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 9

Long-term chemogenetic inhibition of Nav1.8-positive DRG neurons prevents mechanical allodynia and small-fiber degeneration in HFD-fed mice.

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Long-term chemogenetic inhibition of Nav1.8-positive DRG neurons prevent...
(A) Nav1.8-Cre;Ai9;RC::PDi mice were fitted with osmotic mini-pumps i.p. infusing either CNO (10 mg/kg/day) or saline between weeks 2 and 8 of either a RD or HFD. Each arrow represents a time point at which pain behavior was assessed. (B) von Frey testing was performed on Nav1.8-Cre;Ai9;RC::PDi mice 2, 4, 6, and 8 weeks after implantation of an osmotic mini-pump i.p. that delivered CNO (10 mg/kg/day) or saline into RD- or HFD-fed mice. Mice on a HFD showed a reduced withdrawal threshold starting at 6 weeks, which was reversed following CNO treatment. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (n = 9/group). (C) Confocal micrographs of skin from these mice show td-Tomato in the Nav1.8 fibers (red) and merged images with the nuclear marker DAPI (blue). Mice on a RD given either saline or CNO showed normal skin innervation. In diabetic HFD-fed mice given saline, a reduction in skin innervation was observed, but it was reversed for mice on a HFD given CNO. Scale bars: 50 μm. (D) This effect was quantified using IENF density, and the epidermal-dermal junction is outlined in white in C, showing that CNO infusion prevented small-fiber degeneration in HFD-fed mice. **P < 0.01 (n = 6/group, with 3 noncontinuous sections analyzed per sample). Values are expressed as the mean ± SEM. P values were calculated using 2-way ANOVA with Bonferroni’s multiple comparisons test.