Alteration of spinal protein kinase C expression and kinetics in morphine, but not clonidine, tolerance.
Alteration of spinal protein kinase C expression and kinetics in morphine, but not clonidine, tolerance.
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DOI：
10.1016/s0006-2952(99)00107-0
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发表时间：
1999-08
影响因子：
5.8
通讯作者：
Y. Li;S. Roerig
中科院分区：
文献类型：
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作者：
Y. Li;S. Roerig
在对吗啡和可乐定耐受的小鼠中，脊髓注射吗啡和可乐定之间的抗伤害协同作用减弱为相加的相互作用。脊髓给药的蛋白激酶C(PKC)抑制剂也降低了加成的协同作用。为了确定慢性吗啡或可乐定治疗是否改变了脊髓的PKC活性，本研究测定了脊髓胞浆和胞膜部分的PKC活性和PKC亚型蛋白的表达。分别用安慰剂微丸、吗啡微丸、皮下注射治疗小鼠4天。生理盐水，或S.C.可乐定。植入吗啡颗粒的小鼠对吗啡引起的甩尾抗伤害反应有耐受性，但对可乐定没有交叉耐受性。可乐定预处理小鼠对可乐定有耐受性，但对吗啡没有交叉耐受性。诱导吗啡耐受后，脊髓胞浆蛋白激酶C的Km值降低了2倍(安慰剂组为8.24±1.67μM，吗啡组为4.43±1.24μM)，但未见脊髓膜组分的Km值。Vmax值无差异。在生理盐水和可乐定处理的动物的蛋白质之间没有发现Kmor Vmax的差异。在吗啡耐受动物的胞浆中，cPKCα，βI和γ亚型分别减少了14%、26%和17%。在耐受可乐定小鼠的细胞膜或组分中，没有发现PKC亚型的差异。吗啡耐受，但不是可乐定耐受，增加了PKC活性，同时降低了蛋白表达。
Antinociceptive synergism between spinally administered morphine and clonidine decreases to an additive interaction in morphine- and clonidine-tolerant mice. Spinally administered protein kinase C (PKC) inhibitors also decrease the synergism to addition. To determine whether chronic morphine or clonidine treatment alters spinal PKC activity, the present studies measured PKC activity and expression of PKC isoform proteins in spinal cord cytosol and membrane fractions. Mice were treated for 4 days with either placebo pellets, morphine pellets, s.c. saline, or s.c. clonidine. Morphine pellet-implanted mice were tolerant to morphine-induced tail flick antinociception, but not cross-tolerant to clonidine. Clonidine-pretreated mice were tolerant to clonidine, but not cross-tolerant to morphine. Induction of morphine tolerance produced a 2-fold lower Kmvalue for PKC (8.24 ± 1.67 μM in placebo pellet vs 4.43 ± 1.24 μM in morphine pellet) in cytosol, but not membrane fractions from spinal cord. Vmaxvalues were not different. No difference in Kmor Vmaxvalues was found between proteins from saline- and clonidine-pretreated animals. Immunoreactive cPKCα, βI, and γ isoforms decreased 14, 26, and 17%, respectively, in cytosol from morphine-tolerant animals. No difference in PKC isoforms was found in the membranes or in fractions from clonidine-tolerant mice. Morphine tolerance, but not clonidine tolerance, enhanced PKC activity while decreasing protein expression.