Universidade Federal do Rio de Janeiro - Campus Macaé Rio de Janeiro, Brazil ; Laboratório de Morfogênese Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil ; Headache and Orofacial Pain Effort, Department of Biologic and Materials Sciences and Michigan Center for Oral Health Research, School of Dentistry, University of Michigan Ann Arbor, MI, USA.
Laboratório de Morfogênese Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil.
Front Cell Neurosci. 2014 Oct 8;8:302. doi: 10.3389/fncel.2014.00302. eCollection 2014.
The function of the blood-brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major efflux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood-spinal cord barrier and blood-nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine.
血脑屏障（BBB）在慢性疼痛中的功能已被探索，其经典作用是调节细胞间和细胞旁转运，从而控制作用于中枢神经系统的药物的流动，如阿片类镇痛药（如吗啡）和非甾体抗炎药。尽管如此，最近的研究提出了 BBB 通透性的变化可能与慢性疼痛有关的可能性。例如，在炎症性痛觉过敏后，occludin 同工型的相对量发生变化，导致 BBB 通透性显著增加。此外，炎症性疼痛会导致 P-糖蛋白（BBB 上的主要外排转运体）发生结构变化。这些发现的一个可能解释是，通常在外周损伤部位释放的物质的作用，这些物质可能导致脑内皮通透性发生变化，包括 P 物质、降钙素基因相关肽和白细胞介素-1β。有趣的是，炎症性疼痛也会导致小胶质细胞激活，从而加剧 BBB 损伤。事实上，星形胶质细胞和小胶质细胞在维持 BBB 完整性方面起着至关重要的作用，这些细胞的激活被认为是慢性疼痛的关键机制。尽管人们对 BBB 在疼痛发展中的功能及其对镇痛药疗效的干扰有了新的认识，但在这个过程中涉及的分子机制仍有许多未知之处。在这篇综述中，我们探讨了 BBB 以及血脊髓屏障和血神经屏障与疼痛之间的联系，重点关注炎症性或神经性疼痛和偏头痛引起的 BBB 通透性增加的细胞和分子机制。
