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Peptidergic and nonpeptidergic nociceptive neurons represent parallel yet distinct pathways of pain transmission, but the functional consequences of such specificity are not fully understood. Here, we quantified the progression of peptidergic and nonpeptidergic axon loss within the epidermis in the setting of a dying-back neuropathy induced by diabetes. STZ-induced diabetic MrgD mice heterozygous for green fluorescent protein (GFP) in nonpeptidergic DRG neurons were evaluated for sensitivity to mechanical and noxious thermal and chemogenic stimuli 4 or 8 weeks post-STZ. Using GFP expression in conjunction with PGP9.5 staining, nonpeptidergic (PGP+/GFP+) and peptidergic (PGP+/GFP-) intraepidermal nerve fibers (IENFs) were quantified at each time point. At 4 weeks post-STZ, nonpeptidergic epidermal innervation remained unchanged while peptidergic innervation was reduced by 40.6% in diabetic mice. By 8 weeks post-STZ, both nonpeptidergic innervation and peptidergic innervation were reduced in diabetic mice by 34.1% and 43.8%, respectively, resulting in a 36.5% reduction in total epidermal IENFs. Behavioral deficits in mechanical, thermal, and chemogenic sensitivity were present 4 weeks post-STZ, concomitant with the reduction in peptidergic IENFs, but did not worsen over the next 4 weeks as nonpeptidergic fibers were lost, suggesting that the early reduction in peptidergic fibers may be an important driving force in the loss of cutaneous sensitivity. Furthermore, behavioral responses were correlated at the 4 week time point with peptidergic, but not nonpeptidergic, innervation. These results reveal that peptidergic and nonpeptidergic nociceptive neurons are differentially damaged by diabetes, and behavioral symptoms are more closely related to the losses in peptidergic epidermal fibers.

Early loss of peptidergic intraepidermal nerve fibers in an STZ-induced mouse model of insensate diabetic neuropathy