Axons in intact peripheral nerve trunks constitute independent afferent and efferent communication channels. However, when nerves are severed, several different forms of axon-axon cross-excitation develop in association with the injury site. In this study we have examined experimental sciatic nerve-end neuromas in rats with special interest in the compartmentalization of individual axons, and the barriers that separate close neighbours. At postinjury times at which functional coupling is known to occur, neuromas were found to contain many examples of axons in which adjacent membrane faces come into close contact without an intervening Schwann cell process. These occur in bundles containing from two to as many as 30 individual nerve fibres wrapped in a common Schwann cell sheath. The surface area of close apposition between axon pairs ranges up to several tens of μm2. Closely apposed axon profiles may be outgrowing branches of a single parent axon, but anterograde tracer data indicate that many belong to independent neurons. Closely apposed axons are separated from one another, and from associated Schwann cell processes, by a cleft about 130 Å wide. No synapses, gap junctions or tight junctions were observed. Extracellular tracer studies using La3+ and Ruthenium Red indicated that the cleft system is patent, permitting the free diffusion of small molecules between the space adjacent to the axolemma and the bulk extracellular compartment. Together, these data provide a structural basis for interfibre interactions based on local electrical current flow (ephaptic crosstalk), as well as coupling mediated by K+ ions and neurotransmitter molecules.
This is a preview of subscription content, log in to check access.
Amir, R. &Devor, M. (1992) Axonal cross-excitation in nerve-end neuromas: comparison of A- and C-fibers.Journal of Neurophysiology 68, 1160–6.
Bernstein, J. J. &Pagnanelli, D. (1982) Long-term axonal apposition in rat sciatic nerve neuroma.Journal of Neurosurgery 57, 632–84.
Berthold, C.-H. (1978) Morphology of normal peripheral axons. InPhysiology and Pathobiology of Axons (edited byWaxman, S. G.), pp. 3–63, New York, Raven.
Blair, E. A. &Erlanger, J. (1932) On the effects of polarization of nerve fibers by extrinsic action potentials.American Journal of Physiology 101, 559–64.
Blumberg, H. &Janig, W. (1982) Activation of fibers via experimentally produced stump neuromas of skin nerves — ephaptic transmission or retrograde sprouting?Experimental Neurology 76, 468–82.
Brismar, T., Hildebrand, C. &Berglund, S. (1986) Nodes of Ranvier above a neuroma in the rat sciatic nerve: voltage clamp analysis and electron microscopy.Brain Research 378, 347–56.
Cabaud, H. E., Rodkey, W. G. &Nemeth, T. J. (1982) Progressive ultrastructural changes after peripheral nerve transection and repair.Journal of Hand Surgery 4, 353–65.
Clark, J. V. &Plonksy, R. A. (1970) Mathematical study of nerve fiber interaction.Biophysical Journal 10, 937–57.
Conners, B. W., Ransom, B. R., Kunis, D. M. &Gutnick, M. J. (1982) Activity dependent K+ accumulation in the developing rat optic nerve.Science 216, 1341–3.
De Baecque, C., Raine, C. S. &Spencer, P. S. (1976) Copper binding at PNS nodes of Ranvier during demyelination and remyelination in the perineurial window.Neuropathology and Applied Neurobiology 2, 459–70.
Devor, M. (1993) The pathophysiology of damaged peripheral nerves. InTextbook of Pain, third edition (edited byWall, P. D. &Melzack, R.) In press, London, Churchill-Livingstone.
Devor, M. &Bernstein, J. J. (1982) Abnormal impulse generation in neuromas: electrophysiology and ultrastructure. InAbnormal Nerves and Muscles and Impulse Generators (edited byOchoa, J. &Culp, W.) pp. 363–80, Oxford, Oxford University Press.
Devor, M. &Dubner, R. (1988) Centrifugal activity in afferent C-fibers influences the spontaneous afferent barrage generated in nerve end neuromas.Brain Research 446, 396–400.
Devor, M., Fried, K., Govrin-Lippmann, R. &Ellisman, M. (1991) Cytoplasmic and membrane structure of ectopic impulse generation sites in injured peripheral nerve. InLesions of Primary Afferent Fibers as a Tool for the Study of Clinical Pain, (edited byBesson, J.-M. &Guilbaud, G.) pp. 53–64, Amsterdam, Excerpta Medica.
