Human DRG Glucocorticoid Receptor Profiling Reveals Targets for Regionally Delivered Steroid Analgesia

TL;DR

This study shows that glucocorticoid receptors in human dorsal root ganglia are linked to pain relief and suggests targeting these receptors could improve steroid-based pain treatments.

Contribution

The study identifies glucocorticoid receptor localization and function in human DRG neurons and proposes receptor-selective modulation as a novel analgesic strategy.

Findings

Glucocorticoid receptors are predominantly expressed in human DRG and colocalize with CGRP in nociceptive neurons.

Mineralocorticoid receptor signaling acts as a pronociceptive counterpart, suggesting receptor-selective modulation as a therapeutic approach.

GR agonists delivered regionally provide long-term analgesia in chronic radicular pain patients.

Abstract

What are the main findings?
Glucocorticoid receptors (GRs) are the predominant corticosteroid receptors expressed in human dorsal root ganglia (DRG).GRs are preferentially localized to nociceptive DRG neurons, colocalizing with CGRP and only occasionally with GFAP of satellite glial cells.

Glucocorticoid receptors (GRs) are the predominant corticosteroid receptors expressed in human dorsal root ganglia (DRG).

GRs are preferentially localized to nociceptive DRG neurons, colocalizing with CGRP and only occasionally with GFAP of satellite glial cells.

What are the implications of the main findings?
Preclinical and clinical data support a functional role for neuronal GR signaling in attenuating inflammatory and radicular pain, respectively.Mineralocorticoid receptor (MR) signaling emerges as a pronociceptive counterpart, highlighting receptor-selective modulation as a therapeutic strategy.

Preclinical and clinical data support a functional role for neuronal GR signaling in attenuating inflammatory and radicular pain, respectively.

Mineralocorticoid receptor (MR) signaling emerges as a pronociceptive counterpart, highlighting receptor-selective modulation as a therapeutic strategy.

Corticosteroid receptor signaling in primary afferent neurons of the dorsal root ganglion (DRG) has emerged as a potential target to modulate nociception via genomic and nongenomic mechanisms shown in animal pain models. However, the expression landscape of glucocorticoid receptors (GRs) relative to mineralocorticoid receptors (MRs) in human DRG, their association with pain-related markers, and their functional relevance remain incompletely defined. We analyzed human and rat DRG by mRNA profiling and immunofluorescence confocal microscopy to assess GR/MR expression and complemented these studies with a clinical evaluation of neuraxial corticosteroid delivery. Here, GR transcripts in human DRG were the most abundant among corticosteroid receptor-related genes examined (including MR) and were observed alongside transcripts of pain-signaling molecules. Human DRG immunofluorescence analysis revealed substantial colocalization of GR with calcitonin gene-related peptide (CGRP), a marker of nociceptive unmyelinated C-fibers and thinly myelinated Aδ-fibers, as well as with gial fibrillary acidic protein (GFAP), a marker of satellite glial cells (SGCs), but minimal expression in myelinated neurofilament 200 (RT-200) immunoreactive (IR) human DRG neurons. In addition, GR immunoreactivity was primarily distributed to medium-diameter neurons (40–65 µm). Functionally, preclinical experiments showed that GR activation and MR blockade attenuate inflammatory pain via rapid, nongenomic neuronal mechanisms that counter an intrinsic mineralocorticoid receptor-mediated pronociceptive drive. Consistently, clinical analgesia over at least 3 months after transforaminal plus caudal epidural delivery of GR agonists in chronic radicular pain supports a functional role for neuronal GR signaling within spinal cord and DRG circuits. Together, these molecular, functional, and clinical findings identify GR as a key modulator of sensory neuron excitability and pain, highlight MR as a pronociceptive counterpart, and suggest that selectively enhancing GR signaling or inhibiting MR signaling may offer a potential strategy for improving corticosteroid-based analgesic therapies.

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