Intervertebral foramen injection of plerixafor attenuates CCD-induced low back pain in rats through down-regulation of Nav1.8 and Nav1.9

Abstract BackgroundLow back pain, an extremely common chronic pain, is now the number one cause of disability globally. On the chronic compression of the dorsal root ganglion (CCD) model, a typical low back pain model, previous study has discovered that C-X-C chemokine receptor type 4 (CXCR4) involved in mediating low back pain. However, the underlying molecular mechanisms and whether it has the potential to serve as an applicable target for clinical treatment of low back pain remains unclear. MethodsCCD-induced low back pain model was established by inserting stainless steel L-shape rod into the intervertebral foramen at L5 level. Multiple pain behaviors including mechanical hyperalgesia and allodynia, thermal hyperalgesia and cold allodynia were evaluated. The role of CXCR4 in CCD-induced pain was assessed by intraganglionar CXCR4 siRNA injection and intervertebral foramen injection of plerixafor, a selective CXCR4 antagonist. The expression change of CXCR4, Nav1.8 and Nav1.9 was examined by immunofluorescent staining.ResultsWe showed that the CXCR4 were dramatically up-regulated in the compressed dorsal root ganglion (DRG) neurons in CCD model, and intraganglionar CXCR4 siRNA injection significantly reduced CCD-induced multiple pain behaviors, including mechanical hyperalgesia and allodynia, thermal hyperalgesia and cold allodynia. The expression of Nav1.8 and Nav1.9 in the compressed DRG were also enhanced after CCD, and which were remarkably reversed by intervertebral foramen injection of plerixafor at the compression level. Moreover, intervertebral foramen injection at the compression level of plerixafor and ropivacaine as well as A-803467, a Nav1.8 selective blocker, were all able to reverse CCD-induced multiple pain behaviors. However, the analgesic duration of plerixafor maintained at least for 24 h which was much longer than that of A-803467 and ropivacaine. Finally, we found intervertebral foramen injection of plerixafor at the adjacent non-compression level has no effect on CCD-induced pain and intervertebral foramen injection of plerixafor in normal rats did not affect their basal pain sensitivity.ConclusionsOur study provides evidence that CXCR4-Nav1.8/Nav1.9 axis in compressed DRG contributed to CCD-induced low back pain and intervertebral foramen injection of plerixafor was a potential and applicable therapeutic strategy for the treatment of low back pain.