Patients with diabetes and neuropathy report a significantly decreased quality of life secondary to diabetic neuropathic pain (DNP). Patients with DNP experience lower extremity burning or "shock-like sensations" with increased sensitivity to both painful (hyperalgesia) and nonpainful stimuli (allodynia). Despite the high morbidity of DNP, mechanisms underlying the onset and progression of this complication are poorly understood. Our goal is to identify specific proteins that could serve as therapeutic targets in the treatment of DNP. As a first step, we quantitated DNP in a genetic model of type 2 diabetes, the db/db mouse. By 8 weeks of age, these mice experience thermal and mechanical allodynia. These signs of DNP correspond with nerve growth factor (NGF) up-regulation, tropomysin-related kinase (Trk) A receptor activation, subsequent p38 kinase activation, and increased substance P (SP) expression in dorsal root ganglion (DRG) neurons. This proposal will test the hypothesis that NGF signaling in DRG neurons underlies the development of diabetes- induced pain behavior in type 2 diabetes. We hypothesize that diabetes-enhanced NGF expression activates TrkA receptors on DRG neurons, leading to downstream activation of p38 kinase-SP pathway. Activation of this pathway leads to thermal hyperalgesia and mechanical allodynia in animal models of type 2 diabetes and to DNP in man.
Type 2 diabetes is increasing to epidemic proportions within the United States. A common complication of type 2 diabetes is DNP. Currently, DNP is difficult to manage and is responsible for significant patient morbidity and poor quality of life. In this proposal we seek to identify new therapeutic targets for DNP based upon a more thorough understanding of the pathogenesis of this disorder.
|Dauch, Jacqueline R; Bender, Diane E; Luna-Wong, Lucia A et al. (2013) Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia. J Neuroinflammation 10:64|
|Dauch, Jacqueline R; Lindblad, Chelsea N; Hayes, John M et al. (2013) Three-dimensional imaging of nociceptive intraepidermal nerve fibers in human skin biopsies. J Vis Exp :e50331|
|Cheng, Hsinlin T; Dauch, Jacqueline R; Porzio, Michael T et al. (2013) Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy. J Pain 14:941-7|
|Cheng, Hsinlin T; Dauch, Jacqueline R; Hayes, John M et al. (2012) Nerve growth factor/p38 signaling increases intraepidermal nerve fiber densities in painful neuropathy of type 2 diabetes. Neurobiol Dis 45:280-7|
|Thomas Cheng, Hsinlin (2010) Spinal cord mechanisms of chronic pain and clinical implications. Curr Pain Headache Rep 14:213-20|
|Cheng, Hsinlin T; Dauch, Jacqueline R; Oh, Sang Su et al. (2010) p38 mediates mechanical allodynia in a mouse model of type 2 diabetes. Mol Pain 6:28|
|Cheng, Hsinlin T; Dauch, Jacqueline R; Hayes, John M et al. (2009) Nerve growth factor mediates mechanical allodynia in a mouse model of type 2 diabetes. J Neuropathol Exp Neurol 68:1229-43|