Peripheral-Type Benzodiazepine Receptor Antagonist Is Effective in Relieving Neuropathic Pain in Mice
Peripheral-Type Benzodiazepine Receptor Antagonist Is Effective in Relieving Neuropathic Pain in Mice
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DOI：
10.1254/jphs.09028fp
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发表时间：
2009-05-01
影响因子：
3.5
通讯作者：
Tanabe, Tsutomu
中科院分区：
文献类型：
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作者：
Kondo, Daisuke;Saegusa, Hironao;Tanabe, Tsutomu
cDNA微阵列分析显示，与假手术小鼠相比，脊髓神经损伤（SNL）小鼠脊髓中外周型苯二氮卓受体（PBR）mRNA的表达略有增强。 PBR 将胆固醇转运至线粒体，在那里胆固醇转化为孕烯醇酮。然后孕烯醇酮代谢为黄体酮（黄体酮受体的激活剂），并进一步代谢产生别孕酮和 3 α,21-二羟基-5 α-孕-20-酮 (3 α,5 α-THDOC)、正变构调节剂和 GABA(A) 受体激活剂。在本研究中，我们首先测试了 PBR 表达的增强是否与神经性疼痛有因果关系，我们发现 PBR 拮抗剂 PK11195 可有效减轻 SNL 诱导的机械异常性疼痛和热痛觉过敏。接下来，我们测试了 PK11195 诱导的镇痛作用是否可归因于神经类固醇合成减少，这可能导致黄体酮受体和/或 GABA(A) 受体的激活减少。我们发现 allopregnanolone 和 3 α,5 α-THDOC 可有效降低 PK11195 的抗痛觉过敏作用，这表明 GABA(A) 受体激活减少对 PK11195 诱导的镇痛有部分贡献。
cDNA microarray analysis showed the expression of peripheral-type benzodiazepine receptor (PBR) mRNA is slightly enhanced in the spinal cord of mice with spinal nerve injury (SNL) as compared with sham-operated mice. PBR transports cholesterol to the mitochondria, where cholesterol is converted to pregnenolone. Pregnenolone is then metabolized to progesterone, an activator of progesterone receptor, and further metabolized to produce allopregnanolone and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THDOC), positive allosteric modulators and activators of the GABA(A) receptor. In the present study, we first tested whether the enhanced PBR expression is causally related to neuropathic pain, and we found that the PBR antagonist PK11195 is effective in reducing SNL-induced mechanical allodynia and thermal hyperalgesia. Next we tested whether the PK11195-induced antinociception is attributable to reduced neurosteroid synthesis, which may possibly lead to reduced activation of the progesterone receptor and/or GABA(A) receptor. We found that allopregnanolone and 3 alpha,5 alpha-THDOC are effective in reducing the anti-hyperalgesic effect of PK11195, suggesting a partial contribution of reduced GABA(A)-receptor activation to PK11195-induced antinociception.