Devor, M., Govrin-Lippmann, R.. &Angelides, K. (1993) Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation.Journal of Neuroscience,13, 1976–92.
Devor, M. &Janig, W. (1981) Activation of myelinated afferents ending in neuroma by stimulation of the sympathetic supply in the rat.Neuroscience Letters 24, 43–7.
Fried, K., Govrin-Lippmann, R., Rosenthal, F., Ellisman, M. H. &Devor, M. (1991) Ultrastructure of afferent axon endings in neuroma.Journal of Neurocytology 20, 682–701.
Goldstein, R. S., Raber, P., Govrin-Lippmann, R. &Devor, M. (1988) Contrasting time course of catecholamine accumulation and of spontaneous discharge in experimental neuromas in the rat.Neuroscience Letters 94, 58–63.
Habler, H.-J., Janig, W. &Koltzenburg, M. (1987) Activation of unmyelinated afferents in chronically lesioned nerves by adrenaline and excitation of sympathetic efferents in the cat.Neuroscience Letters 82, 35–40.
Hall, S. M. &Gregson, N. A. (1975) The effects of mitomycin C on the process of remyelination in the mammalian peripheral nervous system.Neuropathology and Applied Neurobiology 1, 149–70.
Hall, S. M. &Williams, P. L. (1971) The distribution of electron-dense tracers in peripheral nerve fibres.Journal of Cell Science 8, 541–55.
Hanker, J. S., Yates, P. E., Metz, C. B. &Rustioni, A. (1977) A new, specific and non-carcinogenic reagent for the demonstration of horseradish peroxidase.Histochemical Journal 9, 789–92.
Hayat, M. A. (1986)Basic Techniques for Transmission Electron Microscopy pp. 1–411, San Diego: Academic Press.
Hildebrand, C. &Aldskogius, H. (1976) Electronmicroscopic identification of Marchi-positive bodies and argyrophilic granules in the spinal cord white matter of the guinea pig.Journal of Comparative Neurology 170, 191–204.
Inouye, H. &Kirschner, D. A. (1988) Membrane interactions in nerve myelin. I. Determination of surface charge from effects of pH and ionic strength on period.Biophysical Journal 53, 235–46.
Janig, W. (1990) Activation of afferent fibers ending in an old neuroma by sympathetic stimulation in the rat.Neuroscience Letters 111, 309–14.
Katz, B. &Schmitt, O. H. (1940) Electric interaction between two adjacent nerve fibers.Journal of Physiology 97, 471–88.
Kocsis, J. D., Preston, R. J. &Targ, E. F. (1984) Retrograde impulse activity and horseradish peroxidase tracing of nerve fibers entering neuroma studiedin vitro.Experimental Neurology 85, 400–12.
Kocsis, J. D., Ruiz, J. A. &Cummins, K. L. (1982) Modulation of axonal excitability mediated by surround electric activity: an intra-axonal study.Experimental Brain Research 47, 151–3.
Korenman, E. M. D. &Devor, M. (1981) Ectopic adrenergic sensitivity in damaged peripheral nerve axons in the rat.Experimental Neurology 72, 63–81.
Landon, D. N. (ed.) (1976)The Peripheral Nerve. London: Chapman & Hall.
Lisney, S. J. W. &Devor, M. (1987) Afterdischarge and interactions among fibers in damaged peripheral nerve in the rat.Brain Research 415, 122–36.
Lisney, S. J. W. &Pover, C. M. (1983) Coupling between fibers involved in sensory nerve neuromata in cats.Journal of Neurological Science 59, 255–64.
Lundborg, G., Dahlin, L. B., Danielsen, N. P., Hansson, H. A. &Larsson, K. (1981) Reorganization and orientation of regenerating nerve fibers, perineurium, and epineurium in preformed mesothelial tubes - an experimental study on the sciatic nerve of rats.Journal of Neuroscience Research 6, 265–81.
Mackenzie, M. L., Shorer, Z., Ghabriel, M. N. &Allt, G. (1984) Myelinated nerve fibres and the fate of lanthanum tracer: anin vivo study.Journal of Anatomy 138, 1–14.
Marazzi, A. S. &Lorente De No, R. (1944) Interaction of neighbouring fibers in myelinated nerve.Journal of Neurophysiology 7, 83–101.
