TY - JOUR
T1 - Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy
AU - Jayaraj, Nirupa D.
AU - Bhattacharyya, Bula J.
AU - Belmadani, Abdelhak A.
AU - Ren, Dongjun
AU - Rathwell, Craig A.
AU - Hackelberg, Sandra
AU - Hopkins, Brittany E.
AU - Gupta, Herschel R.
AU - Miller, Richard J.
AU - Menichella, Daniela M.
N1 - Funding Information:
This work was supported by NIH grants K08 NS079482-01 (to DMM) and 5R01DA013141-14 (to RJM) and by NIH/Rush University Medical Center grant 1R01AR064251-01 (to RJM). All statistical analysis was reviewed by the Statistical Core at Northwestern University. We thank Rajeshwar Awatramani (Northwestern University) for helpful discussions. We thank Alexandra Fredrickson (Northwestern University) for helping with the evaluation of IENF density. We thank Susan Dymecki (Harvard Medical School), Xinzhong Dong (Johns Hopkins University), John Wood (University College London), Savio Chan (Northwestern University), and Patricia Jensen (NIH/NIEHS) for the generous gifts of mice (RC::PDi, Pirt-GCaMP3, Nav1.8-Cre, Parvalb-Cre, and RC::L-hM3Dq, respectively).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI92117
DO - 10.1172/JCI92117
M3 - Article
C2 - 29533926
AN - SCOPUS:85048298070
SN - 0021-9738
VL - 128
SP - 2205
EP - 2225
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -
