Smith F L, Dombrowski D S, Dewey W L
Department of Pharmacology and Toxicology, Medical College of Virginia of Virginia Commonwealth University, Richmond 23298-0613, USA.
Pharmacol Biochem Behav. 1999 Feb;62(2):381-8. doi: 10.1016/s0091-3057(98)00168-3.
Opioid analgesic tolerance is associated with a disruption in Ca++ homeostasis. Drugs reducing Ca++ influx can prevent and reverse tolerance. The hypothesis was tested that both Ca++ influx and mobilization from intracellular pools maintains the expression of morphine tolerance. Ca++ modulating drugs were injected ICV at doses not affecting morphine's potency in placebo pellet-implanted mice, in order to determine whether tolerance would be reversed in morphine pellet-implanted mice. The Ca++ chelator EGTA significantly reversed tolerance. The Ca++ channel antagonists nifedipine and omega-conotoxin GVIA also reversed tolerance. The role of intracellular Ca++ was investigated using the membrane permeable intracellular Ca++ chelator EGTA-AM. EGTA-AM reversed tolerance at lower morphine doses, but not at higher morphine doses. Thus, mobilization of intracellular Ca++ contributes to the expression of tolerance. Finally, 1,4-dihydropyridine-sensitive Ca++ channels are known to stimulate Ca++-induced Ca++ release (CICR) from Ca++/caffeine-sensitive microsomal pools possessing ryanodine receptors. We examined whether blocking Ca++ mobilization from these pools with ryanodine would reverse morphine tolerance. Ryanodine's effects were similar to EGTA-AM. Tolerance was reversed at lower morphine doses, but not at higher doses. Thus, morphine tolerance appears to be associated with increases in Ca++ influx and mobilization from Ca++/caffeine-sensitive pools.
阿片类镇痛药耐受性与钙离子稳态破坏有关。减少钙离子内流的药物可预防和逆转耐受性。本研究检验了以下假设：钙离子内流和从细胞内储存库的动员均维持吗啡耐受性的表达。在植入安慰剂丸的小鼠中，以不影响吗啡效力的剂量脑室内注射钙离子调节药物，以确定在植入吗啡丸的小鼠中耐受性是否会被逆转。钙离子螯合剂乙二醇双四乙酸（EGTA）显著逆转了耐受性。钙离子通道拮抗剂硝苯地平和ω-芋螺毒素GVIA也逆转了耐受性。使用细胞膜可渗透的细胞内钙离子螯合剂EGTA-AM研究细胞内钙离子的作用。EGTA-AM在较低吗啡剂量下逆转了耐受性，但在较高吗啡剂量下未逆转。因此，细胞内钙离子的动员有助于耐受性的表达。最后，已知1,4-二氢吡啶敏感的钙离子通道可刺激从具有兰尼碱受体的钙离子/咖啡因敏感微粒体储存库中释放钙离子诱导的钙离子释放（CICR）。我们研究了用兰尼碱阻断这些储存库中的钙离子动员是否会逆转吗啡耐受性。兰尼碱的作用与EGTA-AM相似。在较低吗啡剂量下耐受性被逆转，但在较高剂量下未被逆转。因此，吗啡耐受性似乎与钙离子内流增加以及从钙离子/咖啡因敏感储存库的动员有关。
