Hyperesthesia, i.e., increased sensitivity to somatosensory stimuli, frequently occurs after SCI. Many brain regions that participate in nociception, e.g., the thalamus and nucleus accumbens, undergo neuronal changes following SCI [
30]. For example, spinal cord contusion results in increased responsiveness of thalamic neurons to somatosensory stimuli [
31], and this effect is partially mediated by upregulation of sodium channel Nav1.3 [
32]. In addition, the inflammatory response plays an important role in chronic pain after SCI [
33]. Progressively activated microglia have been observed in the thalamus not only in the acute phase (several days after SCI) but also in the chronic phase (several weeks after SCI) [
34]. Chemokines CCL2 and CCL3, key players in neuropathic pain, were detected in the thalamus and hippocampus in the chronic phase after severe SCI [
35,
36]. Chemokine CCL21, induced in lumbar dorsal horn neurons after SCI, may mediate remote activation of cerebral microglia. Neutralization of CCL21 suppressed microglia activation and subsequent hyperexcitability of thalamic neurons [
37,
38]. Meanwhile, upregulation of proteins involved in the cell cycle (e.g., cyclin D1) has been associated with microglia activation, and thus, ablation of cell cycle signaling could significantly reduce neuroinflammation and ameliorate motor dysfunction and post-traumatic hyperesthesia [
34,
39]. Decreased expression of pro-inflammatory cytokines by progesterone, a neuroactive steroid, also alleviated chronic pain after SCI [
40].
Cognitive impairment is associated with extensive cerebral inflammation after SCI [
41]. Mice undergoing traumatic SCI exhibited impaired learning and memory associated with elevated neuroinflammation in the hippocampus and cortex, whereas interventions that attenuated inflammatory responses facilitated cognitive function recovery [
18,
42,
43]. Nonetheless, a better understanding of the methods and consequences of efficient inhibition of inflammation is necessary to yield significant improvements in human cognitive function following SCI.
Depression is another common complication in SCI patients, especially those with an early onset [
44,
45]. To date, the relationship between depression and neuroinflammation after SCI remains elusive. It has been noted that the serum concentration of corticosterone, an inducer of depressive-like phenotypes in animal models, was elevated shortly after SCI and remained so for at least 1 month after experimental SCI in rats [
11]. Wu et al. also reported depressive-like behaviors in mice with spinal cord contusion [
18]. In a rat model of SCI, high levels of pro-inflammatory cytokines were associated with comorbidity of depression and anxiety, and there was no correlation between these comorbidities and trauma severity [
46]. These results help to explain how activation of microglia and astrocytes may contribute to psychiatric complications; furthermore, they underscore the therapeutic potential of targeting these cells. Recently, a randomized clinical trial revealed the effectiveness of targeting inflammation to improve mood in SCI patients by reducing IL-1β and increasing the levels of a neuroactive compound involved in the kynurenine pathway [
47]. Taken together, brain dysfunction and neurodegeneration, common complications of SCI, may be closely related to cerebral inflammation, characterized by elevated pro-inflammatory cytokines and activation of microglia and astrocytes. Although a better understanding of this relationship is needed, targeting inflammation in the brain may serve as an important therapeutic approach to improve the overall quality of life for SCI patients.