Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure.

Wen Wen,Xiaoping Tong,Yanyan Yang,Jijian Zheng,Hoiyin Cheung,Meihua Cai,Xingrui Gong,Mazhong Zhang

doi:10.3389/fncel.2021.725267

Abstract

Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

Highlights

Neonates and preterm infants in neonatal intensive care units often undergo various invasive and painful procedures, such as intravenous cannulation, adhesive removal, fingerstick, and venous or arterial puncture (Chen et al, 2012)
Short-term pro-inflammatory cytokine production, and microglial activation in the spinal cord were observed in neonatal rats that underwent LPS injection
To test whether the reduction of inflammation cytokines is through the inhibition of M1 microglial polarization by DEX treatment, we found that, DEX pretreatment significantly reduced the Messenger RNA (mRNA) expressions of inducible NO synthase (iNOS) and CD86, which are reported as M1 microglial markers

Summary

Introduction

Neonates and preterm infants in neonatal intensive care units often undergo various invasive and painful procedures, such as intravenous cannulation, adhesive removal, fingerstick, and venous or arterial puncture (Chen et al, 2012). Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity occurrence later in life (Boisse et al, 2005; Hermann et al, 2006; Wang et al, 2011; Ranger et al, 2015; Nuseir et al, 2017). An infection can cause hyperalgesia (Ji et al, 2016), which makes neonates and infants more sensitive and respond more exaggeratedly to painful procedures. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections, such as systemic inflammatory responses and hyperalgesia (Wegner et al, 2014, 2015). LPS injection has been reported to evoke a persistent proinflammatory reactions in the brain, which may correlate with abnormal function in the central nervous system (CNS) (Gisslen et al, 2019)

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