title: Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief.
abstract: The blood-nerve barrier (BNB) is a selectively permeable barrier that creates an immunologically and biochemically privileged space for peripheral axons and supporting cells. The breakdown of the BNB allows access of blood-borne (hematogenous) cells and molecules to the endoneurium to engage in the local inflammatory cascade. This process was examined in a mouse model of trauma-associated neuropathic pain. The impact of nerve injury-triggered opening of the BNB in the development of chronic pain behavior was investigated. Partial ligation of the sciatic nerve led to a long-lasting disruption of the BNB distal to the site of injury. Vascular endothelial growth factor (VEGF) was expressed by resident macrophages after nerve injury. Intraneural injection of VEGF decreased mechanical thresholds while opening the BNB. Serum from nerve-injured or lipopolysaccharide-treated animals elicited mechanical allodynia in naive animals, when allowed to bypass the BNB by intraneural injection. Intraneural injection of fibrinogen, a clotting protein in plasma that was found to deposit in the nerve after nerve injury, also produced a decrease in mechanical thresholds when introduced into naive nerves. These results demonstrate that blood-borne molecules may play a role in the generation of neuropathic pain, suggesting that pain may be driven from infection or injury, at a distance from the nervous system. Furthermore, the breakdown of the BNB in neuropathic conditions was exploited to permit the entry of analgesic molecules that typically cannot pass the BNB, such as ProToxin-II, a BNB-impermeable Nav1.7 inhibitor. Therapeutics utilizing this mechanism could have selective access to injured nerves over healthy tissues.
authors: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada Centre de Recherche du Centre Hospitalier de L'Universite Laval, Quebec, Quebec, Canada Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.
authors: Tony K Y
authors: TKY
authors: Lim
authors: Xiang Qun
authors: XQ
authors: Shi
authors: Hiliary Claire
authors: HC
authors: Martin
authors: Hao
authors: H
authors: Huang
authors: Giamal
authors: G
authors: Luheshi
authors: Serge
authors: S
authors: Rivest
authors: Ji
authors: J
authors: Zhang
mesh_terms: D000818:Animals; D049428:Blood-Nerve Barrier / Q000378:metabolism / Q000503:physiopathology*; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D059408:Pain Management; D017288:Pain Threshold / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D012584:Sciatic Nerve / Q000293:injuries* / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: Blood-borne pronociceptive molecules; Blood-nerve barrier; Macrophage infiltration; Nerve injury; Neuropathic pain; Vascular structure