Pharmacological examination of contractile responses of the guinea-pig isolated ileum produced by μ-opioid receptor antagonists in the presence of, and following exposure to, morphine

Abstract

1. We have assessed the potential of several μ-opioid receptor antagonists to elicit a response in the guinea-pig isolated ileum in the presence of, and following overnight exposure to, morphine. 2. Naloxone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), (-)-5,9α-diethyl-2-(3-furyl-methyl)-2'-hydroxy-6,7-benzomorphan (MR2266), but not D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), produced a transient inhibition of electrically-evoked contractions of the guinea-pig ileum. The effect of 1 μM CTOP, but not that to MR2266, was inhibited by 1 μM somatostatin. 3. Naloxone (0.3 μm), CTOP (3 μm), CTAP (3 μM) and MR2266 (0.3 μM) 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 μM CTOP was significantly smaller than that to 3 μM CTAP. None of the antagonists produced a response in the absence of morphine. 4. Following overnight exposure of the ileum to 0.3 μM morphine (4°C), and repeated washing to remove the agonist, all four antagonists elicited non-sustained contractions. However, the responses to 3 μM CTOP and 0.3 μM MR2266 were significantly smaller than those elicited by 0.3 μM naloxone and 3 μM CTAP. Somatostatin (1 μM) significantly reduced naloxone-induced contractions, but not those to CTAP. 5. While all four μ-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.