Membrane-bound glucocorticoid receptors on distinct nociceptive neurons as potential targets for pain control through rapid non-genomic effects

Abstract

Glucocorticoids were long believed to primarily function through cytosolic glucocorticoid receptor (GR) activation and subsequent classical genomic pathways. Recently, however, evidence has emerged that suggests the presence of rapid non-genomic GR-dependent signaling pathways within the brain, though their existence in spinal and peripheral nociceptive neurons remains elusive. In this paper, we aim to systemically identify GR within the spinal cord and periphery, to verify their putative membrane location and to characterize possible G protein coupling and pain modulating properties. Double immunofluorescence confocal microscopy revealed that GR predominantly localized in peripheral peptidergic and non-peptidergic nociceptive C- and Aδ-neurons and existed only marginally in myelinated mechanoreceptive and proprioreceptive neurons. Within the spinal cord, GR predominantly localized in incoming presynaptic nociceptive neurons, in pre- and postsynaptic structures of the dorsal horn, as well as in microglia. GR saturation binding revealed that these receptors are linked to the cell membrane of sensory neurons and, upon activation, they trigger membrane targeted [S]GTPγS binding, indicating G protein coupling to a putative receptor. Importantly, subcutaneous dexamethasone immediately and dose-dependently attenuated acute nociceptive behavior elicited in an animal model of formalin-induced pain hypersensitivity compared to naive rats. Overall, this study provides firm evidence for a novel neuronal mechanism of GR agonists that is rapid, non-genomic, dependent on membrane binding and G protein coupling, and acutely modulates nociceptive behavior, thus unraveling a yet unconsidered mechanism of pain relief.

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

“…Membrane-bound GR has been found to be responsible for much of the non-genomic actions of glucocorticoids (Perez, Cormack et al 2013). Membrane-bound GRs have been found in monocytes, B-cells, T-cells, and neurons (Bartholome, Spies et al 2004, Lowenberg, Verhaar et al 2006, Tryc, Spies et al 2006, Shaqura, Li et al 2016). …”

Ultrasound‐guided adductor canal block after arthroscopic anterior cruciate ligament reconstruction: Effect of adding dexamethasone to bupivacaine, a randomized controlled trial

“…Some researchers suggest a vasoconstriction effect at the local level, which results in a lower absorption of local anaesthetics (Shishido et al., ). In addition, a systemic anti‐inflammatory effect following vascular uptake of the drug (Albrecht et al., ) may also result from decreased nociceptive C‐fibre activity via a direct effect on glucocorticoid receptors and inhibitory potassium channels (Shaqura et al., ). We hypothesized that dexamethasone combined with LA for peripheral nerve block could prolong the duration of postoperative analgesia.…”

Impaired Spinal Glucocorticoid Receptor Signaling Contributes to the Attenuating Effect of Depression on Mechanical Allodynia and Thermal Hyperalgesia in Rats with Neuropathic Pain

“…Glucocorticoid receptors (GRs), which belong to the classical nuclear receptor family, are widely distributed in the central nervous system (CNS; Fuxe et al, 1987; Shaqura et al, 2016). In the absence of glucocorticoids, GRs reside in the cell cytoplasm as part of a chaperone protein complex.…”