Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy
Nirupa D. Jayaraj, Bula J. Bhattacharyya, Abdelhak A. Belmadani, Dongjun Ren, Craig A. Rathwell, Sandra Hackelberg, Brittany E. Hopkins, Herschel R. Gupta, Richard J. Miller, Daniela M. Menichella
Nirupa D. Jayaraj, Bula J. Bhattacharyya, Abdelhak A. Belmadani, Dongjun Ren, Craig A. Rathwell, Sandra Hackelberg, Brittany E. Hopkins, Herschel R. Gupta, Richard J. Miller, Daniela M. Menichella
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Research Article Neuroscience

Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy

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.

Authors

Nirupa D. Jayaraj, Bula J. Bhattacharyya, Abdelhak A. Belmadani, Dongjun Ren, Craig A. Rathwell, Sandra Hackelberg, Brittany E. Hopkins, Herschel R. Gupta, Richard J. Miller, Daniela M. Menichella

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Figure 4

Selective chemokine receptor CXCR4 deletion from Nav1.8-postive DRG neurons prevents the development of mechanical allodynia and small-fiber degeneration in HFD-induced PDN.

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Selective chemokine receptor CXCR4 deletion from Nav1.8-postive DRG neur...
(A) von Frey testing demonstrated that in HFD (red) Nav1.8-Cre;Ai9;CXCR4fl/+, which had a heterozygous deletion of CXCR4 from Nav1.8-postive DRG neurons, the withdrawal threshold was significantly reduced compared with that in Nav1.8-Cre;Ai9;CXCR4fl/+ mice on a RD (dark blue) and compared with the withdrawal threshold in mice with a homozygous deletion of CXCR4 (Nav1.8-Cre;Ai9;CXCR4fl/fl) on a RD (light blue). In contrast, Nav1.8-Cre;Ai9;CXCR4fl/fl (pink) mice on a HFD showed normalization of the withdrawal thresholds (****P < 0.0001) (n = 6/group). (B) Confocal analysis of Nav1.8-positive fibers from the skin of RD and HFD mice with heterozygous or homozygous deletions of CXCR4, showing td-Tomato (red) and merged images with the nuclear marker DAPI (blue). Nav1.8-Cre;Ai9;CXCR4fl/+ RD mice had normal skin innervation, whereas the same mice on a HFD had reduced innervation. However, selective homozygous deletion of CXCR4 in mice on a HFD prevented small-fiber degeneration. Scale bars: 50 μm. (C) This effect was quantified using IENF density, and the epidermal-dermal junction is outlined in white in B. *P < 0.05 and ***P < 0.001 (n = 7 for all groups, with 3 noncontiguous sections analyzed per sample). Values are expressed as the mean SEM. P values were calculated using 1-way ANOVA with a Bonferroni’s multiple comparisons test.