2. Academic Validation
  3. Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

  • J Neuroinflammation. 2022 May 27;19(1):123. doi: 10.1186/s12974-022-02489-9.
Juan Li  # 1 2,  Yiyong Wei  # 1 3,  Junli Zhou  # 2,  Helin Zou 2,  Lulin Ma 1,  Chengxi Liu 3,  Zhi Xiao 3,  Xingfeng Liu 3,  Xinran Tan 1 2,  Tian Yu 3,  Song Cao 4 5 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Street, Zunyi, 563000, Guizhou, China.
  • 2 Department of Pain Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Street, Zunyi, 563000, Guizhou, China.
  • 3 Guizhou Key Lab of Anesthesia and Organ Protection, Zunyi Medical University, 6 West Xuefu Street, Zunyi, 563099, Guizhou, China.
  • 4 Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Street, Zunyi, 563000, Guizhou, China. [email protected].
  • 5 Department of Pain Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Street, Zunyi, 563000, Guizhou, China. [email protected].
  • 6 Guizhou Key Lab of Anesthesia and Organ Protection, Zunyi Medical University, 6 West Xuefu Street, Zunyi, 563099, Guizhou, China. [email protected].
  • # Contributed equally.
PMID: 35624514 DOI: 10.1186/s12974-022-02489-9
Abstract

Background: The noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury.

Methods: The Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro-adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated.

Results: Activation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice.

Conclusion: These findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Keywords

Astrocyte; Cytokine; Locus coeruleus; Microglia; Noradrenergic; Norepinephrine/noradrenaline; Pain; Spinal cord.

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