Meyer, R. A., Raja, S. N. &Campbell, J. N. (1985a) Coupling of action potential activity between unmyelinated fibers in peripheral nerves of monkey.Science 227, 184–6.
Meyer, R. A., Raja, S. N., Campbell, J. N., Mackinnon, S. E. &Dellon, A. L. (1985b) Neural activity originating from a neuroma in the baboon.Brain Research 325, 255–60.
Mesulam, M.-M. (1978) Tetramethylbenzidine for horseradish peroxidase neurochemistry; a non-carcinogenic blue reaction product with superior sensitivity for visualizing neuronal afferents and efferents.Journal of Histochemistry and Cytochemistry 26, 106–17.
Morris, J. H., Hudson, A. R. &Weddell, G. (1972) A Study of degeneration and regeneration in the divided rat sciatic nerve based on electron microscopy. I and II.Zeitschrift fur Zellforschung und mikroskopische Anatomie 124, 76–130.
Nagy, J. I., Yamamoto, T., Carr, P. A. &Hertzberg, E. L. (1990) Subpopulations of primary sensory neurons in rat are labelled immunohistochemically by an antibody against the 27KD gap junctional protein (connexin-32): implications for electrical coupling between sensory fibers.Pain (suppl. 5) S113.
Nicholson, C. &Phillips, J. M. (1981) Ion diffusion modified by tortuousity and volume fraction in the extracellular microenvironment of the rat cerebellum.Journal of Physiology 321, 225–7.
Orkand, R. K., Nicholls, J. G. &Kuffler, S. W. (1966) Effects of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia.Journal of Neurophysiology 29, 788–806.
Quick, D. C. &Waxman, S. G. (1977) Specific staining of the axon membrane at nodes of Ranvier with ferric ion and ferrocyanide.Journal of the Neurological Sciences 31, 1–11.
Rasminsky, M. (1980) Ephaptic transmission between single nerve fibres in the spinal nerve roots of dystrophic mice.Journal of Neurophysiology 305, 151–69.
Revel, J. P. &Karnovsky, M. J. (1967) Hexagonal array of subunits in intercellular junctions of the mouse heart and liver.Journal of Cell Biology 33, C7-C12.
Rosenblueth, A. (1941) The stimulation of myelinated axons by nerve impulses in adjacent myelinated axons.American Journal of Physiology 132, 119–28.
Rosenblueth, A. (1944) The interaction of myelinated nerve fibres in mammalian nerve trunks.American Journal of Physiology 140, 656–70.
Schatzki, P. F. &Newsome, A. (1975) Neutralized lanthanum solution: a largely noncolloidal ultrastructural tracer.Stain Technology 50, 171–8.
Seltzer, Z. &Devor, M. (1979) Ephaptic transmission in chronically damaged peripheral nerves.Neurology 29, 1061–4.
Small, J. R., Scadding, J. W. &Landon, D. N. (1990) A fluorescence study of changes in noradrenergic sympathetic fibres in experimental peripheral nerve neuromas.Journal of the Neurological Sciences 100, 98–107.
Utzschneider, D., Kocsis, J. &Devor, M. (1992) Mutual excitation among dorsal root ganglion neurons in the rat.Neuroscience Letters 146, 53–6.
Vahle-Hinz, C., Gottschaldt, K.-M. &Kraft, H. (1987) Morphological basis for ‘ephaptic’ excitation in neuroma nerves. InEffects of Nerve Injury on Trigeminal and Spinal Somatosensory Systems, (edited byPubols, L. M. &Sessle, B. J.) p. 487, New York: Liss.
Wall, P. &Gutnick, M. (1974) Ongoing activity in peripheral nerves: the physiology and pharmacology of impulses originating from a neuroma.Experimental Neurology 43, 580–93.
Yarom, Y. &Spira, M. E. (1982) Extracellular potassium ions mediate specific neuronal interactions.Science 216, 80–2.
About this article
Cite this article
Fried, K., Govrin-Lippmann, R. & Devor, M. Close apposition among neighbouring axonal endings in a neuroma. J Neurocytol 22, 663–681 (1993) doi:10.1007/BF01181491
- Close Apposition
- Electrical Current Flow
- Axon Profile
- Anterograde Tracer