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

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 12

Long-term chemogenetic activation of Nav1.8-positive DRG neurons results in significant acceleration of the development of mechanical allodynia and small-fiber degeneration in HFD-fed mice.

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Long-term chemogenetic activation of Nav1.8-positive DRG neurons results...
(A) Experimental setup of osmotic mini-pump implantation in Nav1.8-Cre;RC::L-hM3Dq mice. Nav1.8-Cre;RC::L-hM3Dq mice that expressed excitatory hM3Dq DREADD receptors were fed either a RD or a HFD and underwent i.p. implantation of an osmotic mini-pump, which administered either saline or CNO (10 mg/kg/day) for the period from 2 to 4 weeks following the commencement of a HFD or RD. (B) von Frey pain behavior testing demonstrated the onset of mechanical allodynia (reduction in withdrawal threshold) in HFD-fed mice (red) after 2 or 4 weeks following CNO administration. The RD mice (blue) also showed a reduction of their withdrawal threshold after 4 weeks of CNO administration. *P < 0.05, **P < 0.01, and ***P < 0.001 (n = 6/group). (C and D) Quantification (C) and confocal micrographs (D) of skin from Nav1.8-Cre;RC::L-hM3Dq mice on a RD for 4 weeks with saline mini-pumps showed normal skin innervation using PGP 9.5 (pseudo-colored red). Sections were colabeled with the nuclear marker DAPI (blue). In contrast, HFD mice with CNO mini-pumps had significant depletion of nerve terminals. Interestingly, in RD mice, increased excitability alone, produced by hM3Dq DREADD receptors, was not able to induce small-fiber degeneration in the absence of diabetes. Scale bar: 50 μm. This effect was quantified in C using IENF density, and the epidermal-dermal junction is outlined in white in D. *P < 0.05, **P < 0.01, and ***P < 0.001 (n = 6 from each group, with 3 noncontiguous sections analyzed per sample). P values were calculated using a 1-way ANOVA with Bonferroni’s multiple comparisons test. Values are expressed as the mean ± SEM.