Changes in blood-spinal cord barrier permeability and neuroimmune interactions in the underlying mechanisms of chronic pain

Abstract

Advancing our understanding of the underlying mechanisms of chronic pain is instrumental to the identification of new potential therapeutic targets. Neuroimmune communication throughout the pain pathway is of crucial mechanistic importance and has been a major focus of preclinical chronic pain research over the last 2 decades. In the spinal cord, not only do dorsal horn neurons partake in mechanistically important bidirectional communication with resident immune cells such as microglia, but in some cases, they can also partake in bidirectional crosstalk with immune cells, such as monocytes/macrophages, which have infiltrated into the spinal cord from the circulation. The infiltration of immune cells into the spinal cord can be partly regulated by changes in permeability of the blood-spinal cord barrier (BSCB). Here, we discuss evidence for and against a mechanistic role for BSCB disruption and associated changes in neuroimmune crosstalk in preclinical chronic pain. We also consider recent evidence for its potential involvement in the vincristine model of chemotherapy-induced painful neuropathy. We conclude that current knowledge warrants further investigation to establish whether preventing BSCB disruption, or targeting the changes associated with this disruption, could be used for the development of novel approaches to treating chronic pain.

Keywords: Blood–spinal cord barrier; Chemotherapy-induced pain; Monocytes/macrophages; Neuroimmune interactions.

Figure 1.

Blood–spinal cord barrier disruption and immune cell infiltration into the spinal cord as an underlying mechanism of neuropathic pain. (A) One downstream effect of treatment with chemotherapy agents such as vincristine (VCR) is the activation of endothelial cells of the BSCB and disruption of tight junctions. (B) CCR₂⁺ monocytes infiltrate into the spinal cord in response to the release of CCL₂ from endothelial cells. (B) Monocytes/macrophages release CatS, which cleaves neuronally expressed fractalkine (FKN) producing soluble fractalkine (sFKN). (D) sFKN activates CX₃CR₁ receptors on microglia, which in turn release pronociceptive mediators. (E) After chronic constriction injury (CCI) there is evidence for BSCB disruption. (F) One outcome of such disruption is that CXCR₃-expressing T-cells infiltrate into the spinal cord.