[Met]Enkephalin-Arg6-Gly7-Leu8 is an endogenous opioid peptide, first isolated from the bovine adrenal medulla. Because this octapeptide is specifically contained in the amino acid sequence of preproenkephalin A but not in other opioid precursors like preproopiomelanocortin or preproenkephalin B, [Met]enkephalin-Arg6-Gly7-Leu8 has been regarded as a specific marker for preproenkephalin A and its derivatives. In this study, we examined the occurrence and origin of [Met]enkephalin-Arg6-Gly7-Leu8-immunoreactive nerves in the guinea-pig and rat lung by immunohistochemical techniques, using a specific antiserum against this peptide. In addition, we investigated the possible co-existence of [Met]enkephalin-Arg6-Gly7-Leu8 and vasoactive intestinal peptide immunoreactivity in neuronal elements of the respiratory tract. In both species, [Met]enkephalin-Arg6-Gly7-Leu8 immunoreactivity was localized in nerve fibers chiefly distributed to the trachea and major bronchi, where they were prevalent in smooth muscle bundles, in the lamina propria, around airway glands, and in the walls of pulmonary vessels, but were absent in airway epithelium. Slight differences in the distribution pattern of immunoreactive nerve fibers were noted between the two species: immunoreactive nerve fibers in the smooth muscle bundles were much more abundant in guinea-pigs than in rats, while those in the mucous glands were richer in rats than in guinea-pigs. Neither chemical sympathectomy by 6-hydroxydopamine, nor chemical sensory denervation by capsaicin, changed the density or distribution of [Met]enkephalin-Arg6-Gly7-Leu8-immunoreactive nerve fibers in the airway, suggesting an intrinsic source for these nerve fibers. Colchicine injection into the tracheal wall, to promote the accumulation of neuropeptides in nerve cell bodies, led to the visualization of [Met]enkephalin-Arg6-Gly7-Leu8 immunoreactivity in some neuronal cell bodies within airway ganglia. Immunostaining for [Met]enkephalin-Arg6-Gly7-Leu8 and for vasoactive intestinal polypeptide on serial adjacent sections of airway ganglia obtained from colchicine-treated tracheae, demonstrated the co-existence of these immunoreactivities in a population of nerve cell bodies in these ganglia. The immunohistochemical localization of immunoreactive [Met]enkephalin-Arg6-Gly7-Leu8 in nerve elements in guinea-pig and rat lungs provides a morphological basis for the possibility that pre-proenkephalin A-related opioid peptides may have a neuromodulatory role in mammalian airways and pulmonary vessels.
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