TRPM8 mechanism of cold allodynia after chronic nerve injury
TRPM8 mechanism of cold allodynia after chronic nerve injury
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DOI：
10.1523/jneurosci.2203-07.2007
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发表时间：
2007-12-12
影响因子：
5.3
通讯作者：
Gu, Jianguo G.
中科院分区：
文献类型：
--
作者：
Xing, Hong;Chen, Meng;Gu, Jianguo G.
低温和薄荷醇敏感受体TRPM8（瞬时受体电位美拉他汀8）已被认为在寒冷异常性痛中发挥作用，这是一种临床上常见的顽固性疼痛。我们利用慢性收缩性神经损伤（CCI）大鼠（后肢表现为冷性异常痛的神经性疼痛模型）研究了TRPM8在冷性异常痛中的作用。我们发现，capsazepine （TRPM8和TRPV1（瞬时受体电位香草素1）受体的阻滞剂）显著减弱了CCI动物的冷变动力学反应，但选择性TRPV1拮抗剂I-RTX（5-碘化氨基干扰素）却没有减弱。在CCI大鼠L5背根神经节（DRG）切片中，免疫染色显示与假手术组相比，trpm8免疫反应神经元的百分比增加。利用Ca2+成像技术和与L5 DRGs急性分离的神经元，我们发现CCI导致薄荷醇和冷敏感神经元的百分比显著增加，并且这些神经元对薄荷醇和无害冷的反应性也显著增强。这些变化发生在辣椒素敏感神经元中，这是一类类似伤害的神经元。通过膜片钳记录，我们发现与假药组相比，CCI组薄荷脑和无害冷诱发的膜电流显著增强。通过逆行标记针对后肢皮肤的传入神经元，我们发现皮肤神经元表达TRPM8受体，薄荷醇敏感/冷敏感/辣椒素敏感神经元的比例增加，辣椒素敏感神经元的薄荷和冷诱发反应显著增强。综上所述，trpm8介导的对伤害性传入神经元的冷敏感性的增加提供了一种冷异常性痛的机制。
The cold- and menthol-sensitive receptor TRPM8 ( transient receptor potential melastatin 8) has been suggested to play a role in cold allodynia, an intractable pain seen clinically. We studied how TRPM8 is involved in cold allodynia using rats with chronic constrictive nerve injury (CCI), a neuropathic pain model manifesting cold allodynia in hindlimbs. We found that cold allodynic response in the CCI animals was significantly attenuated by capsazepine, a blocker for both TRPM8 and TRPV1 ( transient receptor potential vanilloid 1) receptors, but not by the selective TRPV1 antagonist I-RTX (5-iodoresiniferatoxin). In L5 dorsal root ganglion (DRG) sections of the CCI rats, immunostaining showed an increase in the percentage of TRPM8-immunoreactive neurons when compared with the sham group. Using the Ca2+ -imaging technique and neurons acutely dissociated from the L5 DRGs, we found that CCI resulted in a significant increase in the percentage of menthol-and cold- sensitive neurons and also a substantial enhancement in the responsiveness of these neurons to both menthol and innocuous cold. These changes occurred in capsaicin-sensitive neurons, a subpopulation of nociceptive-like neurons. Using patch-clamp recordings, we found that membrane currents evoked by both menthol and innocuous cold were significantly enhanced in the CCI group compared with the sham group. By retrograde labeling afferent neurons that target hindlimb skin, we showed that the skin neurons expressed TRPM8 receptors, that the percentage of menthol- sensitive/cold-sensitive/capsaicin-sensitive neurons increased, and that the menthol-and cold- evoked responses were significantly enhanced in capsaicin-sensitive neurons after CCI. Together, the gain of TRPM8-mediated cold sensitivity on nociceptive afferent neurons provides a mechanism of cold allodynia.