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

• Published in: Neuropharmacology 2016-12, Vol.111, p.1-13
• Main Authors: Shaqura, Mohammed, Li, Xiongjuan, Al-Khrasani, Mahmoud, Shakibaei, Mehdi, Tafelski, Sascha, Fürst, Susanna, Beyer, Antje, Kawata, Mitsuhiro, Schäfer, Michael, Mousa, Shaaban A.
• Format: Article
• Language: English
• Subjects: Animals; Ganglia, Spinal - metabolism; Glia; Glucocorticoid receptor; Male; Mechanoreceptors; Membrane Proteins - metabolism; Neuroglia - metabolism; Nociception - physiology; Nociceptive neuron; Nociceptors - metabolism; Non-genomic effect; Pain - metabolism; Pain - physiopathology; Pain Threshold; Protein Binding; Rats; Rats, Wistar; Receptors, Glucocorticoid - metabolism; Receptors, Glucocorticoid - physiology; RNA, Messenger - metabolism; Sciatic Nerve - metabolism; Skin - metabolism; Spinal Cord - metabolism
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.08.019

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 [35S]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. •Neuronal glucocorticoid receptors on peripheral and spinal sensory neurons.•Glial glucocorticoid receptors on Schwann cells accompanying peripheral neurons.•Membrane bound glucocorticoid receptors as potential targets fpr pain modulation.•Glucocorticoid receptor activation triggers G protein coupling to a putative membrane receptor.