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Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy
Nirupa D. Jayaraj, … , Richard J. Miller, Daniela M. Menichella
Nirupa D. Jayaraj, … , Richard J. Miller, Daniela M. Menichella
Published March 13, 2018
Citation Information: J Clin Invest. 2018;128(6):2205-2225. https://doi.org/10.1172/JCI92117.
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Research Article Neuroscience Article has an altmetric score of 17

Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy

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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 10

Chemogenetic inhibition of Nav1.8-positive DRG neurons can reverse small-fiber degeneration and mechanical allodynia in HFD-fed mice.

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Chemogenetic inhibition of Nav1.8-positive DRG neurons can reverse small...
(A) Experimental protocol for osmotic mini-pump implantation in Nav1.8-Cre;Ai9;RC::PDi mice. Nav1.8-Cre;Ai9;RC::PDi mice were put on a RD or a HFD for 10 weeks and then implanted i.p. with an osmotic mini-pump delivering saline or CNO (10 mg/kg/day) for 4 weeks to determine whether CNO could reverse the effects of the HFD. Each arrow represents a time point at which pain behavior was assessed. (B) von Frey pain behavior testing demonstrated the presence of mechanical allodynia (reduction in withdrawal threshold) in mice after 10 weeks on a HFD. This mechanical allodynia was reduced after continuous treatment with CNO tested at the 14-week time point. ***P < 0.001 and ****P < 0.0001 (n = 6/group). (C and D) Confocal micrographs of skin from Nav1.8-Cre;Ai9;RC::PDi mice. td-Tomato–expressing Nav1.8 fibers (red) and merged images with the nuclear marker DAPI (blue). (C) Control mice on a RD with saline or CNO mini-pumps showed normal skin innervation. HFD mice implanted with a saline mini-pump showed reduced skin innervation. HFD mice fitted with CNO mini-pumps showed a significant improvement in skin innervation. Scale bars: 50 μm. (D) This effect was quantified using IENF density, and the intraepidermal-dermal junction is outlined in white in C. *P < 0.05 and **P < 0.01 (n = 6/group, with 3 noncontiguous 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.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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