Pineda-Farias Jorge Baruch, Loeza-Alcocer Emanuel, Nagarajan Vidhya, Gold Michael S, Sekula Raymond F
Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
J Neurosci. 2021 Oct 27;41(43):8991-9007. doi: 10.1523/JNEUROSCI.0547-21.2021. Epub 2021 Aug 26.
Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms, as indicated by the clinical finding that the antiseizure drug carbamazepine (CBZ) relieves pain because of compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a selective increase in the efficacy of the Na1.1 channel blocker ICA-121431 and Na1.1 protein in the ION, but no change in Na1.1 mRNA in trigeminal ganglia. Importantly, local ICA-121431 administration reversed ION CCI-induced hypersensitivity. Our results suggest a novel therapeutic target for the treatment of trigeminal neuropathic pain. This study is based on evidence of differences in pain and its treatment depending on whether the pain is above (trigeminal) or below (somatic) the neck, as well as evidence that voltage-gated sodium channels (VGSCs) may contribute to these differences. The focus of the present study was on channels underlying action potential propagation in peripheral nerves. There were differences between somatic and trigeminal nerves in VGSC subtypes underlying action potential propagation both in the absence and presence of injury. Importantly, because the local block of Na1.1 in the trigeminal nerve reverses nerve injury-induced mechanical hypersensitivity, the selective upregulation of Na1.1 in trigeminal nerves suggests a novel therapeutic target for the treatment of pain associated with trigeminal nerve injury.
不同的周围神经损伤通过不同的机制导致神经性疼痛。正如抗癫痫药物卡马西平（CBZ）可缓解三叉神经而非躯体神经压迫性损伤所致疼痛这一临床发现所表明的，损伤部位甚至可能影响潜在机制。在本研究中，我们利用了这一观察结果，推测由于CBZ阻断电压门控钠通道（VGSCs），其治疗选择性反映了三叉神经和躯体神经在损伤诱导的VGSCs变化方面的差异。CBZ减少了慢性缩窄性损伤（CCI）眶下神经（ION）大鼠的持续性和诱发性疼痛行为，但对坐骨神经CCI大鼠的影响极小。这种行为差异与CBZ诱导的ION复合动作电位抑制效力的选择性增加有关，这一效应在人类三叉神经与躯体神经中也有体现。效力的增加与ION中Na1.1通道阻滞剂ICA - 121431和Na1.1蛋白效力的选择性增加有关，但三叉神经节中Na1.1 mRNA没有变化。重要的是，局部给予ICA - 121431可逆转ION CCI诱导的超敏反应。我们的结果提示了一种治疗三叉神经性疼痛的新治疗靶点。本研究基于疼痛及其治疗因疼痛位于颈部以上（三叉神经）还是以下（躯体神经）而存在差异的证据，以及电压门控钠通道（VGSCs）可能导致这些差异的证据。本研究的重点是外周神经动作电位传导的基础通道。在有无损伤的情况下，躯体神经和三叉神经在动作电位传导的基础VGSC亚型上均存在差异。重要的是，由于三叉神经中Na1.1的局部阻断可逆转神经损伤诱导的机械性超敏反应，三叉神经中Na1.1的选择性上调提示了一种治疗与三叉神经损伤相关疼痛的新治疗靶点。
