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 3

Nav1.8-positive DRG neurons display hyperexcitability in HFD-fed mice.

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Nav1.8-positive DRG neurons display hyperexcitability in HFD-fed mice. (...
(A and B) Current-clamp recordings of DRG primary cultures from Nav1.8-Cre;Ai9 mice. Nav1.8-positive DRG neurons from HFD mice (A, red) (n = 29) had a lower rheobase than did neurons from RD mice (B, blue) (n = 25). (C) A significant decrease in rheobase was observed in HFD neurons (****P < 0.0001). (D) RMPs, (E) AP overshoot, and (F) voltage threshold for AP generation remained unchanged. (G–O) Representative current steps and associated voltage recordings are shown for DRG neurons from RD (blue) and HFD (red) mice, in which 700-ms rheobase current injections were done (G and H) 1× (n = 9; n = 10), (J and K) 2× (n = 9; n = 9), and (M and N) 3× (n = 6; n = 9), respectively. (H, K, and N) An increase in firing frequency was observed in neurons from HFD mice compared with (G, J, and M) neurons from RD mice. A significant increase was observed in the firing frequency in HFD DRG neurons compared with RD DRG neurons after (I) 1× (*P < 0.05), (L) 2× (****P < 0.0001), and (O) 3× (***P < 0.001) rheobase current injections, respectively. Values are expressed as the mean ± SEM. P values were calculated using a Mann-Whitney U test. Vm, voltage membrane.