Nerve growth factor mediates mechanical allodynia in a mouse model of type 2 diabetes.
C57BLKS db/db (db/db) mice develop a neuropathy with features of human type 2 diabetic neuropathy. Here, we demonstrate that these mice develop transient mechanical allodynia at the early stage of diabetes. We hypothesized that nerve growth factor (NGF), which enhances the expression of key mediators of nociception (i.e. substance P [SP] and calcitonin gene-related peptide), contributes to the development of mechanical allodynia in these mice. We found that NGF, SP, and calcitonin gene-related peptide gene expression is upregulated in the dorsal root ganglion (DRG) of db/db mice before or during the period that they develop mechanical allodynia. There were more small- to medium-sized NGF-immunopositive DRG neurons in db/db mice than in control db+ mice; these neurons also expressed SP, consistent with its role in nociception. Nerve growth factor expression in the hind paw skin was also increased in a variety of dermal cell types and nerve fibers, suggesting the contribution of a peripheral source of NGF to mechanical allodynia. The upregulation of NGF coincided with enhanced tropomyosin-related kinase A receptor phosphorylation in the DRG. Finally, an antibody against NGF inhibited mechanical allodynia and decreased the numbers of SP-positive DRG neurons in db/db mice. These results suggest that inhibition of NGF action is a potential strategy for treating painful diabetic neuropathy.
Cheng
Hsinlin T
HT
Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200, USA. chengt@umich.edu
Dauch
Jacqueline R
JR
Hayes
John M
JM
Hong
Yu
Y
Feldman
Eva L
EL
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000502:physiology*; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D010812:Physical Stimulation / Q000379:methods
D020932:Nerve Growth Factor