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Background  The mechanisms by which painful injuries are linked to the multitude of pain-related comorbidities and neuroplastic changes in the brain remain poorly understood. Here we propose a model that relies on epi-neuronal communication through the vascular system to effect various brain structures. Specifically, we hypothesize that the differential vulnerability of the blood–brain barrier (BBB) in different brain regions is associated with region-specific neuroplastic and neurovascular changes that are in turn associated with particular pain-related comorbidities.    Presentation of the hypothesis  We will present our hypothesis by focusing on two main points: (A) chronic pain (CP) is associated with differential BBB compromise. (B) Circulating mediators leaking through the BBB create cytogenic and neovascular niches associated with pain-related co-morbidities.    Testing the hypothesis  Pre-clinically, our hypothesis can be tested by observing, in parallel, BBB compromise, (neo)vascularization, neurogenesis, and their co-localization in animal pain models using imaging, microscopy, biochemical and other tools. Furthermore, the BBB can be experimentally damaged in specific brain regions, and the consequences of those lesions studied on nociception and associated comorbidities. Recently developed imaging techniques allow the analysis of blood brain barrier integrity in patients providing a route for translation of the laboratory findings. Though perhaps more limited, post-mortem examination of brains with available pain histories constitutes a second approach to addressing this hypothesis.    Implications of the hypothesis  Understanding changes in BBB permeability in chronic pain conditions has clear implications both for understanding the pathogenesis of chronic pain and for the design of novel treatments to prevent chronic pain and its consequences. More broadly, this hypothesis may help us to understand how peripheral injuries impact the brain via mechanisms other than commonly studied efferent sensory pathways.

Novel Cytogenic and Neurovascular Niches due to Blood–Brain Barrier Compromise in the Chronic Pain Brain