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Abstract: Most cutaneous C fibers, including both peptidergic and nonpeptidergic subtypes, are presumed to be nociceptors and respond to noxious input in a graded manner. However, mechanically sensitive, nonpeptidergic C fibers also respond to mechanical input in the innocuous range, so the degree to which they contribute to nociception remains unclear. To address this gap, we investigated the function of nonpeptidergic afferents using the MrgprdCre allele. In real-time place aversion studies, we found that low-frequency optogenetic activation of MrgrpdCre lineage neurons was not aversive in naive mice but became aversive after spared nerve injury (SNI). To address the underlying mechanisms of this allodynia, we recorded responses from lamina I spinoparabrachial (SPB) neurons using the semi-intact ex vivo preparation. After SNI, innocuous brushing of the skin gave rise to abnormal activity in lamina I SPB neurons, consisting of an increase in the proportion of recorded neurons that responded with excitatory postsynaptic potentials or action potentials. This increase was likely due, at least in part, to an increase in the proportion of lamina I SPB neurons that received input on optogenetic activation of MrgprdCre lineage neurons. Intriguingly, in SPB neurons, there was a significant increase in the excitatory postsynaptic current latency from MrgprdCre lineage input after SNI, consistent with the possibility that the greater activation post-SNI could be due to the recruitment of a new polysynaptic circuit. Together, our findings suggest that MrgprdCre lineage neurons can provide mechanical input to the dorsal horn that is nonnoxious before injury but becomes noxious afterwards because of the engagement of a previously silent polysynaptic circuit in the dorsal horn. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]