Hippocampal activation of microglia may underlie the shared neurobiology of comorbid posttraumatic stress disorder and chronic pain

Abstract

The high comorbidity rates of posttraumatic stress disorder and chronic pain have been widely reported, but the underlying mechanisms remain unclear. Emerging evidence suggested that an excess of inflammatory immune activities in the hippocampus involved in the progression of both posttraumatic stress disorder and chronic pain. Considering that microglia are substrates underlying the initiation and propagation of the neuroimmune response, we hypothesized that stress-induced activation of hippocampal microglia may contribute to the pathogenesis of posttraumatic stress disorder-pain comorbidity. We showed that rats exposed to single prolonged stress, an established posttraumatic stress disorder model, exhibited persistent mechanical allodynia and anxiety-like behavior, which were accompanied by increased activation of microglia and secretion of pro-inflammatory cytokines in the hippocampus. Correlation analyses showed that hippocampal activation of microglia was significantly correlated with mechanical allodynia and anxiety-like behavior. Our data also showed that both intraperitoneal and intra-hippocampal injection of minocycline suppressed single prolonged stress-induced microglia activation and inflammatory cytokines accumulation in the hippocampus, and attenuated both single prolonged stress-induced mechanical allodynia and anxiety-like behavior. Taken together, the present study suggests that stress-induced microglia activation in the hippocampus may serve as a critical mechanistic link in the comorbid relationship between posttraumatic stress disorder and chronic pain. The novel concept introduces the possibility of cotreating chronic pain and posttraumatic stress disorder.

Minocycline Attenuates Stress-Induced Behavioral Changes via Its Anti-inflammatory Effects in an Animal Model of Post-traumatic Stress Disorder

“…The qPCR and IHC results indicated that IFS increased the level of mRNA of iba-1, the number of Iba-1-positive cells and changed the morphology of the microglia from hyper-ramified to amoeboid shape in the PFC and hippocampus. Consistent with our results, Sun et al also found up-regulation of Iba-1 in the CA1 and CA3 regions of the hippocampus in the animal model of PTSD induced by single prolonged stress ( 36 ). Similarly, other studies also reported that various stressors could induce microglial activation in different animal models ( 39 – 42 ).…”

“…Previous studies have reported that a single dose of minocycline had a potential effect of preventing the deterioration of behavior and exaggeration of neuroinflammation ( 14 ). Similarly, a longer injection of minocycline also attenuated single prolonged stress-induced anxiety-like behavior ( 36 ). In addition, minocycline was able to improve cognitive deficits in a cerebral microvascular amyloid model ( 47 ).…”

“…Previous studies have found that pro-inflammatory cytokines were increased in rodent models of PTSD and patients suffering from PTSD. For example, studies on rodent models of PTSD indicated higher levels of the pro-inflammatory cytokines in the hippocampus and PFC ( 14 , 36 , 37 ). A meta-analysis reported that the levels of IL-6, IL-1β, TNF-α and interferon-γ were up-regulated in patients with PTSD compared with controls ( 38 ).…”

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

“…There is also evidence that glial processes may contribute to post-SPS dysfunction and poor behavioral recovery. For example, microglial activation caused by glucocorticoid signaling in the spinal cord ( 288 , 347 ) and HC ( 348 ) appears to contribute to post-SPS hyperalgesia. Immunohistochemical data indicate that glial cell number is decreased in the HC in a time-dependent manner following SPS, and magnetic resonance spectroscopy findings of decreased choline in the HC ( 312 ) and creatine in the HC ( 312 ) and mPFC ( 154 ) are consistent with a glial-related mechanism ( 312 ).…”

Microglia at center stage: a comprehensive review about the versatile and unique residential macrophages of the central nervous system

“…Interestingly, minor recurrent trauma like concussion during sport (boxing, soccer, etc. ), or injury in a distal CNS region, may also activate microglia in otherwise healthy tissue and result on a longer term in substantial mental disease or chronic pain [ 246 , 247 ]. One has also to consider that injury breaks down the BBB and allows immigration of blood derived immune cells, including macrophages and lymphocytes that contribute to the acute inflammatory reaction and subsequent tissue repair [ 16 , 248 ].…”