Bailey Alexis, Ledent Catherine, Kelly Mary, Hourani Susanna M O, Kitchen Ian
Pharmacology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey, GU2 7XH United Kingdom.
J Neurosci. 2002 Nov 1;22(21):9210-20. doi: 10.1523/JNEUROSCI.22-21-09210.2002.
A large body of evidence indicates important interactions between the adenosine and opioid systems in regulating pain at both the spinal and supraspinal level. Mice lacking the A(2A) receptor gene have been developed successfully, and these animals were shown to be hypoalgesic. To investigate whether there are any compensatory alterations in opioid systems in mutant animals, we have performed quantitative autoradiographic mapping of mu, delta, kappa, and opioid receptor-like (ORL1) opioid receptors in the brains and spinal cords of wild-type and homozygous A(2A) receptor knock-out mice. In addition, mu-, delta-, and kappa-mediated antinociception using the tail immersion test was tested in wild-type and homozygous A(2A) receptor knock-out mice. A significant reduction in [3H]deltorphin-I binding to delta receptors and a significant increase in [3H]CI-977 binding to kappa receptors was detected in the spinal cords but not in the brains of the knock-out mice. Mu and ORL1 receptor expression were not altered significantly. Moreover, a significant reduction in delta-mediated antinociception and a significant increase in kappa-mediated antinociception were detected in mutant mice, whereas mu-mediated antinociception was unaffected. Comparison of basal nociceptive latencies showed a significant hypoalgesia in knock-out mice when tested at 55 degrees C but not at 52 degrees C. The results suggest a functional interaction between the spinal delta and kappa opioid and the peripheral adenosine system in the control of pain pathways.
大量证据表明，腺苷系统与阿片系统在脊髓和脊髓上水平调节疼痛过程中存在重要相互作用。缺乏A(2A)受体基因的小鼠已成功培育出来，这些动物表现出痛觉减退。为了研究突变动物的阿片系统是否存在任何代偿性改变，我们对野生型和纯合A(2A)受体基因敲除小鼠的脑和脊髓中的μ、δ、κ和阿片受体样（ORL1）阿片受体进行了定量放射自显影定位。此外，还在野生型和纯合A(2A)受体基因敲除小鼠中，利用尾部浸没法测试了μ、δ和κ介导的抗伤害感受作用。在基因敲除小鼠的脊髓中检测到[3H]强啡肽-I与δ受体的结合显著减少，[3H]CI-977与κ受体的结合显著增加，但在脑中未检测到。μ和ORL1受体表达没有明显改变。此外，在突变小鼠中检测到δ介导的抗伤害感受作用显著降低，κ介导的抗伤害感受作用显著增加，而μ介导的抗伤害感受作用未受影响。基础痛觉潜伏期的比较显示，基因敲除小鼠在温度为55℃时进行测试时有显著的痛觉减退，但在52℃时没有。结果表明，脊髓δ和κ阿片系统与外周腺苷系统在疼痛通路控制中存在功能相互作用。
