Summary
Opioid receptors can be localized to the hippocampal formation of the rat by autoradiography. The binding of 3H-enkephalinamide to fixed and mounted tissue sections has all the characteristics associated with binding to opioid receptors. It is saturable, of high affinity and displays stereospecificity. The opioid receptor distribution shows striking regional variation throughout the hippocampal formation. Areas with high density include the pyramidal cell layer of both regio superior (CA1) and regio inferior (CA3), stratum moleculare of the hippocampus, the cell layer of subiculum, the superficial part of presubiculum and the deep layer (VI) of the medial and lateral entorhinal cortices. Areas with low to medium densities include regions corresponding to the dendritic field of the pyramidal cells (str. oriens, str. radiatum and the mossy fiber zone), the dentate granule cell layer and the molecular layer of the dentate area. Enkephalin-like immunoreactivity is detected in both intrinsic neuronal systems: 1) the mossy fibers which terminate on the proximal part of the CA3 pyramidal cell dendrites and on CA4 pyramidal cells, 2) cell bodies with multiple short processes, probably interneurons, dispersed throughout the hilus of the dentate area, the pyramidal cell layer of hippocampus, the str. radiatum, and occasionally in the str. moleculare and in the str. oriens, and extrinsic neuronal systems: 1) the lateral perforant path and 2) the lateral temporo-ammonic tract. Thus, the hippocampus contains intrinsic systems of enkephalin-like immunoreactive nerve terminals which may exert their effect on the opioid receptors with a localization corresponding to the pyramidal cells and their apical dendrites. Extrinsic enkephalinergic systems corresponding to the terminal fields of the lateral perforant path and the temporoammonic tract, both of entorhinal origin, may influence the opioid receptors located in the molecular layer of the dentate area, and in the molecular layer of the hippocampus and the subiculum. Thus, the enkephalinlike immunoreactive nerve terminals are all located in areas which contain opioid binding sites. This suggests that the “opioid peptide-opioid receptor” systems may regulate hippocampal neuronal activity via neurotransmission or neuromodulation. However, a high or medium number of opioid binding sites occur over the pyramidal cell bodies and the dentate granule cell bodies, and these opioid binding sites are not in close contact with the major enkephalinergic systems. Such binding sites could represent newly synthesized opioid receptors ready for the enkephalinergic synapses of the cells and/or internalization of opioid receptors after stimulation at the synapses. Another possibility is the existence of cytoplasmic opioid binding sites (possibly t-RNA synthetase) with specific intracellular functions.
Similar content being viewed by others
References
Atweh SF, Kuhar MJ (1977a) Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and medulla. Brain Res 124:53–67
Atweh SF, Kuhar MJ (1977b) Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res 129:1–12
Atweh SF, Kuhar MJ (1977c) Autoradiographic localization of opiate receptors in rat brain. III. The telencephalon. Brain Res 134:393–405
Bradley PB, Gayton RJ, Lambert LA (1978) Electrophysiological effects of opiates and opioid peptides. In: Hughes J (ed) Centrally acting peptides. MacMillan Press, London, pp 215–229
Chang K-J, Cuatrecasas P (1979) Multiple opiate receptors. Enkephalins and morphine bind to receptors of different specificity. J Biol Chem 254:2610–2618
Corrigall WA (1983) Opiates and the hippocampus: A review of the functional and morphological evidence. Pharmacol Biochem Behav 18:255–262
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
Dunwiddie T, Muller A, Palmer M, Steward J, Hoffer B (1980) Electrophysiological interactions of enkephalins with neuronal circuitry in the hippocampus. I. Effects on pyramidal cell activity. Brain Res 184:311–330
Elde R, Hökfelt T, Johansson O, Terenius L (1976) Immunohistochemical studies using antibodies to leucin-enkephalin: initial observations on the nervous system of the rat. Neuroscience 5:349–351
