Stemkowski Patrick, García-Caballero Agustin, Gadotti Vinicius De Maria, M'Dahoma Said, Huang Shuo, Black Stefanie Alice Gertrud, Chen Lina, Souza Ivana Assis, Zhang Zizhen, Zamponi Gerald Werner
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Cell Rep. 2016 Dec 13;17(11):2901-2912. doi: 10.1016/j.celrep.2016.11.047.
Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway.
外周神经损伤和组织炎症导致去泛素化酶USP5上调，从而引起T型钙通道活性失调并增加疼痛敏感性。在此，我们探讨了传入纤维活动在这一过程中的作用。对表达瞬时受体电位香草酸亚型1（TRPV1）的伤害性感受器进行光遗传学靶向的皮肤条件刺激，而非对非伤害性纤维进行刺激，导致小鼠背根神经节和脊髓背角中USP5表达增强，同时热刺激和机械刺激的撤阈降低，且这种降低在24小时后减弱。一种阻止USP5与Cav3.2结合的干扰肽可显著减轻这种敏化作用。通过药理学阻断TRPV1传入纤维可缓解敏化，但阻断有髓神经元则无效。在脊髓切片记录中，我们可以通过光遗传学触发脊髓背角中依赖于Cav3.2通道活性的突触前神经传递的活动依赖性增强。这种神经元活动诱导的USP5上调可能是疼痛通路保护性、短暂敏化的基础。
