Bernstein M A, Welch S P
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Eur J Pharmacol. 1998 Jan 12;341(2-3):173-7. doi: 10.1016/s0014-2999(97)01502-1.
Recently our laboratory found that tolerance to morphine-induced antinociception could be completely reversed with intracerebroventricular (i.c.v.) administration of a protein kinase A inhibitor, whereas intrathecal (i.t.) administration of the inhibitor produced hyperalgesia in morphine-tolerant mice. In the experiments described here, we sought to characterize further the role of phosphorylation events in supraspinal versus spinal opioid-mediated pain pathways and how such events might be involved in the development of antinociceptive tolerance. Two phosphatase inhibitors were administered centrally to determine whether they affected morphine-induced antinociception in naive or chronically morphine-treated mice. By the i.c.v. route, okadaic acid enhanced morphine-induced antinociception in tolerant mice and produced toxicity by the i.t. route. The calcineurin inhibitor ascomycin had no effect on antinociception following acute or chronic morphine treatment. These results suggest that increased activity of protein phosphatase types 1 and/or 2A in the brain may contribute to the development of morphine tolerance.
最近我们实验室发现，通过脑室内（i.c.v.）注射蛋白激酶A抑制剂可完全逆转对吗啡诱导的镇痛作用的耐受性，而鞘内（i.t.）注射该抑制剂会在吗啡耐受小鼠中产生痛觉过敏。在此处描述的实验中，我们试图进一步阐明磷酸化事件在脊髓上与脊髓阿片类药物介导的疼痛通路中的作用，以及这些事件可能如何参与镇痛耐受性的形成。向中枢给予两种磷酸酶抑制剂，以确定它们是否会影响未处理或长期接受吗啡治疗的小鼠中吗啡诱导的镇痛作用。通过i.c.v.途径，冈田酸增强了耐受小鼠中吗啡诱导的镇痛作用，并通过i.t.途径产生毒性。钙调神经磷酸酶抑制剂子囊霉素在急性或慢性吗啡治疗后对镇痛作用没有影响。这些结果表明，大脑中1型和/或2A型蛋白磷酸酶活性的增加可能有助于吗啡耐受性的形成。
