Cahill C M, White T D, Sawynok J
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Eur J Pharmacol. 1996 Feb 29;298(1):45-9. doi: 10.1016/0014-2999(95)00775-x.
Morphine releases adenosine from the spinal cord and this contributes to spinal antinociception. The present study examined possible interactions between mu- and subclasses of delta-opioid receptors in the release of adenosine. Nanomolar (10(-8), 10(-9) M) concentrations of morphine release adenosine from spinal cord synaptosomes under conditions of partial depolarization with elevated K+, and this component of release is mediated by activation of mu-opioid receptors. Subnanomolar (10(-10), 10(-11) M) concentrations of the mu-opioid receptor agonists morphine, [N-MePhe3,D-Pro4]morphiceptin, and [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) have minimal effects on the release of adenosine from the spinal cord. However, [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta 1-opioid receptor agonist, and [D-Ala2,Cys4]deltorphin, a delta 2-opioid receptor agonist, at doses which exhibit no intrinsic effects (10(-8) and 10(-7) M), shifted the dose-response curve for mu-opioid receptor-evoked adenosine release to the left in a dose-dependent manner. DPDPE was more potent than [D-Ala2,Cys4]deltorphin when combined with the highly selective mu-opioid receptor agonist [N-MePhe3,D-Pro4]morphiceptin, but these agents showed similar activity with the less selective agonists DAMGO and morphine. Simultaneous activation of mu- and delta-opioid receptors generates a synergistic release of adenosine from spinal cord synaptosomes. Although agonists for both delta 1- and delta 2-opioid receptor subtypes produce this response, the delta 1-opioid receptor agonist is more potent at eliciting this effect when the most selective mu-opioid receptor ligand is used.
吗啡从脊髓释放腺苷，这有助于脊髓镇痛。本研究考察了μ-阿片受体和δ-阿片受体亚型在腺苷释放过程中可能存在的相互作用。在高钾引起部分去极化的条件下，纳摩尔浓度（10⁻⁸、10⁻⁹ M）的吗啡可从脊髓突触体释放腺苷，且该释放成分由μ-阿片受体的激活介导。纳摩尔以下浓度（10⁻¹⁰、10⁻¹¹ M）的μ-阿片受体激动剂吗啡、[N-甲基苯丙氨酸³，D-脯氨酸⁴]吗啡脑啡肽和[D-丙氨酸²，N-甲基苯丙氨酸⁴，甘氨酸⁵-醇]脑啡肽（DAMGO）对脊髓腺苷释放的影响极小。然而，δ₁-阿片受体激动剂[D-青霉胺²，D-青霉胺⁵]脑啡肽（DPDPE）和δ₂-阿片受体激动剂[D-丙氨酸²，半胱氨酸⁴]强啡肽在无内在效应的剂量（10⁻⁸和10⁻⁷ M）下，以剂量依赖的方式使μ-阿片受体诱发的腺苷释放剂量反应曲线左移。当与高选择性μ-阿片受体激动剂[N-甲基苯丙氨酸³，D-脯氨酸⁴]吗啡脑啡肽联合使用时，DPDPE比[D-丙氨酸²，半胱氨酸⁴]强啡肽更有效，但这些药物与选择性较低的激动剂DAMGO和吗啡表现出相似的活性。μ-和δ-阿片受体的同时激活会使脊髓突触体协同释放腺苷。虽然δ₁-和δ₂-阿片受体亚型的激动剂均可产生此反应，但当使用最具选择性的μ-阿片受体配体时，δ₁-阿片受体激动剂在引发此效应方面更有效。
