The Role of Spinal Disinhibition in Streptozotocin-Induced Diabetic Neuropathic Pain

Patients with diabetes and neuropathy report a significantly decreased quality of life secondary to diabetic neuropathic pain (DNP), which is a major complication of diabetic neuropathy. 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. Pre- and post-synaptic inhibition mediated by GABA expressing inhibitory interneurons in the dorsal horn of the spinal cord plays a major role in the modulation and processing of nociceptive sensory information. The overall hypothesis of this proposal is that inhibition decreases in DNP and this disinhibition contributes to the sensory hypersensitivity characteristic of DNP. The following specific hypotheses will be examined: 1) Blocking GABAergic inhibitory transmission facilitates primary afferent-evoked mono- and poly-synaptic excitatory transmission in the spinal cord of control animals 2) DNP decreases GABAergic postsynaptic inhibition in the dorsal horn, and this coincides with the development and duration of DNP behaviors 3) The reduction in GABAergic postsynaptic inhibition in DNP is the consequence of a decrease in GABA production, and not a loss of inhibitory interneurons, or GABA receptor down-regulation 4) Mimicking endogenous GABAergic inhibition can reduce DNP hypersensitivity, and such an approach can be optimized by combination with treatments targeted at other mechanisms, like central sensitization. There are multiple causes of DNP, but in spite of recent advances, this condition remains poorly controlled and is a major public health problem. Our ultimate goal is the identification of the extent and mechanisms responsible for disinhibition since this may offer new treatment strategies for DNP aimed at preventing or replacing the loss of inhibition.

Project ID:PC10108-1112
External Project ID:NSC101-2314-B182-090