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 7

Expression of the inhibitory DREADD receptor PDi in Nav1.8-positive DRG neurons.

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Expression of the inhibitory DREADD receptor PDi in Nav1.8-positive DRG ...
(A) Breeding scheme and genetic constructs used to generate Nav1.8-Cre;Ai9;RC::PDi inhibitory DREADD mice; the inhibitory PDi DREADD receptor (PDi DREADDs) has an HA tag, and Nav1.8-positive DRG neurons are genetically labeled in red with td-Tomato. X, crossing (breeding mice); F, FRT-flanked transcriptional Stop; P, loxP-flanked-transcriptional Stop. (B) Confocal micrographs of DRGs from RD (top) and HFD (bottom) PDi DREADD–expressing mice (Nav1.8-Cre;Ai9;RC::PDi). Images show PDi DREADDs tagged with an HA epitope (green), Nav1.8 td-Tomato–expressing neurons (red), and IB4-positive neurons (blue). PDi DREADDs were found in small- and medium-diameter DRG neurons, some of which were IB4 positive and some IB4 negative. Large-diameter neurons (indicated by asterisks) did not express PDi DREADDs. Scale bars: 50 μm. Original magnification, ×20 and ×60. (C) Percentage of PDi DREADD–expressing neurons as determined by the HA tag, td-Tomato Nav1.8 neurons, and nonpeptidergic IB4-positive neurons. RD DRGs had 83.9% ± 3.4% HA- or td-Tomato–positive neurons versus 85.7% ± 3.8% for HFD DRGs. RD DRGs had 34.8% ± 3.2% IB4-positive neurons versus 35.4% ± 2.4% for HFD DRGs. There were no significant differences in the sizes of these cell populations between DRGs from RD and HFD PDi DREADD–expressing mice (n = 278 neurons [RD]; n = 227 [HFD]). Values are expressed as the mean ± SEM. P values were calculated using a Mann-Whitney U test.