Beta 2-adrenergic receptor mediates noradrenergic action to induce cyclic adenosine monophosphate response element-binding protein phosphorylation in satellite glial cells of dorsal root ganglia to regulate visceral hypersensitivity
PAIN(2022)
Abstract
Sympathoneuronal outflow into dorsal root ganglia (DRG) is suggested to be involved in sympathetically maintained chronic pain, which is mediated by norepinephrine (NE) action on DRG cells. This study combined in vitro and in vivo approaches to identify the cell types of DRG that received NE action and examined cell type-specific expression of adrenergic receptors (ARs) in DRG. Using DRG explants, we identified that NE acted on satellite glial cells (SGCs) to induce the phosphorylation of cAMP response element-binding protein (CREB). Using primarily cultured SGCs, we identified that beta (beta)2-adrenergic receptor but not alpha (alpha)adrenergic receptor nor other pAR isoforms mediated NE-induced CREB phosphorylation and CRE-promoted luciferase transcriptional activity. Using fluorescence in situ hybridization and affinity purification of mRNA from specific cell types, we identified that beta 2AR was expressed by SGCs but not DRG neurons. We further examined beta 2AR expression and CREB phosphorylation in vivo in a model of colitis in which sympathetic nerve sprouting in DRG was observed. We found that beta 2AR expression and CREB phosphorylation were increased in SGCs of thoracolumbar DRG on day 7 after colitis induction. Inhibition but not augmentation of beta 2AR reduced colitis-induced calcitonin generelated peptide release into the spinal cord dorsal horn and colonic pain responses to colorectal distention. Prolonged activation of beta 2AR in naive DRG increased calcitonin gene-related peptide expression in DRG neurons. These findings provide molecular basis of sympathetic modulation of sensory activity and chronic pain that involves beta 2AR-mediated signaling in SGCs of DRG.
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Key words
beta 2-adrenergic receptor, Sympathoneuronal outflow, Dorsal root ganglia, Satellite glial cells, Pain
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