Morphologically heterogeneous met-enkephalin terminals form synapses with tyrosine hydroxylase-containing dendrites in the rat nucleus locus coeruleus

J Comp Neurol. 1995 Dec 18;363(3):423-38. doi: 10.1002/cne.903630307.


Physiological and anatomical studies have suggested that the endogenous opioid peptide, methionine-enkephalin (ENK), may directly modulate noradrenergic neurons. Additionally, chronic opiate administration has been shown to increase the levels of a number of G-proteins and phosphoproteins including the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). We combined immunogold-silver localization of tyrosine hydroxylase and immunoperoxidase labeling for ENK in single sections through the nucleus locus coeruleus (LC) in the rostral pons to determine potential substrates for the divergent actions of this opioid peptide. Light microscopic analysis of ENK immunoreactivity in the LC area indicated that ENK fibers are dense and highly varicose. In coronal sections, ENK-immunoreactive processes were punctate and appeared to envelop LC-cell bodies. More rostrally, in the region of catecholamine-immunoreactive extranuclear dendrites, ENK-immunoreactive varicose processes were interdigitated with TH-labeled processes. Electron microscopy of this rostral region revealed that ENK-immunoreactive axon terminals contained small clear as well as large dense core vesicles. The large dense core vesicles (1-10/terminal) were consistently the most immunoreactive and were identified toward the periphery of the axon terminal distal to the active zone of the synapse. Unlabeled axon terminals and glial processes were the most commonly observed elements located adjacent to the plasmalemma of axons containing the labeled dense core vesicles. Axon terminals containing ENK immunoreactivity varied in size (0.3 micron to 2.0 microns) as well as formation of synaptic specializations (i.e., asymmetric versus symmetric). The ENK-labeled terminals formed synapses with dendrites with and without detectable TH immunoreactivity. These results provide the first direct ultrastructural evidence that morphologically heterogeneous terminals containing ENK immunoreactivity form synapses with catecholamine dendrites within the LC. The formation of asymmetric and symmetric synaptic specializations suggests that the opioid peptide, ENK, may be colocalized with other neurotransmitters. Furthermore, the distribution of ENK immunoreactivity in axon terminals apposed to other unlabeled afferents or astrocytic processes suggests that actions of ENK may also include presynaptic modulation of other transmitters and/or effects on astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / enzymology
  • Axons / metabolism
  • Axons / ultrastructure
  • Dendrites / enzymology
  • Dendrites / metabolism*
  • Dendrites / ultrastructure
  • Enkephalin, Methionine / metabolism*
  • Immunohistochemistry
  • Locus Coeruleus / cytology
  • Locus Coeruleus / enzymology
  • Locus Coeruleus / metabolism*
  • Male
  • Microscopy, Electron
  • Neuroglia / enzymology
  • Neuroglia / metabolism
  • Neuroglia / ultrastructure
  • Neuronal Plasticity / physiology
  • Neurons, Afferent / enzymology
  • Neurons, Afferent / metabolism
  • Neurons, Afferent / ultrastructure
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / ultrastructure
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / enzymology
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Tyrosine 3-Monooxygenase / metabolism*


  • Enkephalin, Methionine
  • Tyrosine 3-Monooxygenase