PPAR γ Prevents Neuropathic Pain by Down-Regulating CX3CR1 and Attenuating M1 Activation of Microglia in the Spinal Cord of Rats Using a Sciatic Chronic Constriction Injury Model

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.

NAAA-regulated lipid signaling governs the transition from acute to chronic pain

“…Given the paucity of information regarding NAAA’s transcriptional control ( 10 ), a variety of scenarios appear equally plausible. One intriguing possibility is that release of colony stimulating factor 1 ( 78 ) or other cytokines (e.g., CXCL1) ( 79 ) in the dorsal horn might directly or indirectly stimulate NAAA transcription. In this regard, it is important to point out that NAAA may also be activated through a posttranslational mechanism involving the autocatalyzed cleavage of its inactive precursor ( 10 ).…”

Nuclear PPAR-γ Activation Modulates Inflammation and Oxidative Stress in Attenuating Chemotherapy-Induced Neuropathic Pain in Vivo

“…In the present study, pioglitazone administration reduced elevated level of TNF-α in DRGs and spinal cord that was parallel with the alleviation of established allodynia and hyperalgesia. The centrally mediated effects of PPAR- activation have also been reported wherein several PPAR- agonists suppressed microglia and astrocytes activation, reduced the development of spinal neuroinflammation, and showed antinociceptive and neuroprotective effects [14,15,34,35]. A recent study showed decreased transcription factor in parallel with reduced expression of PPAR-γ in spinal cords after paclitaxel administration.…”

Key Role of Post-emptive PPAR-γ Activation in Extenuating Pain Hypersensitivity in Mononeuropathic Rats

“…26,27 Recently, Li et al demonstrated that intrathecal infusion of lentivirus encoding PPAR-γ attenuated neuropathic pain. 28 Adding to this, pioglitazone readily cross blood-brain barrier and showed neuroprotection in the CNS. 14,29 Further, in order to elucidate receptor dependent effects of pioglitazone, BADGE, a PPAR-γ antagonist was employed.…”