mr-2266 and phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide

We have assessed the potential of several mu-opioid receptor antagonists to elicit a response in the guinea-pig isolated ileum in the presence of, and following overnight exposure to, morphine. Naloxone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP), (-)-5, 9alpha-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorphan (MR2266), but not D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), produced a transient inhibition of electrically-evoked contractions of the guinea-pig ileum. The effect of 1 microM CTOP, but not that to MR2266, was inhibited by 1 microM somatostatin. Naloxone (0.3 microM), CTOP (3 microM), CTAP (3 microM) and MR2266 (0.3 microM) antagonized the inhibitory effect of morphine on electrically-evoked contractions of the guinea-pig to a similar degree and, following 60 min exposure to morphine, produced non-sustained contractions. The response to 3 microM CTOP was significantly smaller than that to 3 microM CTAP. None of the antagonists produced a response in the absence of morphine. Following overnight exposure of the ileum to 0.3 microM morphine (4 degrees C), and repeated washing to remove the agonist, all four antagonists elicited non-sustained contractions. However, the responses to 3 microM CTOP and 0.3 microM MR2266 were significantly smaller than those elicited by 0.3 microM naloxone and 3 microM CTAP. Somatostatin (1 microM) significantly reduced naloxone-induced contractions, but not those to CTAP. While all four mu-opioid antagonists elicited contractions in the presence of, and following prolonged exposure to, morphine, differences between them were noted which may be a consequence of non-opioid actions.

Topics: Animals; Benzomorphans; Guinea Pigs; Ileum; In Vitro Techniques; Male; Morphine; Muscle Contraction; Naloxone; Narcotic Antagonists; Peptide Fragments; Peptides; Phentolamine; Receptors, Opioid, mu; Somatostatin