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- Title
Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy.
- Authors
Jayaraj, Nirupa D.; Bhattacharyya, Bula J.; Belmadani, Abdelhak A.; Ren, Dongjun; Rathwell, Craig A.; Hackelberg, Sandra; Hopkins, Brittany E.; Gupta, Herschel R.; Miller, Richard J.; Menichella, Daniela M.
- Abstract
Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Nav1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Nav1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4-mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction.
- Subjects
DIABETIC neuropathies; DIABETES complications; NOCICEPTORS; DEGENERATION (Pathology); DORSAL root ganglia; SKIN physiology; AXONS; ANIMAL experimentation; CELL receptors; CELLULAR signal transduction; COMPARATIVE studies; CYTOKINES; DIABETES; SENSORY ganglia; HYPERALGESIA; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; EVALUATION research
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 6, p2205
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI92117