Effects of GDNF on DRG neurons in normal and diabetic mice

Nociceptive sensory neurons in dorsal root ganglia (DRGs) are first-order neurons conveying pain information to higher centers. Physiological pain has a protective role, which is disrupted in several pathologies leading to neuropathic pain, as the diabetic polyneuropathy (DPN), a common complication of diabetes. Since previous studies showed an involvement (among others) of the glial-derived neurotrophic factor (GDNF) in neuropathic pain, here we investigate the intervention of GDNF in the alterations of DRGs induced by the diabetic neuropathy, combining electrophysiological and morphological approaches. To mimic type 1 diabetes, four week-old male mice are injected intraperitoneally with streptozotocin (STZ, 150 mg/kg). Patch clamp recordings are carried out on intact DRGs, after treatment with collagenase (7 mg/ml) to remove the outer connective layer. In control mice, GDNF reduces excitability of small DRG neurons (<25 µm), while slightly increase it in large ones (>25 µm). By applying hyperpolarizing steps in voltage clamp mode, GDNF induces an inward conductance in small DRG neurons which is likely mediated by voltage-dependent potassium channels. Interestingly, the inhibitory effects of GDNF and the GDNF-induced potassium inward conductance are completely suppressed in small DRG neurons from diabetic mice. Our data indicates that GDNF exerts an inhibitory control on small DRG neurons and that such control is lost in diabetes. Restoring this inhibitory control in sensory neurons from diabetic patients may represent a novel strategies for mitigating the symptoms of painful diabetic neuropathy.