Finley JCW, Maderdrut JL, Petrusz P (1981) The immunocytochemical localization of enkephalin in the central nervous system of the rat. J Comp Neurol 198:541–565
Fitzpatrick D, Johnson RP (1981) Enkephalin-like immunoreactivity in the mossy fiber pathway of the hippocampal formation of the tree shrew (Tupaia Glis). Neuroscience 6:2485–2494
Fredens K, Stengaard-Pedersen K, Larsson L-I (1983) Localization of enkephalin and cholecystokinin immunoreactivities in the perforant path terminal area of the rat hippocampal formation. Brain Res (in press)
French ED, Siggins GR (1980) An iontophoretic survey of opioid peptide actions in the rat limbic system: in search of epileptogenic mechanisms. Regul Pept 1:127–146
Gall C, Brecha N, Karten HJ, Chang K-J (1981) Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus. J Comp Neurol 198:335–350
Gänwiler BH (1981) Excitatory action of opioid peptides and opiates on cultured hippocampal pyramidal cells. Brain Res 194:193–203
Gähwiler BH, Herrling PL (1980) Effects of opioid peptides on synaptic potentials in explants of rat hippocampus. Regul Pept 1:317–326
Goodman RR, Snyder SH, Kuhar MJ, Young WS (1980) Differentiation of delta and mu opiate receptor localizations by light microscopic autoradiography. Proc Natl Acad Sci USA 77:6239–6243
Greenwood RS, Godar SE, Reaves TA, Hayward JN (1981) Cholecystokinin in hippocampal pathways. J Comp Neurol 203:335–350
Haas HL, Ryall RW (1980) Presynaptic facilitation by enkephalin in the hippocampus. J Physiol 301:378–388
Haas HL, Gähwiler BH (1980) Do enkephalins directly affect calcium-spikes in hippocampal hyramidal cells? Neurosci Lett 19:89–92
Herkenham M, Pert CB (1980) In vitro autoradiography of opiate receptors in rat brain suggests loci of “opiatergic” pathways. Proc Natl Acad Sci USA 77(9):5532–5536
Hjorth-Simonsen A (1972) Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentata. J Comp Neurol 146:219–232
Hjorth-Simonsen A, Jeune B (1972) Origin and termination of the hippocampal perforant path in the rat studied by silver impregnation. J Comp Neurol 144:215–232
Hökfelt T, Elde R, Johansson D, Terenius L, Stein L (1977a) Distribution of enkephalin-like immunoreactivity in the rat central nervous system. I. Cell bodies. Neurosci Lett 5:25–31
Hökfelt T, Ljünadal H, Terenius L; Elde R, Nilsson G (1977b) Immunohistochemical analysis of peptide pathways possible related to pain and analgesia: Enkephalin and substance-P. Proc Natl Acad Sci USA 74:3081–3085
Isaacson RL (1974) The limbic system. Plenum Press, New York
Jacobsen C, Frich JR, Steensgaard J (1982) Determination of affinity of monoclonal antibodies aganist human IgG. Immunol Methods 50:77–88
Laidlow SA, Moldave K (1980) The effects of β-endorphin and enkephalins on protein biosynthesis in a eukaryotic cell-free system. J Biol Chem 255(24):1908–1913
Larsson L-I (1981) Peptide Immunocytochemistry. Prog Histochem Cytochem 13:No. 4
Larsson L-I, Rehfeld J (1979) Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Res 165:201–218
Larsson L-I, Stengaard-Pedersen K (1981) Enkephalin/endorphin-related peptides in antropyloric gastrin cells. J Histochem Cytochem 29:1088–1098
Larsson L-I, Stengaard-Pedersen K (1982) Immunocytochemical and ultrastructural differentiation between met-enkephalin, leu-enkephalin and met/leu-enkephalin immunoreactive neurons of feline gut. J Neurosci 2(7):861–878
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
Ljungdahl A, Hökfelt T, Nielsson G (1978) Distribution of substance-P-like immunoreactivity in the central nervous system of the rat. I. Cell bodies and nerve terminals. Neuroscience 3:861–943
Lopes da Silva FH, Arnolds DEAT (1978) Physiology of the hippocampus and related structures. Ann Rev Physiol 40:185–216
Lorén I, Emson PC, Fahrenkrug J, Björklund A, Alumets J, Håkanson R, Sundler F (1979) Distribution of vasoactive intestinal polypeptide in the rat and mouse brain. Neuroscience 4:1953–1976
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275
Lynch SRA, Jensen JL, McGaugh K, Davilla K, Oliver MW (1981) Effects of enkephalin, morphine, and naloxone on the electrical activity of the in vitro hippocampal slice. Exp Neurol 71:527–540
