Dexmedetomidine and Ketamine Attenuated Neuropathic Pain Related Behaviors via STING Pathway to Induce ER-Phagy

Abstract

Our previous work indicated that ER-phagy level had altered in spinal nerve ligation (SNL) rats. In this study, we investigated whether dexmedetomidine or ketamine exhibits anti-anxiety or anti-nociceptive effects via modulation of the spinal STING/TBK pathway to alter ER-phagy in SNL rats. We evaluated the analgesic and anti-anxiety effects of ketamine and dexmedetomidine in SNL rats. 2’3’-cGAMP (a STING pathway agonist) was administrated to investigate whether enhanced spinal STING pathway activation could inhibit dexmedetomidine or ketamine treatment effects in SNL rats. Analgesic effects were assessed with the mechanical withdrawal threshold (MWT) and anti-anxiety effects were measured via an open field test (OFT). Protein expression levels were evaluated by immunoblotting. Distribution and cellular localization of Grp78 (ER stress marker) were evaluated by confocal immunofluorescence. SNL induced mechanical hypersensitivity and anxiety in rats; dexmedetomidine and ketamine both provided analgesia and anti-anxiety effects in SNL rats. Furthermore, the STING pathway was involved in the modulation of ER stress and ER-phagy in SNL rats and dexmedetomidine and ketamine alleviated ER stress by inhibiting STING pathway to enhance ER-phagy. Thus, both ketamine and dexmedetomidine provided anti-anxiety and anti-nociceptive effects by alleviating ER stress through the inhibition of the STING/TBK pathway to modulate spinal ER-phagy in SNL rats.

Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice

“…The role of the STING/IFN-I pathway in nociception has been a subject of debate in recent years. While administration of STING agonists through the central route causes acute analgesia in naive animals, peripheral STING agonists or IFN-I injection promotes mechanical allodynia ( 11 , 14 , 34 ). Furthermore, STING activation in response to exogenous ligands acutely reduces mechanical allodynia in various neuropathic pain models through IFN-I/IFNAR1 signaling ( 11 , 12 ).…”

Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain

“…The role of the STING/IFN-I pathway in nociception has been a subject of debate over the past years. While administration of STING agonists through the central route causes acute analgesia in naive animals, peripheral STING agonists or IFN-I injection promotes mechanical allodynia 11,14,33 . Furthermore, STING activation in response to exogenous ligands, acutely reduces mechanical allodynia in various neuropathic pain models through IFN-I/IFNAR1 signaling 11,12 .…”

Mechanism and effects of STING–IFN-I pathway on nociception: A narrative review

“…M1-polarization microglia express CD16 and induce TNF-α and IL-1β synthesis, which may cause central sensitization ( Mesquida-Veny et al, 2021 ). In a rat SNL model, ketamine and dexmedetomidine induced ER-phagy and alleviated ER stress to provide antianxiety and antinociceptive effects by inhibiting the STING–TBK pathway in the spinal cord ( Liu et al, 2022 ).…”

“…However, the antinociceptive effect was not substantial 11 days after the injection ( Wang et al, 2021 ). Similarly, activation of the STING–IFN-I pathway induces nociception or neuropathic pain at a late stage ( Liu et al, 2022 ; Wu et al, 2022 ). The exact effects of STING–IFN-I remain controversial, and its differential role in different sexes, neuropathic pain models, cells, and stages requires further research.…”