Narita M, Ohsawa M, Mizoguchi H, Kamei J, Tseng L F
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Neuroscience. 1997 Jan;76(1):291-8. doi: 10.1016/s0306-4522(96)00354-5.
The effects of pretreatment with a protein kinase C activator, phorbol 12,13-dibutyrate, on antinociception induced by i.c.v.-administered mu-opioid receptor agonist (D-Ala2, NMePhe4, Gly(ol)5) enkephalin (DAMGO) or morphine and epsilon-opioid receptor agonist beta-endorphin were studied in male ICR mice. The tail-flick responses were used for antinociceptive tests. I.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol) for 30 or 60 but not 10 min attenuated antinociception induced by i.c.v.-administered DAMGO. I.c.v. pretreatment with phorbol 12,13-dibutyrate (10 and 50 pmol) for 60 min caused a dose-dependent attenuation of DAMGO (19.5 pmol)- or morphine (6.0 nmol)-induced antinociception. The dose-response curve for DAMGO-induced antinociception was shifted to the right by 7.3-fold by i.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol) for 60 min. However, the i.c.v.-administered beta-endorphin-induced antinociception was not affected by the same pretreatment with phorbol 12,13-dibutyrate. The attenuation of i.c.v.-administered DAMGO- and morphine-induced antinociception by phorbol 12,13-dibutyrate was reversed by concomitant i.c.v. pretreatment with a selective protein kinase C inhibitor calphostin C. These results suggest that activation of protein kinase C by phorbol 12,13-dibutyrate leads to the desensitization of mu-, but not epsilon-opioid receptor-mediated antinociception. These findings also provide additional evidence for differential intracellular modulation on antinociceptive action of mu- and epsilon-opioid receptor agonists.
在雄性ICR小鼠中，研究了用蛋白激酶C激活剂佛波醇12,13 - 二丁酸酯预处理对脑室内注射μ - 阿片受体激动剂（D - Ala2，NMePhe4，Gly(ol)5）脑啡肽（DAMGO）或吗啡以及ε - 阿片受体激动剂β - 内啡肽诱导的镇痛作用的影响。采用甩尾反应进行镇痛测试。脑室内用佛波醇12,13 - 二丁酸酯（50 pmol）预处理30或60分钟（而非10分钟）可减弱脑室内注射DAMGO诱导的镇痛作用。脑室内用佛波醇12,13 - 二丁酸酯（10和50 pmol）预处理60分钟会导致DAMGO（19.5 pmol）或吗啡（6.0 nmol）诱导的镇痛作用呈剂量依赖性减弱。脑室内用佛波醇12,13 - 二丁酸酯（50 pmol）预处理60分钟可使DAMGO诱导的镇痛作用的剂量 - 反应曲线右移7.3倍。然而，脑室内注射β - 内啡肽诱导的镇痛作用不受相同的佛波醇12,13 - 二丁酸酯预处理的影响。佛波醇12,13 - 二丁酸酯对脑室内注射DAMGO和吗啡诱导的镇痛作用的减弱可通过同时脑室内用选择性蛋白激酶C抑制剂钙泊三醇C预处理来逆转。这些结果表明，佛波醇12,13 - 二丁酸酯激活蛋白激酶C会导致μ - 阿片受体介导的镇痛作用脱敏，但不会导致ε - 阿片受体介导的镇痛作用脱敏。这些发现也为μ - 和ε - 阿片受体激动剂的镇痛作用的细胞内差异调节提供了额外证据。
