Pharmacological characterization of lysophosphatidic acid-induced pain with clinically relevant neuropathic pain drugs
Pharmacological characterization of lysophosphatidic acid-induced pain with clinically relevant neuropathic pain drugs
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DOI：
10.1002/j.1532-2149.2011.00096.x
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发表时间：
2012-08-01
影响因子：
3.6
通讯作者：
Kato, A.
中科院分区：
文献类型：
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作者：
Ogawa, K.;Takasu, K.;Kato, A.
溶血磷脂酸(LPA)是神经病理性疼痛的始发者，会引起痛觉过敏。然而，很少有研究评估LPA诱导的疼痛的药理学特征。在本研究中，我们建立了LPA诱导的疼痛模型，并对临床上用于神经病理性疼痛的药物进行了药理学研究，包括抗癫痫药、非类固醇抗炎药、止痛药、局部麻醉剂/抗心律失常药和抗抑郁药。加巴喷丁(130 mg/kg，P.O.)但对吲哚美辛(30 mg/kg，P.O.)均无明显逆转作用。或吗啡(0.33 mg/kg，S.C.)DID，这表明LPA引起的疼痛主要是神经病理性疼痛而不是炎症性疼痛。普瑞巴林(0.310 mg/kg，P.O.)和？-CgTX MVIIA(0.010.03微克/鼠，I.T.)以剂量依赖的方式完全逆转LPA诱导的痛觉过敏。利多卡因(130 mg/kg，S.C.)、美西律(130 mg/kg，P.O.)卡马西平(10100 mg/kg，P.O.)显著改善LPA诱导的痛觉过敏，并呈剂量依赖关系。米那普兰(30 mg/kg，ip)对LPA所致的痛觉过敏无明显的镇痛作用。在LPA注射的小鼠，电压门控性钙通道(VGCC)的a2d1亚单位在背根神经节(DRG)和脊髓背角的表达增加。此外，LPA和LPA(1mU M)处理的小鼠背根神经节的VGCC电流均增强，加巴喷丁(100mU M)可使VGCC电流增强。本文描述的LPA诱导的疼痛模型模拟了神经病理性疼痛状态的各个方面，包括VGCC的敏化，并可能有助于早期评估治疗神经病理性疼痛的候选药物。
Lysophosphatidic acid (LPA), an initiator of neuropathic pain, causes allodynia. However, few studies have evaluated the pharmacological profile of LPA-induced pain. In this study, a LPA-induced pain model was developed and pharmacologically characterized with clinically relevant drugs used for neuropathic pain, including antiepileptics, non-steroidal anti-inflammatory agents, analgesics, local anaesthetics/antiarrhythmics and antidepressants. Gabapentin (130?mg/kg, p.o.) significantly reversed LPA-induced allodynia, but neither indomethacin (30?mg/kg, p.o.) nor morphine (0.33?mg/kg, s.c.) did, which indicates that LPA-induced pain consists mostly of neuropathic rather than inflammatory pain. Both pregabalin (0.310?mg/kg, p.o.) and ?-CgTX MVIIA (0.010.03?mu g/mouse, i.t.) completely reversed LPA-induced allodynia in a dose-dependent manner. Lidocaine (130?mg/kg, s.c.), mexiletine (130?mg/kg, p.o.) and carbamazepine (10100?mg/kg, p.o.) significantly ameliorated LPA-induced allodynia dose dependently. Milnacipran (30?mg/kg, i.p.) produced no significant analgesic effect in LPA-induced allodynia. In LPA-injected mice, expression of the a2d1 subunit of the voltage-gated calcium channel (VGCC) was increased in the dorsal root ganglion (DRG) and spinal dorsal horn. Furthermore, the VGCC current was potentiated in both the DRG from LPA-injected mice and LPA (1?mu M)-treated DRG from saline-injected mice, and the potentiated VGCC current was amended by treatment with gabapentin (100?mu M). The LPA-induced pain model described here mimics aspects of the neuropathic pain state, including the sensitization of VGCC, and may be useful for the early assessment of drug candidates to treat neuropathic pain.