Interactions between cholecystokinin and opioids in the isolated guinea‐pig ileum

Abstract

1 Although cholecystokinin octapeptide sulphate (CCK-8) activates the opioid system of isolated guinea-pig ileum (GPI) whether it activates the m-or k-system, or both, remains unclear. Neither is it known whether CCK-8 in¯uences the withdrawal responses in GPI preparations brie¯y exposed to opioid agonists. This study was designed to clarify whether CCK-8 activates m-or k-opioid systems or both; and to investigate its eect on the withdrawal contractures in GPI exposed to m-or kagonists and on the development of tolerance to the withdrawal response. 2 In GPI exposed to CCK-8, the selective k-antagonist nor-binaltorphimine elicited contractile responses that were concentration-related to CCK-8 whereas the selective m-antagonist cyprodime did not. 3 In GPI preparations brie¯y exposed to the selective m-agonist, dermorphin, or the selective kagonist, U-50, 488H, and then challenged with naloxone, CCK-8 strongly enhanced the withdrawal contractures. 4 During repeated opioid agonist/CCK-8/opioid antagonist tests tolerance to opioid-induced withdrawal responses did not develop. 5 These results show that CCK-8 preferentially activates the GPI k-opioid system and antagonizes the mechanism(s) that control the expression of acute dependence in the GPI.

Acute withdrawal induced by adenosine A1-receptor activation in isolated guinea-pig ileum: role of opioid receptors and effect of cholecystokinin

“…It has been reported in the literature that the peptide cholecystokinin‐8 (CCk‐8) is able both to reduce or prevent the withdrawal signs precipitated by naloxone and counteract the tolerance development in morphine‐dependent mice [34–39] . In our previous in‐vitro studies, we have also shown that: (i) in guinea‐pig ileum preparations, CCk‐8 induces a contracture, that in turn can be inhibited by opioid agonists; [27] (ii) tissues treated only with CCk‐8 show withdrawal contracture precipitated by μ‐ or κ‐opioid antagonists; [35] and finally (iii) CCk‐8 is able to prevent development of tolerance after repeated tests with agonist/antagonist opioid receptor [27,28] . Based on the observations mentioned above, the final aims of the present study were to further investigate whether CCk‐8 is also able to activate the A 1 ‐adenosine system and whether it is involved in the A 1 ‐antagonist precipitated withdrawal contracture.…”

“…The interactions observed in vivo between the μ‐opioid and A 1 ‐adenosine systems can also be observed in guinea‐pig ileum isolated preparations, where a clear sign of a withdrawal response is represented by a tissue contraction, that occurs even after the acute exposure to a μ‐opioid agonist [27,28] . Guinea‐pig ileum contains many neurotransmitters, modulators and their receptors, including μ‐ and κ‐opioid receptors, [29] and adenosine A 1 ‐ and A 2 ‐receptors [30] .…”

“…The experimental procedure was essentially performed as previously described [27,28] . Male guinea‐pigs, 300–400 g (Morini, Italy), were used.…”

“…The concentrations of CPA and CPT used were in the range used to previously characterise the effect of the adenosine A 1 system on opioid withdrawal [28] . The opioid antagonists were the same as those used in previous works investigating μ/κ and CCk‐8/opioid system interactions [13,27] …”

“…To investigate the effect of opioid antagonists on the effect on the CPA‐induced response to CCk‐8 and CPT, opioid antagonists, BNI (3.4 × 10 −8 m ), cyprodime (1.4 × 10 −6 m ) or naloxone (5.4 × 10 −7 m ), were added 5 min before CPA (1.6 × 10 −8 m ). The concentrations of CCk‐8 were the same as those used in previous works investigating CCk‐8/opioid system interactions [13,27] …”