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

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. Naloxone, D ‐Phe‐Cys‐Tyr‐ D ‐Trp‐Orn‐Thr‐Pen‐Thr‐NH 2 (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‐NH 2 (CTAP), produced a transient inhibition of electrically‐evoked contractions of the guinea‐pig ileum. The effect of 1 μ M CTOP, but not that to MR2266, was inhibited by 1 μ M somatostatin. Naloxone (0.3 μ M ), CTOP (3 μ M ), CTAP (3 μ M ) and MR2266 (0.3 μ M ) 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 μ M CTOP was significantly smaller than that to 3 μ M CTAP. None of the antagonists produced a response in the absence of morphine. Following overnight exposure of the ileum to 0.3 μ M morphine (4°C), and repeated washing to remove the agonist, all four antagonists elicited non‐sustained contractions. However, the responses to 3 μ M CTOP and 0.3 μ M MR2266 were significantly smaller than those elicited by 0.3 μ M naloxone and 3 μ M CTAP. Somatostatin (1 μ M ) significantly reduced naloxone‐induced contractions, but not those to CTAP. 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.British Journal of Pharmacology (2000) 131 , 893–902; doi: 10.1038/sj.bjp.0703659