Acute withdrawal after bremazocine and the interaction between mu- and kappa-opioid receptors in isolated gut tissues.
1. This study was undertaken to investigate whether, after a brief exposure 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 contractures. 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 response whereas in tissues exposed to a lower bremazocine concentration (5.7 x 10(-9) M), naloxone (5 x 10(-7) M) and the selective kappa-opioid antagonist, nor-binaltorphimine (3.4 x 10(-8) M) both produced a strong contracture. 3. Bremazocine (5.7 x 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 x 10(-8) M) did not elicit a withdrawal contracture. 4. Naloxone (5 x 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 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 response. 5. In the rabbit jejunum, bremazocine (1.4-7.1 x 10-8 M) caused a decrease in amplitude in the spontaneous tissue activity. In tissues exposed to these bremazocine concentrations, naloxone(5 x 10-7 M) elicited a marked contracture. A similar contracture occurred when nor-binaltorphimine(3.4 x 10-8 M) was added in place of naloxone. These effects were dose-related to the bremazocine concentration. The specific K-agonist, U-50,488H (5 x 10-8 M), elicited the same effects as bremazocine.6. These findings show that stimulation of K-opioid receptors induces a state of dependence that is not prevented by blocking the pi-opioid system. The observation that low bremazocine concentrations inhibit the morphine-induced withdrawal contractures, indicates an interaction between the micro- and K-opioid system in guinea-pig isolated ileum, similar to that observed in the whole animal.
Valeri
P
P
Institute of Pharmacology and Pharmacognosy, University of Rome La Sapienza, Italy.
Morrone
L A
LA
Romanelli
L
L
Amico
M C
MC
D000818:Animals; D001575:Benzomorphans / Q000009:adverse effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D011817:Rabbits; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D001575:Benzomorphans; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; C027248:bremazocine