Identification of mineralocorticoid and glucocorticoid receptors on peripheral nociceptors: Translation of experimental findings from animal to human biology

•Neuronal MR und GR receptors modulate pain by genomic and non-genomic mechanisms.•Translation of findings in animal models was focussed in this study.•MR and GR are identified on subpopulations of sensory neurons in human skin.•MR predominately colocalize with nociceptive neurons.•GR colocalizewith sensory, sympathetic and mechanoreceptive nerve fibers.•Similar expression patterns in human and ratsuggest a system approach in mammals. Evidence is accumulating that activation of mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons modulates pain sensation. While the expression and exact anatomical localization of MR and GR in the various subpopulations of peripheral sensory neurons has been shown in animals, it is still unknown for the human skin. Therefore, we aimed to identify MR and GR mRNA and protein as well as the exact subpopulations of sensory neurons in human versus rat skin. Tissue samples from rat and human skin were subjected to RT-PCR, Western blot and double immunofluorescence confocal analysis of MR and GR with the neuronal markers calcitonin gene-related peptide (CGRP), neurofilament 200 (NF200) and tyrosine hydroxylase (TH). Using RT-PCR we were able to isolate MR as well as GR specific transcripts from human skin. Consistently, Western blot analysis identified MR- as well as GR- specific protein bands at the expected molecular weights of 110 and 87 kD, respectively. Double immunofluorescence confocal microscopy of human skin revealed that MR predominantly colocalized with calcitonin-gene-related peptide (CGRP)-immunoreactive (IR) nociceptive neurons – similar to rat skin – underscoring a pivotal role for MR in the modulation of pain. The majority of GR-immmunoreactivity was localized in peripheral peptidergic CGRP-IR sensory nerve fibers, but in addition on TH-IR sympathetic postganglionic, and NF200-IR myelinated mechanoreceptive nerve fibers, both within human and rat skin. Moreover, GR but not MR were localized in keratinocytes of the epidermal layer of human and rat skin. Overall, our results indicate considerable overlap in sensory neuron expression of MR and GR in humans and rats endorsing a common systems approach in mammals that may modulate the transmission of sensory information by MR and GR activation.