Widespread projections from myelinated nociceptors throughout the substantia gelatinosa provide novel insights into neonatal hypersensitivity

Abstract

Skin sensory neurons have long been thought to undergo major changes in anatomy and physiology over the first few weeks of postnatal life. Low-threshold mechanoreceptors (LTMRs) are believed to project extensively throughout superficial dorsal horn laminas initially and provide the afferent limb for hyperactive nocifensive reflexes. However, our recent studies revealed that neonatal LTMRs do not project into "pain-specific" regions; instead, they exhibit adult-like anatomy shortly after birth. We sought to determine whether the same might be true for myelinated high-threshold mechanoreceptors (HTMRs). We used an intact, ex vivo somatosensory system preparation from neonatal mice to allow intrasomal recording and neurobiotin labeling of individual sensory neurons characterized via natural skin stimuli. Neonatal HTMRs displayed a number of key hallmarks of their adult counterparts; relative to LTMRs, they exhibited broader, inflected somal spikes and higher mechanical thresholds and/or responded in an increasingly vigorous manner to incrementally graded forces in a manner capable of encoding stimulus intensity. Two types were discerned on the basis of central anatomy: one subset projected to superficial laminas (I/II); the other gave rise to diffuse, dorsally recurving collateral arbors extending throughout the entire dorsal horn (I-V). The latter represent a novel cutaneous afferent morphology that persists in older animals. These studies reveal that inputs from myelinated afferents to superficial pain-specific laminas in neonates arise from HTMRs and not LTMRs as commonly thought. This frequently overlooked population is in a position, therefore, to contribute substantially to paradoxical nocifensive behaviors in neonates and various pain states in adults.