Jeub Monika, Taha Omneya, Opitz Thoralf, Racz Ildiko, Pitsch Julika, Becker Albert, Beck Heinz
Department of Neurology, University of Bonn Medical Center, Bonn, Germany,
Department of Epileptology, University of Bonn Medical Center, Bonn, Germany,
J Pain Res. 2019 Feb 11;12:635-647. doi: 10.2147/JPR.S138708. eCollection 2019.
Neuropathic pain resulting from peripheral nerve lesions is a common medical condition, but current analgesics are often insufficient. The identification of key molecules involved in pathological pain processing is a prerequisite for the development of new analgesic drugs. Hyperexcitability of nociceptive DRG-neurons due to regulation of voltage-gated ion-channels is generally assumed to contribute strongly to neuropathic pain. There is increasing evidence, that T-type Ca-currents and in particular the Ca3.2 T-type-channel isoform play an important role in neuropathic pain, but experimental results are contradicting.
To clarify the role of T-type Ca-channels and in particular the Ca3.2 T-type-channel isoform in neuropathic pain.
The effect of partial sciatic nerve ligation (PNL) on pain behavior and the properties of T-type-currents in nociceptive DRG-neurons was tested in wild-type and Ca3.2-deficient mice.
In wild-type mice, PNL of the sciatic nerve caused neuropathic pain and an increase of T-type Ca-currents in capsaicin-responsive neurons, while capsaicin-unresponsive neurons were unaffected. Pharmacological experiments revealed that this upregulation was due to an increase of a Ni-resistant Ca-current component, inconsistent with Ca3.2 up-regulation. Moreover, following PNL Ca3.2-deficient mice showed neuropathic pain behavior and an increase of T-Type Ca-currents indistinguishable to that of PNL treated wild-type mice.
These data suggest that PNL induces an upregulation of T-Type Ca-currents in capsaicin-responsive DRG-neurons mediated by an increase of a Ni-insensitive current component (possibly Ca3.1 or Ca3.3). These findings provide relevance for the development of target specific analgesic drugs.
周围神经损伤导致的神经性疼痛是一种常见的病症，但目前的镇痛药往往效果不佳。识别参与病理性疼痛处理的关键分子是开发新型镇痛药的前提。一般认为，由于电压门控离子通道的调节，伤害性背根神经节（DRG）神经元的过度兴奋在神经性疼痛中起重要作用。越来越多的证据表明，T型钙电流，尤其是Ca3.2 T型通道亚型在神经性疼痛中起重要作用，但实验结果相互矛盾。
阐明T型钙通道，尤其是Ca3.2 T型通道亚型在神经性疼痛中的作用。
在野生型和Ca3.2基因缺陷小鼠中，测试坐骨神经部分结扎（PNL）对疼痛行为和伤害性DRG神经元中T型电流特性的影响。
在野生型小鼠中，坐骨神经PNL导致神经性疼痛，并使辣椒素敏感神经元中的T型钙电流增加，而辣椒素不敏感神经元未受影响。药理学实验表明，这种上调是由于镍抗性钙电流成分增加所致，与Ca3.2上调不一致。此外，PNL后，Ca3.2基因缺陷小鼠表现出神经性疼痛行为，且T型钙电流增加，与接受PNL治疗的野生型小鼠无异。
这些数据表明，PNL通过增加镍不敏感电流成分（可能是Ca3.1或Ca3.3）介导，诱导辣椒素敏感DRG神经元中T型钙电流上调。这些发现为开发靶向特异性镇痛药提供了依据。
