ACUTE WITHDRAWAL AFTER BREMAZOCINE AND THE INTERACTION BETWEEN MU-OPIOID AND KAPPA-OPIOID RECEPTORS IN ISOLATED GUT TISSUES

1 This study was undertaken to investigate whether, after a brief expo sure of guinea-pig isolated ileum and rabbit jejunum to bremazocine, a kappa-opioid agonist also possessing antagonist activity at mu-opioid receptors, the addition of opioid antagonists produced withdrawal con tractures. Our aim was to verify in these tissues the existence of an interaction between the mu- and kappa-opioid systems. 2 In guinea-pig ileum preparations previously exposed for 5 min to bremazocine at 5.7 x 10(-7) M and 5.7 x 10(-8) M, naloxone (5 x 10(-7) M) elicited no res ponse whereas in tissues exposed to a lower bremazocine concentration (5.7 x 10(-9) M), naloxone (5 x 10(-7) M) and the selective K-opioid a ntagonist, nor-binaltorphimine (3.4 x 10(-8) M) both produced a strong contracture. 3 Bremazocine (5.7 x 10(-7) M) administered to guinea-pi g isolated ileum, previously exposed for 5 min to morphine (10(-7) M), induced a withdrawal contracture. In contrast, lower bremazocine conc entrations (1.4 and 7.1 x 10(-8) M) did not elicit a withdrawal contra cture. 4 Naloxone (5 x 10(-7) M), added to the bath after a 5 min expo sure of guinea-pig ileum to morphine (10(-7) M), elicited the characte ristic withdrawal contracture. Bremazocine (1.4-7.1 x 10(-8) M) added 1 min before naloxone (5 x 10(-7) M) inhibited the naloxone withdrawal contracture in a dose-related way whereas naloxone 5 x 10(-8) M added 1 min before naloxone 5 x 10(-7) M, did not affect the withdrawal res ponse. 5 In the rabbit jejunum, bremazocine (1.4-7.1 x 10(-8) M) cause d a decrease in amplitude in the spontaneous tissue activity. In tissu es exposed to these bremazocine concentrations, naloxone (5 x 10(-7) M ) elicited a marked contracture. A similar contracture occurred when n or-binaltorphimine (3.4 x 10(-8) M) was added in place of naloxone. Th ese effects were dose-related to the bremazocine concentration. The sp ecific Ic-agonist, U-50,488H (5 x 10(-8) M), elicited the same effects as bremazocine. 6 These findings show that stimulation of kappa-opioi d receptors induces a state of dependence that is not prevented by blo cking the mu-opioid system. The observation that low bremazocine conce ntrations inhibit the morphine-induced withdrawal contractures, indica tes an interaction between the mu- and kappa-opioid system in guinea-p ig isolated ileum, similar to that observed in the whole animal.