McGinty JF, Henriksen SJ, Goldstein A, Terenius L, Bloom FE (1983) Dynorphin is contained within hippocampal mossy fibers: Immunochemical alterations after kainic acid administration and colchicine-induced neurotoxicity. Proc Natl Acad Sci USA 80:589–593
Meibach RC, Maayani S (1980) Localization of naloxone-sensitive [3H]dihydromorphine binding sites within the hippocampus of the rat. Eur J Pharmacol 68:175–179
Miller RJ (1982) Multiple opiate receptors for multiple opioid peptides. Med Biol 60:1–6
Morrison JH, Benoit R, Magistretti PJ, Ling N, Bloom FE (1982) Immunohistochemical distribution of pro-somatostatin-related peptides in hippocampus. Neurosci Lett 34:137–142
Nicoll RA, Siggins GR, Ling N, Bloom FE, Guillimin R (1977) Neuronal actions of endorphins and enkephalins among brain regions: a comparative microiontophoretic study. Proc Natl Acad Sci USA 74:2584–2588
North RA (1979) Opiates, opioid peptides and single neurons. Life Sci 24:1527–1546
Palacios JM, Niehoff DL, Kuhar MJ (1981) Receptor autoradiography with tritium sensitive film: Potential for computerized densitometry. Neurosci Lett 25:101–105
Paterson SJ, Robson LE, Kosterlitz HW (1983) Classification of opioid receptors. Br Med Bul 39(1):31–36
Pert CB, Kuhar MJ, Snyder SH (1975) Autoradiographic localization of the opiate receptor in the brain. Life Sci 16:1849–1854
Pert CB, Kuhar MJ, Snyder SH (1976) Opiate receptor: autoradiographic localization in the brain. Proc Natl Acad Sci USA 73:3729–2733
Petrusz P, Sar M, Grossman GH, Kizer JS (1977) Synaptic terminals with somatostatin-like immunoreactivity in the rat brain. Brain Res 137:181–187
Sar M, Stumpf WE, Miller RJ, Chang K-J, Cuatrecasas P (1978) Immunohistochemical localization of enkephalin in rat brain and spinal cord. J Comp Neurol 182:17–38
Schubert P, Höllt V, Herz A (1975) Autoradiographic evaluation of the intracerebral distribution of 3H-etorphine in the mouse brain. Life Sci 16:1855–1856
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
Simantov R, Kuhar MJ, Uhl GR, Snyder SH (1977) Opioid peptide enkephalin: immunohistochemical mapping in rat central nervous system. Proc Natl Acad Sci USA 74:2167–2171
Stengaard-Pedersen K (1982) Inhibition of enkephalin binding to opiate receptors by zine ions: possible physiological importance in the brain. Acta Pharmacol Toxicol 50:213–220
Stengaard-Pedersen K, Fredens K, Larsson L-I (1981) Enkephalin and zinc in the hippocampal mossy fiber system. Brain Res 212:230–233
Stengaard-Pedersen K, Larsson L-I (1981) Interaction of putative opioid peptides with opiate receptors. Acta Pharmacol Toxicol 48:39–46
Stengaard-Pedersen K, Fredens K, Larsson L-I (1983) Comparative localization of enkephalin and cholecystokinin immunoreactivities and heavy metals in the hippocampus. Brain Res (in press)
Sternberger LA (1979) Immunocytochemistry, 2nd edn. John Wiley and Sons, New York
Steward O (1976) Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat. J Comp Neurol 167:285–314
Storm-Mathisen (1977) Localization of transmitter candidates in the brain: The hippocampal formation as a model. Prog Neurobiol 8:119–181
Vincent SR, Kimura H, McGeer EG (1981) Organization of substance-P fibers within the hippocampal formation demonstrated with a biotin-avidin immunoperoxidase technique. J Comp Neurol 199:113–123
Weber E, Evans CJ, Barchas JD (1982a) Predominance of the amino-terminal octapeptide fragment of dynorphin in rat brain regions. Nature 299:77–79
Weber E, Roth KA, Bafchas JD (1982b) Immunohistochemical distribution of α-neo-endorphin/dynorphin neuronal systems in rat brain: Evidence for colocalization. Proc Natl Acad Sci USA 79:3062–3066
Yamamura HJ, Enna SJ, Kuhar MJ (1978) Neurotransmitter receptor binding. Raven Press, New York
Young WS, Kuhar MJ (1979) A new method for receptor autoradiography: [3H]opioid receptors in rat brain. Brain Res 179:255–270
Zieglgänsberger W, French ED, Siggins GR, Bloom FE (1979) Opioid peptides may excite hippocampal pyramidal neurons by inhibiting adjacent inhibitory interneurons. Science 205:415–417
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stengaard-Pedersen, K. Comparative mapping of opioid receptors and enkephalin immunoreactive nerve terminals in the rat hippocampus. Histochemistry 79, 311–333 (1983). https://doi.org/10.1007/BF00491768
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00491768