Opioid receptor selectivity of β-endorphin in vitro and in vivo: Mu, delta and epsilon receptors

The relative contributions of mu and delta opioid receptors in the response to Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr- Leu-Phe-Lys-Asn-Ala-Ileu-Ileu-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (B-endorphin) were assessed as reductions in B-endorphin potency in the presence of mu and delta receptor selective antagonists in the guinea pig ileum, mouse vas deferens, rat vas deferens and in analgesic and gastrointestinal transit time tests in mice. We used the nonselective antagonist naloxone, the mu antagonist D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH₂ (CTP) and the delta antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864) in each test system at concentrations that effectively antagonized the respective mu and delta agonists, Tyr-Pro-N-MePhe-D-Pro-NH₂ and Tyr-D-Pen-Gly-Phe-D-Pen. In the guinea pig ileum, the inhibitory effects of 1 μM B-endorphin were blocked by 1 μM CTP and 1 μM naloxone, but not by 1 μM ICI 174,864. In the mouse vas deferens, B-endorphin (0.2 μM) was antagonized by 1 μM CTP, 1 μM ICI 174,864 and by 1 μM naloxone. In contrast, in the rat vas deferens, B-endorphin (0.01-1 μM) produced potent inhibitory actions that were blocked by 1 μM naloxone, but not by 1 μM-CTP or by 1 μM ICI 174,864. The mu agonist Tyr-Pro-N-MePhe-D-Pro-NH₂ (0.1-10 μM), like B-endorphin, also had inhibitory actions in the rat vas deferens, but its effects were blocked by 1 μM CTP. The delta agonist Tyr-D-Pen-Gly-Phe-D-Pen (1-10 μM) caused weak inhibition at very high concentrations and, like B-endorphin, was blocked by 1 μM naloxone, but not by 1 μM CTP or 1 μM ICI 174,864. When tested in vivo, centrally administered B-endorphin (0.1-5 μg i.c.v.) produced analgesia and slowed the rate of gastrointestinal transit. Both effects were inhibited by 1 μg of i.c.v. CTP, 3 μg of i.c.v. ICI and 1 μg of i.c.v. naloxone. These findings indicate that B-endorphin enlists both mu and delta receptors to produce its effects in vitro and in vivo, and that B-endorphin in the rat vas deferens acts at another non-mu, non-delta opioid receptor, which may be the putative epsilon receptor. In addition to the epsilon receptor, the rat vas deferens also contains mu, but not delta, opioid receptors.