title: CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy.
abstract: BACKGROUND
  Painful Diabetic Neuropathy (PDN) is a debilitating syndrome present in a quarter of diabetic patients that has a substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the cellular mechanisms underlying PDN are not well understood. Neuropathic pain is caused by a variety of phenomena including sustained excitability in sensory neurons that reduces the pain threshold so that pain is produced in the absence of appropriate stimuli. Chemokine signaling has been implicated in the pathogenesis of neuropathic pain in a variety of animal models. We therefore tested the hypothesis that chemokine signaling mediates DRG neuronal hyperexcitability in association with PDN.
  
  
  RESULTS
  We demonstrated that intraperitoneal administration of the specific CXCR4 antagonist AMD3100 reversed PDN in two animal models of type II diabetes. Furthermore DRG sensory neurons acutely isolated from diabetic mice displayed enhanced SDF-1 induced calcium responses. Moreover, we demonstrated that CXCR4 receptors are expressed by a subset of DRG sensory neurons. Finally, we observed numerous CXCR4 expressing inflammatory cells infiltrating into the DRG of diabetic mice.
  
  
  CONCLUSIONS
  These data suggest that CXCR4/SDF-1 signaling mediates enhanced calcium influx and excitability in DRG neurons responsible for PDN. Simultaneously, CXCR4/SDF-1 signaling may coordinate inflammation in diabetic DRG that could contribute to the development of pain in diabetes. Therefore, targeting CXCR4 chemokine receptors may represent a novel intervention for treating PDN.
authors: Department of Neurology, Robert Lurie Medical Research Center, Northwestern University, Lurie 8-123, 303 E, Superior St, Chicago, IL, USA. d-menichella@md.northwestern.edu.
authors: Daniela Maria
authors: DM
authors: Menichella
authors: Belmadani
authors: B
authors: Abdelhak
authors: Dongjun
authors: D
authors: Ren
authors: Andrew
authors: A
authors: Shum
authors: Caroline
authors: C
authors: Frietag
authors: Richard J
authors: RJ
authors: Miller
mesh_terms: D000818:Animals; D001596:Benzylamines; D002478:Cells, Cultured; D000080027:Cyclams; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000209:etiology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; C539620:Dock7 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; C088327:plerixafor