The Contribution of Gi/o Protein to Opioid Antinociception in an Oxaliplatin-Induced Neuropathy Rat Model
The Contribution of Gi/o Protein to Opioid Antinociception in an Oxaliplatin-Induced Neuropathy Rat Model
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DOI：
10.1254/jphs.14133fp
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发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Kanemasa, Toshiyuki
中科院分区：
文献类型：
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作者：
Kanbara, Tomoe;Nakamura, Atsushi;Kanemasa, Toshiyuki
奥沙利铂是一种化疗药物，可导致慢性难治性神经病变。为了确定阿片类药物是否有效地缓解这种慢性神经病变，我们研究了吗啡、羟考酮和芬太尼在奥沙利铂诱导的大鼠神经病变中的疗效以及阿片类药物抗伤害作用的机制。奥沙利铂慢性给药2周后，大鼠表现出明显的机械性痛觉异常。在未引起镇静和/或肌肉僵硬的剂量范围内，吗啡(3 mg/kg，皮下注射)羟考酮(0.3-0.56 mg/kg，S.C.)可完全逆转奥沙利铂所致的机械性痛觉过敏，而芬太尼(0.017-0.03 mg/kg，S.C.)表现出部分的抗伤害性。在草酸铂模型中，最佳剂量的吗啡和羟考酮的抗伤害作用可被Gi/o蛋白抑制剂百日咳毒素(PTX；0.5mUg/只，i.c.v)完全抑制，而芬太尼的部分作用不受影响。在[S-35]-GTP-S结合实验中，奥沙利铂组大鼠丘脑内侧背侧核对阿片受体的激活可被芬太尼显著降低，而吗啡和羟考酮则不能。这些结果表明，在奥沙利铂模型中，芬太尼的抗伤害效应降低可能部分是由于失去了对PTX敏感的Gi/o蛋白的激活，而Gi/o蛋白的激活程度可能与阿片类药物在该模型中的抗伤害效应有关。
Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3 - 0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017 - 0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 mu g/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [S-35]-GTP gamma S binding assay, activation of mu-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.