Abstract
BackgroundPrevious studies have proved that peripheral nerve injury is involved in the pathogenesis of neuropathic pain (NP). The peripheral nerve injury primes spinal M1 microglia phenotype and produces pro-inflammatory cytokines, which are responsible for neurotoxic and neuronal hyper-excitable outcomes. Spinal peroxisome proliferator-activated receptor gamma (PPAR γ) has been shown to play an anti-inflammatory role in the development of NP. However, the role of PPAR γ in attenuating the pathological pathway of spinal microgliosis is still unknown.MethodsSprague-Dawley rats (male, aged 8–10 weeks) were randomly divided into three groups, i.e., a control group, a NP group, and a NP + lentivirus encoding PPAR γ (LV-PPAR γ) group. The sciatic chronic constriction injury (CCI) model was used to induce NP in rats. Pain behavior was assessed by monitoring the rat hind-paw withdrawal threshold to mechanical stimuli and withdrawal latency to radiant heat. The LV-PPAR γ was intrathecally infused 1 day before CCI. Western blot analysis and real-time qPCR were used to detect the microglia phenotypic molecules and CX3CR1 expression in the spinal cord. In vitro, BV-2 microglia cells were transfected with LV-PPAR γ and incubated with lipopolysaccharides (LPS), and the levels of M1 microglia phenotypic molecules and CX3CR1 in BV-2 microglia cells were assessed by western blot analysis, real-time qPCR, and enzyme-linked immunosorbent assay.ResultsPreoperative intrathecal infusion of LV-PPAR γ attenuated pain in rats 7 days post-CCI. The M1-microglia marker, CX3CR1, and pro-inflammatory signaling factors were increased in the spinal cord of CCI rats, while the preoperative intrathecal infusion of LV-PPAR γ attenuated these changes and increased the expression of IL-10. In vitro, the overexpression of PPAR γ in BV-2 cells reduced LPS-induced M1 microglia polarization and the levels of CX3CR1 and pro-inflammatory cytokines.ConclusionIntrathecal infusion of LV-PPAR γ exerts a protective effect on the development of NP induced by CCI in rats. The overexpression of PPAR γ may produce both analgesic and anti-inflammatory effects due to inhibition of the M1 phenotype and CX3CR1 signaling pathway in spinal microglia.
Highlights
Neuropathic pain (NP) following an injury to the nervous system is characterized by sustained allodynia and hyperalgesia
The reactive microglia participating in the neuroinflammation are classified into two main states of activation: the M1 phenotype characterized by secretion of pro-inflammatory factors, and the alternative anti-inflammatory M2 phenotype involved in the resolution of inflammation
The results showed that PPAR γ inhibited the activation of M1 microglia and CX3CR1, p38MAPK, and ERK signaling pathways in the spinal cord of constriction injury (CCI) rats
Summary
Neuropathic pain (NP) following an injury to the nervous system is characterized by sustained allodynia and hyperalgesia. Microglia respond to a peripheral nerve injury by producing inflammatory mediators, which lead to neuronal hyper-excitability and central sensitization (Gu et al, 2016; Donatien et al, 2018; Shen et al, 2020). It is clear that the M1 microglia phenotype and its cytokines, such as tumor necrosis factoralpha (TNF-α) and interleukin-1 beta (IL-1β), cause prolonged neuroinflammation and pain pathology in the central nervous system (CNS) (Xu et al, 2016; Lee et al, 2018). The peripheral nerve injury primes spinal M1 microglia phenotype and produces pro-inflammatory cytokines, which are responsible for neurotoxic and neuronal hyper-excitable outcomes. The role of PPAR γ in attenuating the pathological pathway of spinal microgliosis is still unknown
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