GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice

Sensory deficits induced by diabetes commonly affect small unmyelinated pep tidergic and nonpeptidergic sensory neurons. The peptidergic population res ponds to nerve growth factor (NGF), while the nonpeptidergic DRG neurons po stnatally switch their dependency from NGF to glial cell line-derived neuro trophic factor (GDNF). Recent studies have demonstrated that deficient NGF support of peptidergic nociceptors is involved in problems with small-fiber diabetic neuropathy. To determine if nonpeptidergic GDNF-responsive neuron s are similarly affected by hyperglycemia, diabetes was induced in mice usi ng streptozotocin (STZ). Four weeks following diabetes induction, staining of axon terminals of nonpeptidergic unmyelinated neurons labeled with the i solectin IB4 or enzyme activity for thiamine monophosphatase (TMP) was redu ced in lamina iii of the lumbar dorsal horn, particularly in the medial reg ion which receives distal sciatic afferents. In contrast, NGF-responsive CG ;RP-immunoreactive (ir) axons showed no or only a slight decrease in spinal terminations. Insulin treatment in diabetic mice failed to improve deficit s in IB4/TMP central afferents. To test whether GDNF or NGF could restore s pinal deficits in nonpeptidergic afferents, STZ-treated mice were treated i ntrathecally for 2 weeks with NGF or GDNF. NGF administration enhanced CGRP -ir staining but failed to improve IB4/TMP projections. GDNF treatment had no effect on CGRP-ir projections but restored TMP labeling in lamina IIi. O ur results demonstrate that nonpeptidergic unmyelinated sensory neurons are vulnerable to diabetes and that GDNF administration can selectively revers e deficits caused by diabetes in the IB4/TMP subpopulation. (C) 2001 Academ ic Press.