Mu and kappa opioid system interactions in the expression of acute opioid dependence in isolated guinea-pig ileum

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

“…To test whether μ‐opioid receptor blockade influenced the contractile response to the κ‐opioid antagonist, and vice versa , in some preparations, cyprodime (4.5 and 14×10 −7 M ) or nor‐binaltorphimine (1.1 and 3.4×10 −8 M ) were added 1 or 5 min before CCK‐8 (2×10 −9 M ). These antagonist concentrations were those previously found to block the inhibitory effect of indirect μ‐activation on κ‐withdrawal contracture and vice versa ( Valeri et al ., 1996 ).…”

“…On the other hand, the selective μ‐antagonist, cyprodime contracted only tissues exposed to CCK‐8 10 −8 M and the response was much weaker than that to nor‐binaltorphimine and naloxone. At these concentrations, cyprodime and nor‐binaltorphimine are selective because cyprodime (1.4×10 −6 M ) evoked a withdrawal contracture only in the tissue preparations exposed to the μ‐agonist, dermorphin, and, conversely, nor‐binaltorphimine (3.4×10 −8 M ) evoked a withdrawal contracture only in the preparations exposed to the κ‐agonist, U‐50,488H ( Valeri et al ., 1996 ). Hence, CCK‐8 appears to activate preferentially the κ‐opioid receptor system in isolated GPI.…”

“…To eliminate possible spontaneous responses to opioid antagonists in naïve tissues ( Valeri et al ., 1996 ), before the experiments, tissue preparations were exposed for 5 min to naloxone (5.4×10 −7 M ), naloxone was washed out and 30 min later the experiments began.…”

“…In preliminary experiments, these antagonist concentrations were found to yield maximal, reproducible responses. In addition, at these concentrations the antagonists are selective because we had previously found that cyprodime (1.4×10 −6 M ) evoked a withdrawal contracture only in tissue preparations exposed to the μ‐agonist, dermorphin, and, conversely, nor‐binaltorphimine (3.4×10 −8 M ) evoked a withdrawal contracture only in preparations exposed to the κ‐agonist, U‐50,488H ( Valeri et al ., 1996 ). To test whether μ‐opioid receptor blockade influenced the contractile response to the κ‐opioid antagonist, and vice versa , in some preparations, cyprodime (4.5 and 14×10 −7 M ) or nor‐binaltorphimine (1.1 and 3.4×10 −8 M ) were added 1 or 5 min before CCK‐8 (2×10 −9 M ).…”

“…Because withdrawal responses in GPI preparations briefly exposed to opioid agonists show strong self blockade ( Cruz et al ., 1991 ), μ ( Chahl, 1990 ) and κ withdrawal contractions ( Brent et al ., 1993 ) can be obtained only once in an isolated preparation. In an earlier study we showed that stimulation of the μ‐opioid system with selective μ‐agonists indirectly activates the κ‐system, which in turn inhibits the μ‐system withdrawal response, and conversely, stimulation of κ‐opioid system with selective κ‐agonists indirectly activates the μ‐system, which in turn inhibits the κ‐system withdrawal response ( Valeri et al ., 1996 ). Hence, we attributed the declining responsiveness of GPI preparations to repeated μ‐ or κ‐agonist/antagonist tests to a mutual antagonistic interaction between the μ‐ and κ‐opioid systems.…”