brain slices for multidisciplinary studies of synaptic function. Ann Rev Neurosci 3: 1–22

  32. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197: 517–532

  33. Martinez JL jr, Jensen RA, Creagrer R, VeLiquette J, Messing RB, McGaugh JL, Lynch G (1979) Selective effects of enkephalin on electrical activity of the in vitro hippocampal slice. Behav Neur Biol 26: 128–131

  34. Nicoll RA, Siggins GR, Ling N, Bloom FE, Guillemin R (1977) Neuronal actions of endorphin and enkephalins among brain regions: A comparative microiontophoretic study. Proc Natl Acad Sci USA 74: 2584–2588

  35. Nicoll RA, Alger BE, Jahr CE (1980) Enkephalin blocks inhibitory pathways in the vertebrate CNS. Nature 287: 22–25

  36. Robinson JH, Deadwyler SA (1980) Morphine excitation: effects on field potentials recorded in the in vitro hippocampal slice. Neuropharmacology 19: 507–514

  37. Robson LE, Kosterlitz HW (1979) Specific protection of the binding sites of D-Ala2-D-Leu5-enkephalin (delta-receptors) and dihydromorphine (mu-receptors). Proc R Soc London Ser B 205: 425–432

  38. Rothman RB, Westfall TC (1981) Allosteric modulation by leucine-enkephalin of 3H-Naloxone binding in rat brain. Eur J Pharmacol 72: 365–368

  39. Sar MW, Stumpf W, Miller R, Chang KJ, Cuatrecasas P (1978) Immunohistochemical localization of enkephalin in the rat brain and spinal cord. J Comp Neurol 182: 17–38

  40. Schulz R, Wüster M, Krenss H, Herz A (1980) Lack of cross-tolerance on multiple opiate receptors in the mouse vas deferens. Mol Pharmacol 18: 365–401

  41. Siggins GR, Zieglgänsberger W (1981) Morphine and opioid peptides reduce inhibitory synaptic potentials in hippocampal pyramidal cells in vitro without alteration of membrane potential. Proc Natl Acad Sci USA 78: 5235–5239

  42. Smith JR, Simon EJ (1980) Selective protection of stereospecific enkephalin and opiate binding against inactivation by N- ethylmaleimide: evidence for two classes of opiate receptors. Proc Natl Acad Sci USA 77: 281–284

  43. Vaught JL, Kitano T, Takemori AE (1980) Interactions of leucine enkephalin and narcotics with opioid receptors. Mol Pharmacol 19: 236–241

  44. Williams JT, Zieglgänsberger W (1981) Neurons in the frontal cortex of the rat carry multiple opiate receptors. Brain Res 226: 304–308

  45. Zieglgänsberger W, French ED, Siggins GR, Bloom FE (1979) Opioid peptides may excite hippocampal pyramidal neurones by inhibiting adjacent inhibitory interneurones. Science 205: 415–417

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Correspondence to Dr. W. Zieglgänsberger.

Additional information

E.D. French was a Humboldt Fellow

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French, E.D., Zieglgänsberger, W. The excitatory response of in vitro hippocampal pyramidal cells to normorphine and methionine-enkephalin may be mediated by different receptor populations. Exp Brain Res 48, 238–244 (1982).

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Key words

  • Hippocampus slice
  • Opiate agonists
  • Multiple receptors