The bidirectional roles of the cGAS-STING pathway in pain processing: Cellular and molecular mechanisms

Abstract

Pain is a common clinical condition. However, the mechanisms underlying pain are not yet fully understood. It is known that the neuroimmune system plays a critical role in the pathogenesis of pain. Recent studies indicated that the cyclic-GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can activate the innate immune system by sensing both extrinsic and intrinsic double-stranded DNA in the cytoplasm, which is involved in pain processing. In this review, we summarise (1) the roles of the cGAS-STING pathway in different pain models, (2) the effect of the cGAS-STING pathway in different cells during pain regulation, and (3) the downstream molecular mechanisms of the cGAS-STING pathway in pain regulation. This review provides evidence that the cGAS-STING pathway has pro- and anti-nociceptive effects in pain models. It has different functions in neuron, microglia, macrophage, and T cells. Its downstream molecules include IFN-I, NF-κB, NLRP3, and eIF2α. The bidirectional roles of the cGAS-STING pathway in pain processing are mediated by regulating nociceptive neuronal sensitivity and neuroinflammatory responses. However, their effects in special brain regions, activation of astrocytes, and the different phases of pain require further exploration.

Keywords: Astrocyte; Chronic pain; Microglia; Neuroinflammation; Nociceptive neuron; cGAS-STING.