Mineralocorticoid receptor signaling reduces somatostatin expression in developing sensory neurons and drives neonatal pain after early-life stress

Abstract

Early-life stress (ELS) causes pain hypersensitivity in neonatal mice and alters the transcriptional profile of the immature dorsal root ganglia (DRG), highlighted by a marked reduction in the expression of a neuropeptide, somatostatin (Sst), which is known to constitutively suppress peripheral nociceptive transmission during adulthood. However, the mechanisms that drive plasticity in gene expression within the developing DRG and neonatal pain after ELS remain unclear. Here, we investigated the degree to which ELS-induced neonatal pain was mediated by corticosterone signaling onto sensory neurons and potential changes in peripheral Sst transmission. The conditional knockout of the mineralocorticoid receptor (MR), but not the glucocorticoid receptor, from immature DRG neurons prevented ELS-evoked neonatal pain. In contrast, the systemic administration of the selective MR antagonist eplerenone failed to acutely influence pain after ELS, thus suggesting that MR activation enhances pain during the neonatal period via canonical effects on gene transcription. Meanwhile, hind paw injection of the Sst receptor antagonist cyclo-somatostatin increased spontaneous nocifensive behaviors in control pups, but not in pups previously subjected to ELS, raising the possibility that a disruption in tonic antinociception mediated by peripheral Sst contributes to neonatal pain after ELS. Furthermore, administration of the peripherally restricted Sst analog octreotide reversed noxious cold and pressure hypersensitivity in neonatal mice after ELS. Finally, the selective deletion of MR from sensory neurons prevented the ELS-induced decrease in Sst expression. Collectively, these results provide novel mechanistic insight into the effects of chronic early-life adversity on nociceptive processing in the developing nervous system.