Brain cytochrome P450 epoxygenases were recently shown to play an essential role in mediating the pain-relieving properties of morphine. To identify the CNS sites containing the morphine-relevant P450s, the effects of intracerebral (ic) microinjections of the P450 inhibitor CC12 were determined on morphine antinociception in rats. CC12 inhibited morphine antinociception when both drugs were injected into the rostral ventromedial medulla (RVM), but not following co-injections into the periaqueductal gray (PAG) or into the spinal subarachnoid space. In addition, intra-RVM CC12 pretreatment nearly completely blocked the effects of morphine following intracerebroventricular (icv) administration. Although morphine is thought to act in both the PAG and RVM by pre-synaptic inhibition of inhibitory GABAergic transmission, the present findings show that 1) the mechanism of morphine action differs between these two brainstem areas, and 2) P450 activity within the RVM is important for supraspinal morphine antinociception. Characterization of morphine-P450 interactions within RVM circuits will further enhance the understanding of the biochemistry of pain relief.

译文

脑细胞色素P450环氧合酶最近被证明在介导吗啡的止痛特性中起重要作用。为了鉴定含有吗啡相关P450的CNS位点,确定了脑内 (ic) 微注射P450抑制剂CC12对大鼠吗啡抗伤害感受的影响。当将两种药物注射到延髓腹内侧髓质 (RVM) 中时,CC12抑制了吗啡的抗伤害感受,但在将两种药物注射到导水管周围灰色 (PAG) 或脊髓蛛网膜下腔后不进行。此外,RVM内CC12预处理几乎完全阻断了脑室内 (icv) 给药后吗啡的作用。尽管吗啡被认为通过突触前抑制抑制性gaba能传递而在PAG和RVM中起作用,但目前的发现表明: 1) 吗啡作用的机制在这两个脑干区域之间有所不同,并且2) RVM内的P450活性对于脊髓上吗啡抗伤害感受很重要。RVM回路内morphine-P450相互作用的表征将进一步增强对缓解疼痛的生物化学的理解。

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