TNF and Pain: It is reported that pro-inflammatory cytokines led to hyperalgesia (Schiavuzzo et al., 2015); meanwhile, pro-inflammatory cytokines also induced depressive-like behaviors in animals (Norman et al., 2010); In human studies, pro-inflammatory cytokines such as TNF-α and IL-1β are increased in the cerebrospinal fluid and blood in patients with chronic neuropathic pain (Alexander et al., 2005), suggesting a critical role of M1-mediated neuroinflammation in this disorder.