Program in Neurosciences & Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto, and University of Toronto Centre for the Study of Pain, Toronto, ON, Canada.
Mol Pain. 2010 Nov 2;6:74. doi: 10.1186/1744-8069-6-74.
The blood-brain barrier (BBB) plays the crucial role of limiting exposure of the central nervous system (CNS) to damaging molecules and cells. Dysfunction of the BBB is critical in a broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB) remains an open question.
Here we show that peripheral nerve injury (PNI) produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24-48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain.
We have discovered that injury to a peripheral nerve and electrical stimulation of C-fibers each cause an increase in the permeability of the BSCB and the BBB. The increase in permeability is delayed in onset, peaks at about 24 hours and is dependent upon action potential propagation. As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons. Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury. In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.
血脑屏障（BBB）在限制中枢神经系统（CNS）暴露于有害分子和细胞方面起着至关重要的作用。BBB 功能障碍在广泛的 CNS 疾病中至关重要，包括神经退行性变、CNS 的炎症或创伤性损伤以及中风。在外周组织中，血管组织的通透性通常大于 BBB 通透性，但初级感觉神经元的传出放电活动可诱导血管渗漏，导致血浆渗出到血管外空间。进入 CNS 的感觉传入的放电活动是否会打开 BBB 或血脊髓屏障（BSCB）仍然是一个悬而未决的问题。
我们在这里表明，通过坐骨神经结扎或切断其两个主要分支之一造成的周围神经损伤（PNI）导致 BSCB 通透性增加，通过使用 Evans Blue 染料或辣根过氧化物酶进行评估。PNI 后 6 小时未观察到 BSCB 通透性增加，但损伤后 24 小时明显增加。BSCB 通透性的增加是短暂的，在 PNI 后约 24-48 小时达到峰值，7 天后 BSCB 完整性恢复正常水平。在神经损伤部位给予局部麻醉剂利多卡因可预防 BSCB 通透性增加。坐骨神经电刺激强度足以激活 C 纤维时，24 小时后 BSCB 通透性也会增加，但仅激活 A 纤维时则不会。同样，辣椒素应用于神经也会增加 BSCB 的通透性。C 纤维刺激或 PNI 引起的通透性增加不仅局限于来自坐骨神经的初级传入纤维在腰脊髓中的中枢末端部位，而是延伸到整个脊髓并进入大脑。
我们发现，周围神经损伤和 C 纤维电刺激都会导致 BSCB 和 BBB 的通透性增加。通透性的增加延迟发作，在约 24 小时时达到峰值，并且依赖于动作电位传播。由于将辣椒素应用于神经可以模拟通透性增加，因此我们发现最合理的解释是通透性增加是由 TRPV1 表达的初级感觉神经元的激活介导的。我们的发现可能与神经损伤后 CNS 中疼痛和神经可塑性变化的发展有关。此外，我们的发现可能为开发在需要增加通常被完整 BBB 排除的治疗剂对大脑的穿透时有意打开 BBB 的方法提供基础。
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