Spared Nerve Injury Increases the Expression of Microglia M1 Markers in the Prefrontal Cortex of Rats and Provokes Depression-Like Behaviors

Abstract

Pain and depression are frequently co-existent in clinical practice, yet the underlying mechanisms remain largely to be determined. Microglia activation and subsequent pro-inflammatory responses play a crucial role in the development of neuropathic pain and depression. The process of microglia polarization to the pro-inflammatory M1 or anti-inflammatory M2 phenotypes often occurs during neuroinflammation. However, it remains unclear whether M1/M2 microglia polarization is involved in the neuropathic pain induced by spared nerve injury (SNI). In the present study, the mechanical withdrawal threshold, forced swim test, sucrose preference test, and open field test were performed. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), M1 markers including CD68, inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-a (TNF-α), 8-hydroxy-2-deoxyguanosine (8-OH-dG), and M2 markers including CD206, arginase 1 (Arg1), IL-4 in the prefrontal cortex were determined on day 14 after SNI. The results showed that SNI produced mechanical allodynia and depressive-like behaviors, and also increased the expressions of microglia markers (Iba1, CD11b) and M1 markers (CD68, iNOS, IL-1β, TNF-α, and 8-OH-dG) in the prefrontal cortex. Notably, minocycline administration reversed these abnormalities. In addition, minocycline also promoted M2 microglia polarization as evidenced by up-regulation of CD206 and Arg1. In conclusion, data from our study suggest that SNI can lead to depression-like behaviors, while M1 polarization and consequent overproduction of pro-inflammatory cytokines plays a key role in the pathogenesis of neuropathic pain. The data furthermore indicate that modulation of inflammation by inhibition of M1 polarization could be a strategy for treatment of neuropathic pain, and might prevent the induction of neuropathic pain-induced depression symptoms.

Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state

“… 24 , 25 In the present study, SNI-induced mechanical allodynia and depressive-like behaviors were confirmed by increased withdrawal threshold and immobility time as well as reduced sucrose preference, which suggested that SNI induced the comorbidity of chronic pain and depression. 15 , 16 Previous studies indicate that SNI surgery induced depression-like behaviors in the early days (7 day 16 or 14 days 15 , 26 after surgery). However, the present study found that depression-like behaviors, such as walking distances in OFT, immobility time in FST, and sucrose preference in SPT, began to decrease on day 28 after surgery, but no statistical difference was found.…”

Heme oxygenase-1 inducer and carbon monoxide–releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice

“… 15 Spared nerve injury has been shown to increase M1 microglia in the central nervous system. 41 The fact that inhibition of microglial activity by minocycline reversed SNI-induced mechanical allodynia further supports the hypothesis that CoPP or CORM-2 treatment exerts antiallodynic effects through reductions in M1 microglia.…”

Botulinum toxin type A promotes microglial M2 polarization and suppresses chronic constriction injury-induced neuropathic pain through the P2X7 receptor

“…Piotrowska et al [11] reported that chronic intrathecal administration of maraviroc diminished NP symptoms and nociceptive threshold as well as decreased levels of pro-inflammatory cytokines in Wistar rats post-CCI. Convincing researches have indicated that switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for NP [10][11][12][13]. For example, Willemen et al [13] proposed that persistent hyperalgesia in GRK2 (G protein-coupled receptor kinase)-deficient mice was associated with an increased ratio of M1/M2 type markers in spinal cord microglia/macrophages.…”

“…The microglial polarization toward the pro-inflammatory M1 phenotype often occurs during NP. Convincing evidence has indicated that modulation of inflammation by inhibition of M1 polarization can be a strategy for treatment of NP [10][11][12][13].…”