δ-opioid receptor-induced late preconditioning is mediated by cyclooxygenase-2 in conscious rabbits

Although activation of δ-opioid receptors is known to induce both early and late preconditioning (PC) against myocardial infarction, the mechanisms for this salubrious effect are unclear. Furthermore, it is unknown whether δ-opioid receptors can also induce late PC against myocardial stunning. By using conscious rabbits (n = 120) in this study, we found that the δ-opioid receptor agonist (±)-4-{(α-R*)- α-[(2S*,5R*)- 4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl}-N,N-diethylbenzamide (BW-373U86) induced late PC against myocardial stunning 24 h after treatment and that this effect was abolished by the selective cyclooxygenase-2 (COX-2) inhibitors N-[2-(cyclohexyloxy)4-nitrophenyl]methanesulfonamide (NS-398) and celecoxib. This protective effect was also abrogated by the selective δ₁-opioid receptor antagonist 7-benzylidenenaltrexone, indicating that the δ₁-opioid receptor is necessary for BW-373U86-induced late PC. BW-373U86 did not induce early PC against stunning. In addition, BW-373U86 induced late PC against infarction, which was blocked by NS-398. At 24 h after BW-373U86 administration, myocardial COX-2 protein expression and PGE₂ and 6-keto-PGF_1α levels were significantly increased. These results demonstrate that activation of δ-opioid receptors induces late PC against both stunning and infarction via a COX-2-dependent mechanism.