Enkephalin derivative, cyclo[Nε,Nβ-carbonyl-d-Lys2, Dap5] enkephalinamide (cUENK6), induces a highly potent antinociception in rats

The aim of the study was to evaluate whether the newly synthesized analog of enkephalin, cyclo[Nε,Nβ-carbonyl-D-Lys2, Dap5] enkephalinamide (cUENK6), a highly potent μ- (guinea pig ileum assay) and δ-receptors (mouse vas deferens assay) ligand, induces an antinociceptive effect in the hot-plate test and tail-immersion test after intracerebroventricular administration. Our study indicated that this peptide at the dose of 0.25 nmol produced comparable but at the dose of 0.5 nmol stronger than morphine (13 nmol), antinociceptive effect in both tests. Furthermore, rats with developed tolerance to morphine indicated cross-tolerance to antinociceptive effects of cUENK6. The antinociceptive effects of cUENK6 and morphine were inhibited by non-selective opioid receptor antagonist – naloxone. More detailed study indicated that the δ-opioid receptor antagonist – naltrindole very strongly and, to the lower extent, μ-opioid antagonist – β-funaltrexamine (β-FNA), inhibited antinociceptive effect of cUENK6 in the tail-immersion test. Nor-binaltorphimine (nor-BNI), a κ-opioid receptor antagonist, did not influence this effect. These data suggest the dominant role of δ-opioid receptors as compared with μ-receptors in mediation antinociceptive effect of cUENK6. Furthermore, we found that cUENK6 is much more effective in inhibiting pain in the hot-plate (ED50 = 0.0792 nmol) than in the tail-immersion (ED50 = 0.3526 nmol) test. However, cUENK6 at the antinociceptive doses induced hypolocomotion, and although this effect is observed after administration of opioid agonists in rats as a one phase of their biphasic action (inhibition followed by activation), in our study it was not naloxone-reversible. Therefore, our study suggests that not only opioid receptors may be involved in behavioral effects of cUENK6.