Acute withdrawal after bremazocine and the interaction between μ‐ and κ‐opioid receptors in isolated gut tissues

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Abstract
1 This study was undertaken to investigate whether, after a brief exposure of guinea‐pig isolated ileum and rabbit jejunum to bremazocine, a κ‐opioid agonist also possessing antagonist activity at μ‐opioid receptors, the addition of opioid antagonists produced withdrawal contractures. Our aim was to verify in these tissues the existence of an interaction between the μ‐ and κ‐opioid systems.2 In guinea‐pig ileum preparations previously exposed for 5 min to bremazocine at 5.7 times 10−7 m and 5.7 times 10−8 m, naloxone (5 times 10−7 m) elicited no response whereas in tissues exposed to a lower bremazocine concentration (5.7 times 10−9 m), naloxone (5 times 10−7 m) and the selective κ‐opioid antagonist, nor‐binaltorphimine (3.4 times 10−8 m) both produced a strong contracture.3 Bremazocine (5.7 times 10−7 m) administered to guinea‐pig isolated ileum, previously exposed for 5 min to morphine (10−7 m), induced a withdrawal contracture. In contrast, lower bremazocine concentrations (1.4 and 7.1 times 10−8 m) did not elicit a withdrawal contracture.4 Naloxone (5 times 10−7 m), added to the bath after a 5 min exposure of guinea‐pig ileum to morphine (10−7 m), elicited the characteristic withdrawal contracture. Bremazocine (1.4–7.1 times 10−8 m) added 1 min before naloxone (5 times 10−7 m) inhibited the naloxone withdrawal contracture in a dose‐related way whereas naloxone 5 times 10−8 m added 1 min before naloxone 5 times 10−7m, did not affect the withdrawal response.5 In the rabbit jejunum, bremazocine (1.4–7.1 times 10−8 m) caused a decrease in amplitude in the spontaneous tissue activity. In tissues exposed to these bremazocine concentrations, naloxone (5 times 10−7 m) elicited a marked contracture. A similar contracture occurred when nor‐binaltorphimine (3.4 times 10−8 m) was added in place of naloxone. These effects were dose‐related to the bremazocine concentration. The specific κ‐agonist, U‐50,488H (5 times 10−8 m), elicited the same effects as bremazocine.6 These findings show that stimulation of κ‐opioid receptors induces a state of dependence that is not prevented by blocking the μ‐opioid system. The observation that low bremazocine concentrations inhibit the morphine‐induced withdrawal contractures, indicates an interaction between the μ‐ and κ‐opioid system in guinea‐pig isolated ileum, similar to that observed in the whole animal.