δ-Opioid Receptor Antagonist Inhibits Immunomodulation by Met-Enkephalin Analogs

The methionine-enkephalin (Met-enkephalin, Tyr-Gly- Gly-Phe-Met) analogs Tyr-D-Ala-Gly-MePhe-Met NHC 3 H 7 - iso (1) and Tyr-D-Ala-Gly-MePhe-Gly-NHC 3 H 7 -iso (2) have been shown to enhance human T cell proliferation in in vitro treatment. Their immunomodulatory activities were completely blocked by naloxone, an opioid antagonist. Now we demonstrate that a selective δ-opioid receptor antagonist, ICI-174,864, completely blocks enhancement of T cell proliferation by analogs (1) and (2). The T cell-stimulatory effect was only partially inhibited by the µ-receptor-selective antagonist, β-funaltrexamine hydrochloride. The κ-opioid receptor antagonist, nor-binaltorphimine dihydrochloride, showed no effect on T cell-proliferation stimulated by analogs (1) and (2). These observations suggest that analogs (1) and (2) of Met-enkephalin stimulate T cell proliferation predominantly via δ-opioid receptor present on T cells.