TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord
TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord
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DOI：
10.1016/j.neuron.2012.02.039
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发表时间：
2012-05-24
期刊：
影响因子：
16.2
通讯作者：
Oh, Seog Bae
中科院分区：
文献类型：
--
作者：
Kim, Yong Ho;Back, Seung Keun;Oh, Seog Bae
神经病理性疼痛和异常性疼痛可由中枢回路的敏化引起。我们报告了一种基于去抑制的中枢敏化机制，这种机制是由于TRPV 1在脊髓中的激活导致GABA能中间神经元的长期抑制（LTD）。鞘内给药TRPV 1激动剂导致机械性异常性疼痛，不依赖于外周TRPV 1神经元。TRPV 1在GABA能脊髓中间神经元中功能性表达，并且脊髓TRPV 1的激活导致兴奋性输入的LTD和脊髓丘脑束（STT）投射神经元的抑制性信号的减少。周围神经损伤后的机械超敏反应在TRPV 1（-/-）小鼠中减弱，但在缺乏TRPV 1表达的周围神经元的小鼠中没有减弱。机械性疼痛通过脊柱应用TRPV 1拮抗剂逆转，同时避免了全身治疗的高热副作用。我们的研究结果表明，脊髓TRPV 1起着关键的作用，作为一个突触调节器，并建议使用中枢神经系统特异性TRPV 1拮抗剂治疗神经性疼痛。
Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. TRPV1 was functionally expressed in GABAergic spinal interneurons and activation of spinal TRPV1 resulted in LTD of excitatory inputs and a reduction of inhibitory signaling to spinothalamic tract (STT) projection neurons. Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1(-/-) mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.