Inhibitory Control of the Acute Mu-Withdrawal Response by Indirectly Activated Adenosine A1 and Kappa-Opioid Systems in the Guinea-Pig Ileum; Reversal by Cholecystokinin

In the isolated guinea-pig ileum (GPI), the acute μ-opioid withdrawal response is inhibited by the κ-opioid system, indirectly activated by the opioid agonist; yet, other inhibitory mechanisms are probably operating. On the other hand, cholecystokinin (CCK-8) strongly enhances the withdrawal response. In this study, we have shown that the adenosine A1 antagonist 8-cyclopenthyl-1,3-dimethylxantine (CPT) increased the withdrawal response in dermorphin/naloxone (NLX) tests but lacked any effect if the withdrawal tests were carried out in presence of CCK-8. In tissue preparations coming from a same animal both CPT and the κ-opioid antagonist, nor-binaltorphimine (BNI), increased the intensity of the withdrawal responses; the effects of the two antagonists were additive. The intensity of withdrawal contractile responses in presence of CCK-8 was similar to those obtained in presence of the two antagonists. Tissue preparations tested with dermorphin/CCK-8/NLX and then washed out yielded contractile responses when subsequently challenged with CPT, BNI or BNI + CPT, with a percentage markedly higher than the percentage of the response to NLX challenge. BNI + CPT also increased the intensity of the response to NLX challenge. These data suggest that acute exposure of GPI to dermorphin induces the activation of both the adenosine A1 and κ-opioid systems, which in turns inhibit the μ-withdrawal response. CCK-8 antagonises the inhibitory effect of the indirectly activated systems.